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Angiotensin Receptor Blockers Cut Epilepsy Risk in Patients With Hypertension
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
FROM AES 2024
When Is the Best Time to Deliver for Pregnant Patients With Chronic Hypertension?
TOPLINE:
Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.
METHODOLOGY:
- A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
- Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
- Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
- Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.
TAKEAWAY:
- The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
- Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
- At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
- According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.
IN PRACTICE:
“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.
SOURCE:
The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.
LIMITATIONS:
According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.
DISCLOSURES:
The authors did not report any potential conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.
METHODOLOGY:
- A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
- Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
- Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
- Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.
TAKEAWAY:
- The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
- Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
- At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
- According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.
IN PRACTICE:
“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.
SOURCE:
The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.
LIMITATIONS:
According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.
DISCLOSURES:
The authors did not report any potential conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.
METHODOLOGY:
- A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
- Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
- Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
- Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.
TAKEAWAY:
- The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
- Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
- At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
- According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.
IN PRACTICE:
“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.
SOURCE:
The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.
LIMITATIONS:
According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.
DISCLOSURES:
The authors did not report any potential conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
As-Needed Blood Pressure Medication Linked to Higher Risk for Acute Kidney Injury
TOPLINE:
Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.
METHODOLOGY:
- Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
- The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
- Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
- The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
- Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.
TAKEAWAY:
- Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
- Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
- The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).
IN PRACTICE:
“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.
SOURCE:
The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.
LIMITATIONS:
The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.
DISCLOSURES:
Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.
METHODOLOGY:
- Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
- The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
- Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
- The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
- Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.
TAKEAWAY:
- Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
- Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
- The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).
IN PRACTICE:
“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.
SOURCE:
The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.
LIMITATIONS:
The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.
DISCLOSURES:
Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.
METHODOLOGY:
- Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
- The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
- Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
- The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
- Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.
TAKEAWAY:
- Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
- Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
- The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).
IN PRACTICE:
“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.
SOURCE:
The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.
LIMITATIONS:
The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.
DISCLOSURES:
Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
New ‘Touchless’ Blood Pressure Screening Tech: How It Works
When a patient signs on to a telehealth portal, there’s little more a provider can do than ask questions. But a new artificial intelligence (AI) technology could allow providers to get feedback about the patient’s blood pressure and diabetes risk just from a video call or a smartphone app.
Researchers at the University of Tokyo in Japan are using AI to determine whether people might have high blood pressure or diabetes based on video data collected with a special sensor.
The technology relies on photoplethysmography (PPG), which measures changes in blood volume by detecting the amount of light absorbed by blood just below the skin.
Wearable devices like Apple Watches and Fitbits also use PPG technologies to detect heart rate and atrial fibrillation.
“If we could detect and accurately measure your blood pressure, heart rate, and oxygen saturation non-invasively that would be fantastic,” said Eugene Yang, MD, professor of medicine in the division of cardiology at the University of Washington School of Medicine in Seattle who was not involved in the study.
How Does PPG Work — and Is This New Tech Accurate?
Using PPG, “you’re detecting these small, little blood vessels that sit underneath the surface of your skin,” explained Yang.
“Since both hypertension and diabetes are diseases that damage blood vessels, we thought these diseases might affect blood flow and pulse wave transit times,” said Ryoko Uchida, a project researcher in the cardiology department at the University of Tokyo and one of the leaders of the study.
PPG devices primarily use green light to detect blood flow, as hemoglobin, the oxygen-carrying molecule in blood, absorbs green light most effectively, Yang said. “So, if you extract and remove all the other channels of light and only focus on the green channel, then that’s when you’ll be able to potentially see blood flow and pulsatile blood flow activity,” he noted.
The University of Tokyo researchers used remote or contactless PPG, which requires a short video recording of someone’s face and palms, as the person holds as still as possible. A special sensor collects the video and detects only certain wavelengths of light. Then the researchers developed an AI algorithm to extract data from participants’ skin, such as changes in pulse transit time — the time it takes for the pulse to travel from the palm to the face.
To correlate the video algorithm to blood pressure and diabetes risk, the researchers measured blood participants’ pressure with a continuous sphygmomanometer (an automatic blood pressure cuff) at the same time as they collected the video. They also did a blood A1c test to detect diabetes.
So far, they’ve tested their video algorithm on 215 people. The algorithm applied to a 30-second video was 86% accurate in detecting if blood pressure was above normal, and a 5-second video was 81% accurate in detecting higher blood pressure.
Compared with using hemoglobin A1c blood test results to screen for diabetes, the video algorithm was 75% accurate in identifying people who had subtle blood changes that correlated to diabetes.
“Most of this focus has been on wearable devices, patches, rings, wrist devices,” Yang said, “the facial video stuff is great because you can imagine that there are other ways of applying it.”
Yang, who is also doing research on facial video processing, pointed out it could be helpful not only in telehealth visits, but also for patients in the hospital with highly contagious diseases who need to be in isolation, or just for people using their smartphones.
“People are tied to their smartphones, so you could imagine that that would be great as a way for people to have awareness about their blood pressure or their diabetes status,” Yang noted.
More Work to Do
The study has a few caveats. The special sensor they used in this study isn’t yet integrated into smartphone cameras or other common video recording devices. But Uchida is hopeful that it could be mass-produced and inexpensive to someday add.
Also, the study was done in a Japanese population, and lighter skin may be easier to capture changes in blood flow, Uchida noted. Pulse oximeters, which use the same technology, tend to overestimate blood oxygen in people with darker skin tones.
“It is necessary to test whether the same results are obtained in a variety of subjects other than Japanese and Asians,” Uchida said, in addition to validating the tool with more participants.
The study has also not yet undergone peer review.
And Yang pointed out that this new AI technology provides more of a screening tool to predict who is at high risk for high blood pressure or diabetes, rather than precise measurements for either disease.
There are already some devices that claim to measure blood pressure using PPG technology, like blood pressure monitoring watches. But Yang warns that these kinds of devices aren’t validated, meaning we don’t really know how well they work.
One difficulty in getting any kind of PPG blood pressure monitoring device to market is that the organizations involved in setting medical device standards (like the International Organization for Standards) doesn’t yet have a validation standard for this technology, Yang said, so there’s really no way to consistently verify the technology’s accuracy.
“I am optimistic that we are capable of figuring out how to validate these things. I just think we have so many things we have to iron out before that happens,” Yang explained, noting that it will be at least 3 years before a remote blood monitoring system is widely available.
A version of this article first appeared on Medscape.com.
When a patient signs on to a telehealth portal, there’s little more a provider can do than ask questions. But a new artificial intelligence (AI) technology could allow providers to get feedback about the patient’s blood pressure and diabetes risk just from a video call or a smartphone app.
Researchers at the University of Tokyo in Japan are using AI to determine whether people might have high blood pressure or diabetes based on video data collected with a special sensor.
The technology relies on photoplethysmography (PPG), which measures changes in blood volume by detecting the amount of light absorbed by blood just below the skin.
Wearable devices like Apple Watches and Fitbits also use PPG technologies to detect heart rate and atrial fibrillation.
“If we could detect and accurately measure your blood pressure, heart rate, and oxygen saturation non-invasively that would be fantastic,” said Eugene Yang, MD, professor of medicine in the division of cardiology at the University of Washington School of Medicine in Seattle who was not involved in the study.
How Does PPG Work — and Is This New Tech Accurate?
Using PPG, “you’re detecting these small, little blood vessels that sit underneath the surface of your skin,” explained Yang.
“Since both hypertension and diabetes are diseases that damage blood vessels, we thought these diseases might affect blood flow and pulse wave transit times,” said Ryoko Uchida, a project researcher in the cardiology department at the University of Tokyo and one of the leaders of the study.
PPG devices primarily use green light to detect blood flow, as hemoglobin, the oxygen-carrying molecule in blood, absorbs green light most effectively, Yang said. “So, if you extract and remove all the other channels of light and only focus on the green channel, then that’s when you’ll be able to potentially see blood flow and pulsatile blood flow activity,” he noted.
The University of Tokyo researchers used remote or contactless PPG, which requires a short video recording of someone’s face and palms, as the person holds as still as possible. A special sensor collects the video and detects only certain wavelengths of light. Then the researchers developed an AI algorithm to extract data from participants’ skin, such as changes in pulse transit time — the time it takes for the pulse to travel from the palm to the face.
To correlate the video algorithm to blood pressure and diabetes risk, the researchers measured blood participants’ pressure with a continuous sphygmomanometer (an automatic blood pressure cuff) at the same time as they collected the video. They also did a blood A1c test to detect diabetes.
So far, they’ve tested their video algorithm on 215 people. The algorithm applied to a 30-second video was 86% accurate in detecting if blood pressure was above normal, and a 5-second video was 81% accurate in detecting higher blood pressure.
Compared with using hemoglobin A1c blood test results to screen for diabetes, the video algorithm was 75% accurate in identifying people who had subtle blood changes that correlated to diabetes.
“Most of this focus has been on wearable devices, patches, rings, wrist devices,” Yang said, “the facial video stuff is great because you can imagine that there are other ways of applying it.”
Yang, who is also doing research on facial video processing, pointed out it could be helpful not only in telehealth visits, but also for patients in the hospital with highly contagious diseases who need to be in isolation, or just for people using their smartphones.
“People are tied to their smartphones, so you could imagine that that would be great as a way for people to have awareness about their blood pressure or their diabetes status,” Yang noted.
More Work to Do
The study has a few caveats. The special sensor they used in this study isn’t yet integrated into smartphone cameras or other common video recording devices. But Uchida is hopeful that it could be mass-produced and inexpensive to someday add.
Also, the study was done in a Japanese population, and lighter skin may be easier to capture changes in blood flow, Uchida noted. Pulse oximeters, which use the same technology, tend to overestimate blood oxygen in people with darker skin tones.
“It is necessary to test whether the same results are obtained in a variety of subjects other than Japanese and Asians,” Uchida said, in addition to validating the tool with more participants.
The study has also not yet undergone peer review.
And Yang pointed out that this new AI technology provides more of a screening tool to predict who is at high risk for high blood pressure or diabetes, rather than precise measurements for either disease.
There are already some devices that claim to measure blood pressure using PPG technology, like blood pressure monitoring watches. But Yang warns that these kinds of devices aren’t validated, meaning we don’t really know how well they work.
One difficulty in getting any kind of PPG blood pressure monitoring device to market is that the organizations involved in setting medical device standards (like the International Organization for Standards) doesn’t yet have a validation standard for this technology, Yang said, so there’s really no way to consistently verify the technology’s accuracy.
“I am optimistic that we are capable of figuring out how to validate these things. I just think we have so many things we have to iron out before that happens,” Yang explained, noting that it will be at least 3 years before a remote blood monitoring system is widely available.
A version of this article first appeared on Medscape.com.
When a patient signs on to a telehealth portal, there’s little more a provider can do than ask questions. But a new artificial intelligence (AI) technology could allow providers to get feedback about the patient’s blood pressure and diabetes risk just from a video call or a smartphone app.
Researchers at the University of Tokyo in Japan are using AI to determine whether people might have high blood pressure or diabetes based on video data collected with a special sensor.
The technology relies on photoplethysmography (PPG), which measures changes in blood volume by detecting the amount of light absorbed by blood just below the skin.
Wearable devices like Apple Watches and Fitbits also use PPG technologies to detect heart rate and atrial fibrillation.
“If we could detect and accurately measure your blood pressure, heart rate, and oxygen saturation non-invasively that would be fantastic,” said Eugene Yang, MD, professor of medicine in the division of cardiology at the University of Washington School of Medicine in Seattle who was not involved in the study.
How Does PPG Work — and Is This New Tech Accurate?
Using PPG, “you’re detecting these small, little blood vessels that sit underneath the surface of your skin,” explained Yang.
“Since both hypertension and diabetes are diseases that damage blood vessels, we thought these diseases might affect blood flow and pulse wave transit times,” said Ryoko Uchida, a project researcher in the cardiology department at the University of Tokyo and one of the leaders of the study.
PPG devices primarily use green light to detect blood flow, as hemoglobin, the oxygen-carrying molecule in blood, absorbs green light most effectively, Yang said. “So, if you extract and remove all the other channels of light and only focus on the green channel, then that’s when you’ll be able to potentially see blood flow and pulsatile blood flow activity,” he noted.
The University of Tokyo researchers used remote or contactless PPG, which requires a short video recording of someone’s face and palms, as the person holds as still as possible. A special sensor collects the video and detects only certain wavelengths of light. Then the researchers developed an AI algorithm to extract data from participants’ skin, such as changes in pulse transit time — the time it takes for the pulse to travel from the palm to the face.
To correlate the video algorithm to blood pressure and diabetes risk, the researchers measured blood participants’ pressure with a continuous sphygmomanometer (an automatic blood pressure cuff) at the same time as they collected the video. They also did a blood A1c test to detect diabetes.
So far, they’ve tested their video algorithm on 215 people. The algorithm applied to a 30-second video was 86% accurate in detecting if blood pressure was above normal, and a 5-second video was 81% accurate in detecting higher blood pressure.
Compared with using hemoglobin A1c blood test results to screen for diabetes, the video algorithm was 75% accurate in identifying people who had subtle blood changes that correlated to diabetes.
“Most of this focus has been on wearable devices, patches, rings, wrist devices,” Yang said, “the facial video stuff is great because you can imagine that there are other ways of applying it.”
Yang, who is also doing research on facial video processing, pointed out it could be helpful not only in telehealth visits, but also for patients in the hospital with highly contagious diseases who need to be in isolation, or just for people using their smartphones.
“People are tied to their smartphones, so you could imagine that that would be great as a way for people to have awareness about their blood pressure or their diabetes status,” Yang noted.
More Work to Do
The study has a few caveats. The special sensor they used in this study isn’t yet integrated into smartphone cameras or other common video recording devices. But Uchida is hopeful that it could be mass-produced and inexpensive to someday add.
Also, the study was done in a Japanese population, and lighter skin may be easier to capture changes in blood flow, Uchida noted. Pulse oximeters, which use the same technology, tend to overestimate blood oxygen in people with darker skin tones.
“It is necessary to test whether the same results are obtained in a variety of subjects other than Japanese and Asians,” Uchida said, in addition to validating the tool with more participants.
The study has also not yet undergone peer review.
And Yang pointed out that this new AI technology provides more of a screening tool to predict who is at high risk for high blood pressure or diabetes, rather than precise measurements for either disease.
There are already some devices that claim to measure blood pressure using PPG technology, like blood pressure monitoring watches. But Yang warns that these kinds of devices aren’t validated, meaning we don’t really know how well they work.
One difficulty in getting any kind of PPG blood pressure monitoring device to market is that the organizations involved in setting medical device standards (like the International Organization for Standards) doesn’t yet have a validation standard for this technology, Yang said, so there’s really no way to consistently verify the technology’s accuracy.
“I am optimistic that we are capable of figuring out how to validate these things. I just think we have so many things we have to iron out before that happens,” Yang explained, noting that it will be at least 3 years before a remote blood monitoring system is widely available.
A version of this article first appeared on Medscape.com.
Deprescribe Low-Value Meds to Reduce Polypharmacy Harms
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FMF 2024
As Populations Age, Occam’s Razor Loses Its Diagnostic Edge
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Vitamin D May Lower Blood Pressure in Seniors With Overweight
TOPLINE:
Supplementation with vitamin D and calcium can reduce systolic and diastolic blood pressure in older individuals with overweight, particularly in those with a body mass index (BMI) > 30 and those diagnosed with hypertension.
METHODOLOGY:
- Large cohort data have provided epidemiologic evidence linking vitamin D deficiency to a higher risk for cardiovascular disorders, including hypertension; however, evidence on the beneficial effects of vitamin D supplementation on blood pressure outcomes remains inconclusive.
- A post hoc analysis of a randomized controlled trial was conducted to investigate the effect of two doses of cholecalciferol (vitamin D3) on blood pressure in individuals aged 65 years or older with a BMI > 25 and serum vitamin D levels of 10-30 ng/mL.
- A total of 221 participants were recruited through outpatient departments, clinics, and advertisements in the greater Beirut area and received calcium supplementation in combination with either a low dose (600 IU/d, as recommended by the Institute of Medicine [IOM]) or a high dose (3750 IU/d) of vitamin D3.
- Blood pressure measurements were taken at baseline, 6 months, and 12 months using a SureSigns VS3 monitor.
- Participants were also stratified by BMI and hypertension status to assess the effects of vitamin D and calcium on blood pressure.
TAKEAWAY:
- Systolic and diastolic blood pressures were significantly reduced with vitamin D supplementation in the overall cohort (mean difference, 3.5 and 2.8 mm Hg, respectively; P = .005 and P = .002, respectively), with the effect more prominent in those in the high-dose vitamin D group.
- Participants with a BMI > 30 experienced reductions in both systolic and diastolic blood pressures in the overall cohort (P < .0001 and P = .01, respectively); although the systolic blood pressure was significantly reduced with both high- and low-dose vitamin D, the diastolic blood pressure decreased in the high-dose group only.
- Patients with hypertension benefited from all doses of vitamin D, regardless of the BMI.
- Systolic blood pressure at 6 and 12 months was significantly predicted by BMI and baseline systolic blood pressure measurements, although not by the dose of vitamin D received.
IN PRACTICE:
“Our study found vitamin D supplementation may decrease blood pressure in specific subgroups such as older people, people with obesity, and possibly those with low vitamin D levels,” said study author Ghada El-Hajj Fuleihan, MD, MPH, of the American University of Beirut Medical Center in Beirut, Lebanon, said in a news release. “High vitamin D doses compared to the IOM’s recommended daily dose did not provide additional health benefits.”
SOURCE:
This study was led by Maya Rahme, Department of Internal Medicine, Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, World Health Organization Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center in Beirut, Lebanon. It was published online in Journal of the Endocrine Society.
LIMITATIONS:
This study’s limitations included the exploratory nature of the analyses and the low power of the subgroup analyses. Additionally, the study focused on older individuals who were sedentary and had overweight, many of whom had prediabetes — conditions known to influence blood pressure. The possible effect of calcium alone on blood pressure reduction was also unclear.
DISCLOSURES:
This study was supported by grants from the American University of Beirut, St Joseph University, and the Lebanese Council for National Scientific Research. No relevant conflicts of interest were disclosed by the authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
TOPLINE:
Supplementation with vitamin D and calcium can reduce systolic and diastolic blood pressure in older individuals with overweight, particularly in those with a body mass index (BMI) > 30 and those diagnosed with hypertension.
METHODOLOGY:
- Large cohort data have provided epidemiologic evidence linking vitamin D deficiency to a higher risk for cardiovascular disorders, including hypertension; however, evidence on the beneficial effects of vitamin D supplementation on blood pressure outcomes remains inconclusive.
- A post hoc analysis of a randomized controlled trial was conducted to investigate the effect of two doses of cholecalciferol (vitamin D3) on blood pressure in individuals aged 65 years or older with a BMI > 25 and serum vitamin D levels of 10-30 ng/mL.
- A total of 221 participants were recruited through outpatient departments, clinics, and advertisements in the greater Beirut area and received calcium supplementation in combination with either a low dose (600 IU/d, as recommended by the Institute of Medicine [IOM]) or a high dose (3750 IU/d) of vitamin D3.
- Blood pressure measurements were taken at baseline, 6 months, and 12 months using a SureSigns VS3 monitor.
- Participants were also stratified by BMI and hypertension status to assess the effects of vitamin D and calcium on blood pressure.
TAKEAWAY:
- Systolic and diastolic blood pressures were significantly reduced with vitamin D supplementation in the overall cohort (mean difference, 3.5 and 2.8 mm Hg, respectively; P = .005 and P = .002, respectively), with the effect more prominent in those in the high-dose vitamin D group.
- Participants with a BMI > 30 experienced reductions in both systolic and diastolic blood pressures in the overall cohort (P < .0001 and P = .01, respectively); although the systolic blood pressure was significantly reduced with both high- and low-dose vitamin D, the diastolic blood pressure decreased in the high-dose group only.
- Patients with hypertension benefited from all doses of vitamin D, regardless of the BMI.
- Systolic blood pressure at 6 and 12 months was significantly predicted by BMI and baseline systolic blood pressure measurements, although not by the dose of vitamin D received.
IN PRACTICE:
“Our study found vitamin D supplementation may decrease blood pressure in specific subgroups such as older people, people with obesity, and possibly those with low vitamin D levels,” said study author Ghada El-Hajj Fuleihan, MD, MPH, of the American University of Beirut Medical Center in Beirut, Lebanon, said in a news release. “High vitamin D doses compared to the IOM’s recommended daily dose did not provide additional health benefits.”
SOURCE:
This study was led by Maya Rahme, Department of Internal Medicine, Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, World Health Organization Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center in Beirut, Lebanon. It was published online in Journal of the Endocrine Society.
LIMITATIONS:
This study’s limitations included the exploratory nature of the analyses and the low power of the subgroup analyses. Additionally, the study focused on older individuals who were sedentary and had overweight, many of whom had prediabetes — conditions known to influence blood pressure. The possible effect of calcium alone on blood pressure reduction was also unclear.
DISCLOSURES:
This study was supported by grants from the American University of Beirut, St Joseph University, and the Lebanese Council for National Scientific Research. No relevant conflicts of interest were disclosed by the authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
TOPLINE:
Supplementation with vitamin D and calcium can reduce systolic and diastolic blood pressure in older individuals with overweight, particularly in those with a body mass index (BMI) > 30 and those diagnosed with hypertension.
METHODOLOGY:
- Large cohort data have provided epidemiologic evidence linking vitamin D deficiency to a higher risk for cardiovascular disorders, including hypertension; however, evidence on the beneficial effects of vitamin D supplementation on blood pressure outcomes remains inconclusive.
- A post hoc analysis of a randomized controlled trial was conducted to investigate the effect of two doses of cholecalciferol (vitamin D3) on blood pressure in individuals aged 65 years or older with a BMI > 25 and serum vitamin D levels of 10-30 ng/mL.
- A total of 221 participants were recruited through outpatient departments, clinics, and advertisements in the greater Beirut area and received calcium supplementation in combination with either a low dose (600 IU/d, as recommended by the Institute of Medicine [IOM]) or a high dose (3750 IU/d) of vitamin D3.
- Blood pressure measurements were taken at baseline, 6 months, and 12 months using a SureSigns VS3 monitor.
- Participants were also stratified by BMI and hypertension status to assess the effects of vitamin D and calcium on blood pressure.
TAKEAWAY:
- Systolic and diastolic blood pressures were significantly reduced with vitamin D supplementation in the overall cohort (mean difference, 3.5 and 2.8 mm Hg, respectively; P = .005 and P = .002, respectively), with the effect more prominent in those in the high-dose vitamin D group.
- Participants with a BMI > 30 experienced reductions in both systolic and diastolic blood pressures in the overall cohort (P < .0001 and P = .01, respectively); although the systolic blood pressure was significantly reduced with both high- and low-dose vitamin D, the diastolic blood pressure decreased in the high-dose group only.
- Patients with hypertension benefited from all doses of vitamin D, regardless of the BMI.
- Systolic blood pressure at 6 and 12 months was significantly predicted by BMI and baseline systolic blood pressure measurements, although not by the dose of vitamin D received.
IN PRACTICE:
“Our study found vitamin D supplementation may decrease blood pressure in specific subgroups such as older people, people with obesity, and possibly those with low vitamin D levels,” said study author Ghada El-Hajj Fuleihan, MD, MPH, of the American University of Beirut Medical Center in Beirut, Lebanon, said in a news release. “High vitamin D doses compared to the IOM’s recommended daily dose did not provide additional health benefits.”
SOURCE:
This study was led by Maya Rahme, Department of Internal Medicine, Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, World Health Organization Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center in Beirut, Lebanon. It was published online in Journal of the Endocrine Society.
LIMITATIONS:
This study’s limitations included the exploratory nature of the analyses and the low power of the subgroup analyses. Additionally, the study focused on older individuals who were sedentary and had overweight, many of whom had prediabetes — conditions known to influence blood pressure. The possible effect of calcium alone on blood pressure reduction was also unclear.
DISCLOSURES:
This study was supported by grants from the American University of Beirut, St Joseph University, and the Lebanese Council for National Scientific Research. No relevant conflicts of interest were disclosed by the authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Is Acute Kidney Injury Really a Single Disease?
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?
“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”
AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
‘Mediocre Markers’
AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.
Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.
“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”
Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”
What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.
“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.
NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.
There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.
“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”
If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.
“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”
Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.
However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.
“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
A New Biomarker for AIN?
Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.
“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.
“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”
“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”
Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”
Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.
“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”
In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”
Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.
Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”
Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.
A version of this article first appeared on Medscape.com.
Angiotensin Receptor Blockers May Lead to Worse Outcomes in Celiac Disease
PHILADELPHIA — , according to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
The association may be related to the similar pathophysiology between ARB-associated enteropathy and celiac disease, though additional research is needed.
“Based on our findings, people should take caution when prescribing angiotensin receptor blockers to people with celiac disease,” said lead author Isabel Hujoel, MD, clinical assistant professor of gastroenterology and clinic director of the Celiac Disease Center at the University of Washington, Seattle.
“When we see someone with nonresponsive celiac disease, meaning persistent symptoms despite a gluten-free diet, I do think we should review their medication list, and if they’re on an ARB, we should consider a trial off those medications to see if they respond,” she said. “A primary care provider may choose other hypertensives as well.”
Hujoel and co-author Margaux Hujoel, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital, Boston; Broad Institute, Cambridge; and Harvard Medical School, Boston, analyzed data from the National Institutes of Health’s All of Us, a large publicly available US longitudinal dataset.
The researchers conducted a survival analysis of time-to-first event after celiac disease diagnosis, allowing patients to have a time-dependent covariate of ARB use. They looked at outcomes such as iron deficiency, diarrhea, abdominal pain, vitamin deficiency, vitamin D deficiency, malabsorption, low hemoglobin, and weight loss.
The analysis included 1849 patients with celiac disease, including 1460 women and 389 men, with a median age of nearly 50 years at diagnosis. While the vast majority of patients (nearly 1600) didn’t take an ARB, 120 started one before celiac disease diagnosis and 142 started one after diagnosis.
Overall, taking an ARB was associated with increased hazard ratios [HRs] for low hemoglobin, iron deficiency, diarrhea, and abdominal pain. There weren’t increased risks for weight loss, malabsorption, or vitamin deficiencies.
When excluding those who had an ARB prescription before diagnosis, the HRs remained significantly higher for low hemoglobin (HR, 1.98) and iron deficiency (HR, 1.72) for those who started an ARB after diagnosis.
“The use of angiotensin receptor blockers may be associated with worse outcomes in the setting of celiac disease, specifically persistent symptoms and possibly poor small bowel healing as evidenced by malabsorption,” Hujoel said.
Future studies could look specifically at losartan, which was the most common ARB prescribed in this analysis, she said. Other studies could also analyze different patient outcomes, whether patients were on a gluten-free diet, medication adherence, and recurrence or persistence of symptoms rather than initial occurrence. The associations between ARB use and celiac disease could shift among patients who are in remission, for instance.
“ARBs are some of the most widely used medications, so studies like these can help people to understand that they may have symptoms but not know it’s related to their medication. Public awareness of this fact is key,” said Patricia Jones, MD, a hepatologist and associate professor of clinical medicine at the University of Miami Miller School of Medicine, Miami. Jones co-moderated the plenary session on small intestine, functional, and liver research.
“There are many types of antihypertensives, so while ARBs are used often, other options are available if people have symptoms, especially if they have worsening symptoms with celiac disease,” she said. “It’s important to make changes in your practice.”
The study was named an ACG Newsworthy Abstract. Isabel Hujoel and Patricia Jones reported no relevant disclosures.
A version of this article appeared on Medscape.com.
PHILADELPHIA — , according to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
The association may be related to the similar pathophysiology between ARB-associated enteropathy and celiac disease, though additional research is needed.
“Based on our findings, people should take caution when prescribing angiotensin receptor blockers to people with celiac disease,” said lead author Isabel Hujoel, MD, clinical assistant professor of gastroenterology and clinic director of the Celiac Disease Center at the University of Washington, Seattle.
“When we see someone with nonresponsive celiac disease, meaning persistent symptoms despite a gluten-free diet, I do think we should review their medication list, and if they’re on an ARB, we should consider a trial off those medications to see if they respond,” she said. “A primary care provider may choose other hypertensives as well.”
Hujoel and co-author Margaux Hujoel, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital, Boston; Broad Institute, Cambridge; and Harvard Medical School, Boston, analyzed data from the National Institutes of Health’s All of Us, a large publicly available US longitudinal dataset.
The researchers conducted a survival analysis of time-to-first event after celiac disease diagnosis, allowing patients to have a time-dependent covariate of ARB use. They looked at outcomes such as iron deficiency, diarrhea, abdominal pain, vitamin deficiency, vitamin D deficiency, malabsorption, low hemoglobin, and weight loss.
The analysis included 1849 patients with celiac disease, including 1460 women and 389 men, with a median age of nearly 50 years at diagnosis. While the vast majority of patients (nearly 1600) didn’t take an ARB, 120 started one before celiac disease diagnosis and 142 started one after diagnosis.
Overall, taking an ARB was associated with increased hazard ratios [HRs] for low hemoglobin, iron deficiency, diarrhea, and abdominal pain. There weren’t increased risks for weight loss, malabsorption, or vitamin deficiencies.
When excluding those who had an ARB prescription before diagnosis, the HRs remained significantly higher for low hemoglobin (HR, 1.98) and iron deficiency (HR, 1.72) for those who started an ARB after diagnosis.
“The use of angiotensin receptor blockers may be associated with worse outcomes in the setting of celiac disease, specifically persistent symptoms and possibly poor small bowel healing as evidenced by malabsorption,” Hujoel said.
Future studies could look specifically at losartan, which was the most common ARB prescribed in this analysis, she said. Other studies could also analyze different patient outcomes, whether patients were on a gluten-free diet, medication adherence, and recurrence or persistence of symptoms rather than initial occurrence. The associations between ARB use and celiac disease could shift among patients who are in remission, for instance.
“ARBs are some of the most widely used medications, so studies like these can help people to understand that they may have symptoms but not know it’s related to their medication. Public awareness of this fact is key,” said Patricia Jones, MD, a hepatologist and associate professor of clinical medicine at the University of Miami Miller School of Medicine, Miami. Jones co-moderated the plenary session on small intestine, functional, and liver research.
“There are many types of antihypertensives, so while ARBs are used often, other options are available if people have symptoms, especially if they have worsening symptoms with celiac disease,” she said. “It’s important to make changes in your practice.”
The study was named an ACG Newsworthy Abstract. Isabel Hujoel and Patricia Jones reported no relevant disclosures.
A version of this article appeared on Medscape.com.
PHILADELPHIA — , according to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
The association may be related to the similar pathophysiology between ARB-associated enteropathy and celiac disease, though additional research is needed.
“Based on our findings, people should take caution when prescribing angiotensin receptor blockers to people with celiac disease,” said lead author Isabel Hujoel, MD, clinical assistant professor of gastroenterology and clinic director of the Celiac Disease Center at the University of Washington, Seattle.
“When we see someone with nonresponsive celiac disease, meaning persistent symptoms despite a gluten-free diet, I do think we should review their medication list, and if they’re on an ARB, we should consider a trial off those medications to see if they respond,” she said. “A primary care provider may choose other hypertensives as well.”
Hujoel and co-author Margaux Hujoel, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital, Boston; Broad Institute, Cambridge; and Harvard Medical School, Boston, analyzed data from the National Institutes of Health’s All of Us, a large publicly available US longitudinal dataset.
The researchers conducted a survival analysis of time-to-first event after celiac disease diagnosis, allowing patients to have a time-dependent covariate of ARB use. They looked at outcomes such as iron deficiency, diarrhea, abdominal pain, vitamin deficiency, vitamin D deficiency, malabsorption, low hemoglobin, and weight loss.
The analysis included 1849 patients with celiac disease, including 1460 women and 389 men, with a median age of nearly 50 years at diagnosis. While the vast majority of patients (nearly 1600) didn’t take an ARB, 120 started one before celiac disease diagnosis and 142 started one after diagnosis.
Overall, taking an ARB was associated with increased hazard ratios [HRs] for low hemoglobin, iron deficiency, diarrhea, and abdominal pain. There weren’t increased risks for weight loss, malabsorption, or vitamin deficiencies.
When excluding those who had an ARB prescription before diagnosis, the HRs remained significantly higher for low hemoglobin (HR, 1.98) and iron deficiency (HR, 1.72) for those who started an ARB after diagnosis.
“The use of angiotensin receptor blockers may be associated with worse outcomes in the setting of celiac disease, specifically persistent symptoms and possibly poor small bowel healing as evidenced by malabsorption,” Hujoel said.
Future studies could look specifically at losartan, which was the most common ARB prescribed in this analysis, she said. Other studies could also analyze different patient outcomes, whether patients were on a gluten-free diet, medication adherence, and recurrence or persistence of symptoms rather than initial occurrence. The associations between ARB use and celiac disease could shift among patients who are in remission, for instance.
“ARBs are some of the most widely used medications, so studies like these can help people to understand that they may have symptoms but not know it’s related to their medication. Public awareness of this fact is key,” said Patricia Jones, MD, a hepatologist and associate professor of clinical medicine at the University of Miami Miller School of Medicine, Miami. Jones co-moderated the plenary session on small intestine, functional, and liver research.
“There are many types of antihypertensives, so while ARBs are used often, other options are available if people have symptoms, especially if they have worsening symptoms with celiac disease,” she said. “It’s important to make changes in your practice.”
The study was named an ACG Newsworthy Abstract. Isabel Hujoel and Patricia Jones reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ACG 2024
Can We Repurpose Obesity Drugs to Reverse Liver Disease?
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.