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Artificial intelligence poised to change paradigm of CV risk prevention
Causal-based algorithm personalizes strategies
Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.
“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).
In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
Causal AI can predict treatment effect
The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.
“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.
As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.
In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.
“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.
Deep-learning AI evaluated more than 300 gene variants
The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.
In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.
It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.
However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
Embedded causal effects precisely predicts outcomes
Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.
“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.
In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.
“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.
In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.
The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.
“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.
By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
Routine application awaits further steps
Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.
However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.
“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.
“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.
Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.
Causal-based algorithm personalizes strategies
Causal-based algorithm personalizes strategies
Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.
“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).
In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
Causal AI can predict treatment effect
The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.
“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.
As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.
In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.
“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.
Deep-learning AI evaluated more than 300 gene variants
The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.
In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.
It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.
However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
Embedded causal effects precisely predicts outcomes
Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.
“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.
In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.
“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.
In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.
The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.
“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.
By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
Routine application awaits further steps
Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.
However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.
“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.
“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.
Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.
Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.
“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).
In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
Causal AI can predict treatment effect
The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.
“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.
As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.
In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.
“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.
Deep-learning AI evaluated more than 300 gene variants
The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.
In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.
It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.
However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
Embedded causal effects precisely predicts outcomes
Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.
“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.
In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.
“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.
In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.
The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.
“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.
By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
Routine application awaits further steps
Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.
However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.
“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.
“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.
Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.
FROM ESC CONGRESS 2022
Albuminuria linked to higher CVD risk in diabetes
BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.
Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.
This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.
The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.
The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
A lower threshold for albuminuria?
“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.
Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.
The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.
The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.
Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.
More albuminuria measurement needed in primary care
“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.
Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.
During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.
The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.
The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.
BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.
Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.
This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.
The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.
The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
A lower threshold for albuminuria?
“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.
Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.
The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.
The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.
Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.
More albuminuria measurement needed in primary care
“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.
Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.
During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.
The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.
The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.
BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.
Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.
This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.
The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.
The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
A lower threshold for albuminuria?
“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.
Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.
The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.
The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.
Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.
More albuminuria measurement needed in primary care
“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.
Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.
During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.
The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.
The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.
AT ESC CONGRESS 2022
DANCAVAS misses primary endpoint but hints at benefit from comprehensive CV screening
Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.
The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.
“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.
“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”
He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”
Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.
Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”
The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.
Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.
In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).
The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).
The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).
There were no significant between-group differences in safety outcomes.
Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.
Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.
In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.
The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.
Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.
“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”
He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
Increased medical therapy
Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”
“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.
Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.
“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.
Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.
Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74.
Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.
Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.
“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.
“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”
Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”
Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.
The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.
A version of this article first appeared on Medscape.com.
Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.
The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.
“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.
“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”
He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”
Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.
Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”
The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.
Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.
In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).
The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).
The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).
There were no significant between-group differences in safety outcomes.
Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.
Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.
In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.
The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.
Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.
“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”
He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
Increased medical therapy
Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”
“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.
Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.
“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.
Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.
Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74.
Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.
Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.
“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.
“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”
Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”
Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.
The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.
A version of this article first appeared on Medscape.com.
Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.
The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.
“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.
“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”
He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”
Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.
Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”
The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.
Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.
In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).
The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).
The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).
There were no significant between-group differences in safety outcomes.
Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.
Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.
In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.
The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.
Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.
“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”
He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
Increased medical therapy
Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”
“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.
Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.
“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.
Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.
Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74.
Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.
Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.
“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.
“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”
Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”
Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.
The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.
A version of this article first appeared on Medscape.com.
AT ESC CONGRESS 2022
Dapagliflozin’s HFpEF benefit recasts heart failure treatment: DELIVER
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.
These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).
The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.
The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.
A key finding of DELIVER, confirmed in several combined analyses also reported at the congress, was that the benefit of dapagliflozin treatment extended to patients with HFpEF in the highest ranges of ejection fraction, stressed Dr. Solomon, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Combined analyses document consistency
Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.
The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.
A second, prespecified combined analysis coupled the DELIVER findings with the results of a prior large trial that assessed empagliflozin in patients with HFpEF, EMPEROR-Preserved, which had shown similar findings but with an apparent diminishment of activity in patients at the highest range of preserved left ventricular function, with ejection fractions in excess of about 65%, a tail-off of effect not seen in DELIVER.
In EMPEROR-Preserved alone, patients with ejection fractions of 60% or greater did not show a significant benefit from empagliflozin treatment, although the data showed a numerical trend toward fewer adverse outcome events. When combined with the DELIVER data in a total of 12,251 patients, the subgroup of more than 3,800 patients with an ejection fraction of at least 60% showed a significant 19% relative reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, reported Muthiah Vaduganathan, MD, in a separate talk at the congress, a finding that confirms the efficacy of SGLT2 inhibitors in this subgroup of patients.
A third combined analysis, also presented by Dr. Vaduganathan, added to these 12,000 patients’ data from DAPA-HF, the empagliflozin trial in patients with HFrEF called EMPEROR-Reduced, and a study of a third SGLT2 inhibitor, sotagliflozin, SOLOIST-WHF, an amalgam of more than 21,000 patients. Again, the results showed cross-trial consistency, and a significant, overall 23% reduction, compared with placebo in the rate of cardiovascular death or hospitalization for heart failure, with a number-needed-to-treat of 25 to prevent one of these events during an average follow-up of 23 months.
“The totality of evidence supports prioritizing the use of SGLT2 inhibitors in all patients with heart failure irrespective of phenotype or care setting,” concluded Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital, Boston. Simultaneous with his talk the details of the two combined analyses he presented appeared in The Lancet.
A ‘swan song’ for ejection fraction
“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.
“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.
DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.
AT ESC CONGRESS 2022
TIME: CV events similar with evening or morning dose of BP meds
BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.
The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology.
“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).
The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.
Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.
“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.
The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.
“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said.
Non-dippers
Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.
“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”
The study did find some differences in the blood pressure profile between the two dosing schedules.
“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said.
“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.
The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.
TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.
The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.
The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).
What to recommend in clinical practice?
Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.
Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”
She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.
“The finding of no difference in event rate in the TIME study is therefore very intriguing.”
She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.
“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.
Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”
The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions.
And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”
The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.
“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.
On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”
Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”
One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.
“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.
Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.
“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.
Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”
The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.
“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.
“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”
Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.
“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”
She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”
The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.
A version of this article first appeared on Medscape.com.
BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.
The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology.
“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).
The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.
Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.
“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.
The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.
“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said.
Non-dippers
Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.
“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”
The study did find some differences in the blood pressure profile between the two dosing schedules.
“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said.
“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.
The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.
TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.
The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.
The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).
What to recommend in clinical practice?
Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.
Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”
She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.
“The finding of no difference in event rate in the TIME study is therefore very intriguing.”
She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.
“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.
Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”
The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions.
And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”
The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.
“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.
On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”
Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”
One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.
“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.
Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.
“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.
Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”
The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.
“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.
“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”
Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.
“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”
She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”
The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.
A version of this article first appeared on Medscape.com.
BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.
The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology.
“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).
The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.
Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.
“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.
The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.
“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said.
Non-dippers
Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.
“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”
The study did find some differences in the blood pressure profile between the two dosing schedules.
“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said.
“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.
The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.
TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.
The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.
The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).
What to recommend in clinical practice?
Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.
Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”
She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.
“The finding of no difference in event rate in the TIME study is therefore very intriguing.”
She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.
“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.
Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”
The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions.
And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”
The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.
“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.
On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”
Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”
One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.
“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.
Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.
“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.
Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”
The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.
“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.
“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”
Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.
“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”
She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”
The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.
A version of this article first appeared on Medscape.com.
AT ESC CONGRESS 2022
Sacubitril/valsartan shows cognitive safety in heart failure: PERSPECTIVE
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
AT ESC CONGRESS 2022
State of the science in PCOS: Emerging neuroendocrine involvement driving research
Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.
Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”
One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.
Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.
Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.
“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
The hypothalamic-pituitary-gonadal axis
In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.
“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.
The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.
But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.
But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
Remaining chicken-and-egg questions
A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.
It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”
Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.
“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.
Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.
Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.
Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.
These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
Recent and upcoming changes in treatment
Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.
In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.
“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.
Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.
“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”
Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.
And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.
Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.
“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”
This story was updated on Sept. 6, 2022.
Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.
Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”
One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.
Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.
Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.
“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
The hypothalamic-pituitary-gonadal axis
In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.
“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.
The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.
But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.
But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
Remaining chicken-and-egg questions
A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.
It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”
Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.
“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.
Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.
Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.
Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.
These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
Recent and upcoming changes in treatment
Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.
In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.
“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.
Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.
“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”
Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.
And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.
Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.
“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”
This story was updated on Sept. 6, 2022.
Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.
Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”
One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.
Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.
Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.
“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
The hypothalamic-pituitary-gonadal axis
In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.
“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.
The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.
But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.
But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
Remaining chicken-and-egg questions
A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.
It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”
Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.
“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.
Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.
Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.
Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.
These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
Recent and upcoming changes in treatment
Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.
In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.
“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.
Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.
“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”
Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.
And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.
Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.
“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”
This story was updated on Sept. 6, 2022.
Secondary CV prevention benefit from polypill promises global health benefit
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
FROM ESC CONGRESS 2022
Congressman’s wife died after taking herbal remedy marketed for diabetes and weight loss
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.
Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.
The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”
Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.
It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.
Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.
“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.
Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.
“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”
Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.
Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.
The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”
Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.
Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.
At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”
“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”
According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”
Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.
If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.
“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.
The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.
Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.
Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.
While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.
White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.
White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.
Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.
Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.
The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.
Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.
But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.
Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.
“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”
The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.
Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.
Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.
But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.
“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”
It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.
“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Long COVID mimics other postviral conditions
When Jaime Seltzer first heard about a new virus that was spreading globally early in 2020, she was on full alert. As an advocate for the post-viral condition known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), she worried about a new wave of people having long-term disabilities.
“The hair on my arms stood on end,” said Ms. Seltzer, director of scientific and medical outreach at the advocacy group MEAction and a consultant researcher at Stanford University.
Ms. Seltzer, who has had ME/CFS herself, said she wondered.
Sure enough, later in 2020, reports began emerging about people with extreme fatigue, postexertion crashes, brain fog, unrefreshing sleep, and dizziness when standing up months after a bout with the then-new viral illness. Those same symptoms had been designated as “core criteria” of ME/CFS by the National Academy of Medicine in a 2015 report.
Now, advocates like Ms. Seltzer are hoping the research and medical communities will give ME/CFS and other postviral illnesses the same attention they have increasingly focused on long COVID.
The emergence of long COVID was no surprise to researchers who study ME/CFS, because the same set of symptoms has arisen after many other viruses.
“This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” said David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital in Boston, who studies people with both diagnoses.
The actual numbers are hard to determine, since many people who meet ME/CFS criteria aren’t formally diagnosed. But a combined analysis of data from several studies published in March found that about one in three people had fatigue and about one in five reported having a hard time with thinking and memory 12 or more weeks after they had COVID-19.
According to some estimates, about half of people with long COVID will meet the criteria for ME/CFS, whether they’re given that specific diagnosis or not.
Other conditions that often exist with ME/CFS are also being seen in people with long COVID, including postural orthostatic tachycardia syndrome, which causes people to feel dizzy when they stand, along with other symptoms; other problems with the autonomic nervous system, which controls body systems such as heart rate, blood pressure, and digestion, known together as dysautonomia; and a condition related to allergies called mast cell activation disorder.
Post–acute infection syndromes have been linked to a long list of viruses, including Ebola, the 2003-2004 SARS virus, and Epstein-Barr – the virus most commonly associated with ME/CFS.
The problem in clinical medicine is that once an infection has cleared, the teaching has been that the person should no longer feel sick, said Nancy G. Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University in Miami. “I was taught that there has to be an antigen [such as a viral protein] in the system to drive the immune system to make it create sickness, and the immune system should shut off when it’s done,” she said.
Thus, if virus is gone and other routine lab tests come up negative, doctors often deem the person’s reported symptoms to be psychological, which can upset patients, Anthony Komaroff, MD, of Brigham and Women’s Hospital in Boston, wrote in July 2021.
Only recently have doctors started to appreciate the idea that the immune system may be overreacting long term, Dr. Klimas said.
Now, long COVID appears to be speeding up that recognition. Dr. Systrom said he has “absolutely” seen a change in attitude among fellow doctors who had been skeptical of ME/CFS as a “real” illness because there’s no test for it.
“I’m very keenly aware of a large group of health care professionals who really had not bought into the concept of ME/CFS as a real disease who have had an epiphany of sorts with long COVID and now, in a backwards way, have applied that same thinking to their very same patients with ME/CFS,” he said.
Science showing ‘frighteningly similar’ symptoms
Dr. Systrom has spent several years researching how ME/CFS patients cannot tolerate exercise and now is doing similar studies in people with long COVID. “Several months into the pandemic, we began receiving reports of patients who had survived COVID and maybe even had a relatively mild disease ... and as the summer of 2020 moved into the fall, it became apparent that there was a subset of patients who for all the world appeared to meet ME/CFS clinical criteria,” he said.
Using bicycle exercise tests on long COVID patients with catheters placed in their veins, Dr. Systrom and associates have shown a lack of exercise capacity that isn’t caused by heart or lung disease but instead is related to abnormal nerves and blood vessels, just as they’d shown previously in ME/CFS patient.
Avindra Nath, MD, senior investigator and clinical director of intramural research at the National Institute of Neurological Disorders and Stroke, Bethesda, Md., was doing a deep-dive scientific study on ME/CFS when the COVID-19 pandemic hit. Since then, he›s begun another study using the same protocol and sophisticated laboratory measurement to evaluate people with long COVID.
“As terrible as [long COVID] is, it’s kind of a blessing in disguise for ME/CFS because there’s just so much overlap between the two and they could very well be in many ways one in the same thing. The problem with studying ME/CFS is oftentimes you didn’t know what the trigger was. You see patients many years later, then try to backtrack and find out what happened,” said Dr. Nath, a neuroimmunologist.
With long COVID, on the other hand, “we know when they got infected and when their symptoms actually started, so it becomes much more uniform. ... It gives us an opportunity to maybe solve certain things in a much more well-defined population and try to find answers.”
Advocacy groups want to see more.
In February 2021, Solve M.E. launched the Long COVID Alliance, made up of several organizations, companies, and people with a goal to influence policy and speed up research into a range of postviral illnesses.
Solve M.E. has also pushed for inclusion of language regarding ME/CFS and related conditions into congressional bills addressing long COVID, including those that call for funding of research and clinical care.
“On the political front, we’ve really capitalized on a moment in time in which we have the spotlight,” said Emily Taylor, vice president of advocacy and engagement for Solve M.E.
“One of the hardest parts about ME/CFS is how to show that it’s real when it’s invisible. Most people agree that COVID is real and therefore if somebody gets ME/CFS after COVID, it’s real,” she said.
The advocacy groups are now pushing for non-COVID postinfection illnesses to be included in efforts aimed at helping people with long COVID, with mixed results. For example, the RECOVER Initiative, established in February 2021 with $1.5 billion in funding from Congress to the National Institutes of Health, is specifically for studying long COVID and does not fund research into other postinfection illnesses, although representatives from the ME/CFS community are advisers.
Language addressing ME/CFS and other postinfectious chronic illnesses has been included in several long COVID bills now pending in Congress, including the Care for Long COVID Act in the Senate and its companion COVID-19 Long Haulers Act in the House. “Our goal is to push for passage of a long COVID bill by the end of the year,” Ms. Taylor said.
A version of this article first appeared on WebMD.com.
When Jaime Seltzer first heard about a new virus that was spreading globally early in 2020, she was on full alert. As an advocate for the post-viral condition known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), she worried about a new wave of people having long-term disabilities.
“The hair on my arms stood on end,” said Ms. Seltzer, director of scientific and medical outreach at the advocacy group MEAction and a consultant researcher at Stanford University.
Ms. Seltzer, who has had ME/CFS herself, said she wondered.
Sure enough, later in 2020, reports began emerging about people with extreme fatigue, postexertion crashes, brain fog, unrefreshing sleep, and dizziness when standing up months after a bout with the then-new viral illness. Those same symptoms had been designated as “core criteria” of ME/CFS by the National Academy of Medicine in a 2015 report.
Now, advocates like Ms. Seltzer are hoping the research and medical communities will give ME/CFS and other postviral illnesses the same attention they have increasingly focused on long COVID.
The emergence of long COVID was no surprise to researchers who study ME/CFS, because the same set of symptoms has arisen after many other viruses.
“This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” said David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital in Boston, who studies people with both diagnoses.
The actual numbers are hard to determine, since many people who meet ME/CFS criteria aren’t formally diagnosed. But a combined analysis of data from several studies published in March found that about one in three people had fatigue and about one in five reported having a hard time with thinking and memory 12 or more weeks after they had COVID-19.
According to some estimates, about half of people with long COVID will meet the criteria for ME/CFS, whether they’re given that specific diagnosis or not.
Other conditions that often exist with ME/CFS are also being seen in people with long COVID, including postural orthostatic tachycardia syndrome, which causes people to feel dizzy when they stand, along with other symptoms; other problems with the autonomic nervous system, which controls body systems such as heart rate, blood pressure, and digestion, known together as dysautonomia; and a condition related to allergies called mast cell activation disorder.
Post–acute infection syndromes have been linked to a long list of viruses, including Ebola, the 2003-2004 SARS virus, and Epstein-Barr – the virus most commonly associated with ME/CFS.
The problem in clinical medicine is that once an infection has cleared, the teaching has been that the person should no longer feel sick, said Nancy G. Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University in Miami. “I was taught that there has to be an antigen [such as a viral protein] in the system to drive the immune system to make it create sickness, and the immune system should shut off when it’s done,” she said.
Thus, if virus is gone and other routine lab tests come up negative, doctors often deem the person’s reported symptoms to be psychological, which can upset patients, Anthony Komaroff, MD, of Brigham and Women’s Hospital in Boston, wrote in July 2021.
Only recently have doctors started to appreciate the idea that the immune system may be overreacting long term, Dr. Klimas said.
Now, long COVID appears to be speeding up that recognition. Dr. Systrom said he has “absolutely” seen a change in attitude among fellow doctors who had been skeptical of ME/CFS as a “real” illness because there’s no test for it.
“I’m very keenly aware of a large group of health care professionals who really had not bought into the concept of ME/CFS as a real disease who have had an epiphany of sorts with long COVID and now, in a backwards way, have applied that same thinking to their very same patients with ME/CFS,” he said.
Science showing ‘frighteningly similar’ symptoms
Dr. Systrom has spent several years researching how ME/CFS patients cannot tolerate exercise and now is doing similar studies in people with long COVID. “Several months into the pandemic, we began receiving reports of patients who had survived COVID and maybe even had a relatively mild disease ... and as the summer of 2020 moved into the fall, it became apparent that there was a subset of patients who for all the world appeared to meet ME/CFS clinical criteria,” he said.
Using bicycle exercise tests on long COVID patients with catheters placed in their veins, Dr. Systrom and associates have shown a lack of exercise capacity that isn’t caused by heart or lung disease but instead is related to abnormal nerves and blood vessels, just as they’d shown previously in ME/CFS patient.
Avindra Nath, MD, senior investigator and clinical director of intramural research at the National Institute of Neurological Disorders and Stroke, Bethesda, Md., was doing a deep-dive scientific study on ME/CFS when the COVID-19 pandemic hit. Since then, he›s begun another study using the same protocol and sophisticated laboratory measurement to evaluate people with long COVID.
“As terrible as [long COVID] is, it’s kind of a blessing in disguise for ME/CFS because there’s just so much overlap between the two and they could very well be in many ways one in the same thing. The problem with studying ME/CFS is oftentimes you didn’t know what the trigger was. You see patients many years later, then try to backtrack and find out what happened,” said Dr. Nath, a neuroimmunologist.
With long COVID, on the other hand, “we know when they got infected and when their symptoms actually started, so it becomes much more uniform. ... It gives us an opportunity to maybe solve certain things in a much more well-defined population and try to find answers.”
Advocacy groups want to see more.
In February 2021, Solve M.E. launched the Long COVID Alliance, made up of several organizations, companies, and people with a goal to influence policy and speed up research into a range of postviral illnesses.
Solve M.E. has also pushed for inclusion of language regarding ME/CFS and related conditions into congressional bills addressing long COVID, including those that call for funding of research and clinical care.
“On the political front, we’ve really capitalized on a moment in time in which we have the spotlight,” said Emily Taylor, vice president of advocacy and engagement for Solve M.E.
“One of the hardest parts about ME/CFS is how to show that it’s real when it’s invisible. Most people agree that COVID is real and therefore if somebody gets ME/CFS after COVID, it’s real,” she said.
The advocacy groups are now pushing for non-COVID postinfection illnesses to be included in efforts aimed at helping people with long COVID, with mixed results. For example, the RECOVER Initiative, established in February 2021 with $1.5 billion in funding from Congress to the National Institutes of Health, is specifically for studying long COVID and does not fund research into other postinfection illnesses, although representatives from the ME/CFS community are advisers.
Language addressing ME/CFS and other postinfectious chronic illnesses has been included in several long COVID bills now pending in Congress, including the Care for Long COVID Act in the Senate and its companion COVID-19 Long Haulers Act in the House. “Our goal is to push for passage of a long COVID bill by the end of the year,” Ms. Taylor said.
A version of this article first appeared on WebMD.com.
When Jaime Seltzer first heard about a new virus that was spreading globally early in 2020, she was on full alert. As an advocate for the post-viral condition known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), she worried about a new wave of people having long-term disabilities.
“The hair on my arms stood on end,” said Ms. Seltzer, director of scientific and medical outreach at the advocacy group MEAction and a consultant researcher at Stanford University.
Ms. Seltzer, who has had ME/CFS herself, said she wondered.
Sure enough, later in 2020, reports began emerging about people with extreme fatigue, postexertion crashes, brain fog, unrefreshing sleep, and dizziness when standing up months after a bout with the then-new viral illness. Those same symptoms had been designated as “core criteria” of ME/CFS by the National Academy of Medicine in a 2015 report.
Now, advocates like Ms. Seltzer are hoping the research and medical communities will give ME/CFS and other postviral illnesses the same attention they have increasingly focused on long COVID.
The emergence of long COVID was no surprise to researchers who study ME/CFS, because the same set of symptoms has arisen after many other viruses.
“This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” said David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital in Boston, who studies people with both diagnoses.
The actual numbers are hard to determine, since many people who meet ME/CFS criteria aren’t formally diagnosed. But a combined analysis of data from several studies published in March found that about one in three people had fatigue and about one in five reported having a hard time with thinking and memory 12 or more weeks after they had COVID-19.
According to some estimates, about half of people with long COVID will meet the criteria for ME/CFS, whether they’re given that specific diagnosis or not.
Other conditions that often exist with ME/CFS are also being seen in people with long COVID, including postural orthostatic tachycardia syndrome, which causes people to feel dizzy when they stand, along with other symptoms; other problems with the autonomic nervous system, which controls body systems such as heart rate, blood pressure, and digestion, known together as dysautonomia; and a condition related to allergies called mast cell activation disorder.
Post–acute infection syndromes have been linked to a long list of viruses, including Ebola, the 2003-2004 SARS virus, and Epstein-Barr – the virus most commonly associated with ME/CFS.
The problem in clinical medicine is that once an infection has cleared, the teaching has been that the person should no longer feel sick, said Nancy G. Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University in Miami. “I was taught that there has to be an antigen [such as a viral protein] in the system to drive the immune system to make it create sickness, and the immune system should shut off when it’s done,” she said.
Thus, if virus is gone and other routine lab tests come up negative, doctors often deem the person’s reported symptoms to be psychological, which can upset patients, Anthony Komaroff, MD, of Brigham and Women’s Hospital in Boston, wrote in July 2021.
Only recently have doctors started to appreciate the idea that the immune system may be overreacting long term, Dr. Klimas said.
Now, long COVID appears to be speeding up that recognition. Dr. Systrom said he has “absolutely” seen a change in attitude among fellow doctors who had been skeptical of ME/CFS as a “real” illness because there’s no test for it.
“I’m very keenly aware of a large group of health care professionals who really had not bought into the concept of ME/CFS as a real disease who have had an epiphany of sorts with long COVID and now, in a backwards way, have applied that same thinking to their very same patients with ME/CFS,” he said.
Science showing ‘frighteningly similar’ symptoms
Dr. Systrom has spent several years researching how ME/CFS patients cannot tolerate exercise and now is doing similar studies in people with long COVID. “Several months into the pandemic, we began receiving reports of patients who had survived COVID and maybe even had a relatively mild disease ... and as the summer of 2020 moved into the fall, it became apparent that there was a subset of patients who for all the world appeared to meet ME/CFS clinical criteria,” he said.
Using bicycle exercise tests on long COVID patients with catheters placed in their veins, Dr. Systrom and associates have shown a lack of exercise capacity that isn’t caused by heart or lung disease but instead is related to abnormal nerves and blood vessels, just as they’d shown previously in ME/CFS patient.
Avindra Nath, MD, senior investigator and clinical director of intramural research at the National Institute of Neurological Disorders and Stroke, Bethesda, Md., was doing a deep-dive scientific study on ME/CFS when the COVID-19 pandemic hit. Since then, he›s begun another study using the same protocol and sophisticated laboratory measurement to evaluate people with long COVID.
“As terrible as [long COVID] is, it’s kind of a blessing in disguise for ME/CFS because there’s just so much overlap between the two and they could very well be in many ways one in the same thing. The problem with studying ME/CFS is oftentimes you didn’t know what the trigger was. You see patients many years later, then try to backtrack and find out what happened,” said Dr. Nath, a neuroimmunologist.
With long COVID, on the other hand, “we know when they got infected and when their symptoms actually started, so it becomes much more uniform. ... It gives us an opportunity to maybe solve certain things in a much more well-defined population and try to find answers.”
Advocacy groups want to see more.
In February 2021, Solve M.E. launched the Long COVID Alliance, made up of several organizations, companies, and people with a goal to influence policy and speed up research into a range of postviral illnesses.
Solve M.E. has also pushed for inclusion of language regarding ME/CFS and related conditions into congressional bills addressing long COVID, including those that call for funding of research and clinical care.
“On the political front, we’ve really capitalized on a moment in time in which we have the spotlight,” said Emily Taylor, vice president of advocacy and engagement for Solve M.E.
“One of the hardest parts about ME/CFS is how to show that it’s real when it’s invisible. Most people agree that COVID is real and therefore if somebody gets ME/CFS after COVID, it’s real,” she said.
The advocacy groups are now pushing for non-COVID postinfection illnesses to be included in efforts aimed at helping people with long COVID, with mixed results. For example, the RECOVER Initiative, established in February 2021 with $1.5 billion in funding from Congress to the National Institutes of Health, is specifically for studying long COVID and does not fund research into other postinfection illnesses, although representatives from the ME/CFS community are advisers.
Language addressing ME/CFS and other postinfectious chronic illnesses has been included in several long COVID bills now pending in Congress, including the Care for Long COVID Act in the Senate and its companion COVID-19 Long Haulers Act in the House. “Our goal is to push for passage of a long COVID bill by the end of the year,” Ms. Taylor said.
A version of this article first appeared on WebMD.com.