Clinician Reviews

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

TOPLINE:

Nirmatrelvir-ritonavir doesn’t reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
 

METHODOLOGY:

• A retrospective study of 9,593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post–COVID-19 conditions (PCCs).
• Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
• The incidence of PCCs was analyzed 31-180 days after treatment.

TAKEAWAY:

• The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
• No statistically significant reduction of other conditions was found.
• Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.

IN PRACTICE:

“Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions,” the authors write.

SOURCE:

The study was funded by the Department of Veterans Affairs and was published online in Annals of Internal Medicine. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.

LIMITATIONS:

A large number of outcomes were observed, so it’s possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.

Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the ICD-10, which was used for diagnosis codes.

Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
 

DISCLOSURES:

The authors reported relationships with the Korean Diabetes Association, the American Diabetes Association, the International Society for the Diabetic Foot, Quality Insights, Brown University, and the Society for Women in Urology, among others.

A version of this article appeared on Medscape.com.

TOPLINE:

Nirmatrelvir-ritonavir doesn’t reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
 

METHODOLOGY:

• A retrospective study of 9,593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post–COVID-19 conditions (PCCs).
• Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
• The incidence of PCCs was analyzed 31-180 days after treatment.

TAKEAWAY:

• The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
• No statistically significant reduction of other conditions was found.
• Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.

IN PRACTICE:

“Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions,” the authors write.

SOURCE:

The study was funded by the Department of Veterans Affairs and was published online in Annals of Internal Medicine. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.

LIMITATIONS:

A large number of outcomes were observed, so it’s possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.

Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the ICD-10, which was used for diagnosis codes.

Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
 

DISCLOSURES:

The authors reported relationships with the Korean Diabetes Association, the American Diabetes Association, the International Society for the Diabetic Foot, Quality Insights, Brown University, and the Society for Women in Urology, among others.

A version of this article appeared on Medscape.com.

TOPLINE:

Nirmatrelvir-ritonavir doesn’t reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
 

METHODOLOGY:

• A retrospective study of 9,593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post–COVID-19 conditions (PCCs).
• Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
• The incidence of PCCs was analyzed 31-180 days after treatment.

TAKEAWAY:

• The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
• No statistically significant reduction of other conditions was found.
• Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.

IN PRACTICE:

“Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions,” the authors write.

SOURCE:

The study was funded by the Department of Veterans Affairs and was published online in Annals of Internal Medicine. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.

LIMITATIONS:

A large number of outcomes were observed, so it’s possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.

Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the ICD-10, which was used for diagnosis codes.

Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
 

DISCLOSURES:

The authors reported relationships with the Korean Diabetes Association, the American Diabetes Association, the International Society for the Diabetic Foot, Quality Insights, Brown University, and the Society for Women in Urology, among others.

A version of this article appeared on Medscape.com.

Patients with hand osteoarthritis (OA) and MRI-detected synovitis who took methotrexate (MTX) 20 mg weekly over a 6-month period had a significant and potentially clinically meaningful reduction in pain and stiffness over those who received placebo in the first randomized controlled trial of its kind to show positive results with the drug.

Patients who were randomly assigned to MTX took 10 mg orally for the first 4 weeks then increased to 20 mg for the rest of the trial, with differences in the primary outcome of pain measured by visual analog scale (VAS) first becoming significant over placebo at 3 months.

Senior author of the METHODS study (Methotrexate to Treat Hand Osteoarthritis with Synovitis), Flavia Cicuttini, PhD, MSc, head of the musculoskeletal unit at Monash University and head of rheumatology at Alfred Hospital, Melbourne, Australia, noted that the effect of MTX was higher than effect sizes that have been reported for NSAIDs on pain in hip or knee OA.

Astrid Gast/Thinkstock

The study was published online October 12 in The Lancet.

METHODS makes improvements on past studies

While OA is traditionally categorized as a noninflammatory process, it’s known that there are some patients who have a clinical phenotype characterized by joint swelling (synovitis) and others develop erosive disease. MTX is one of the most common therapies for inflammatory arthritis and standard of care for rheumatoid arthritis (RA) management. Previous studies of methotrexate showed lack of efficacy in hand OA but may have been because of the use of a low dose, poor power due to moderate sample size, and failure to target the specific inflammatory OA phenotype.

Dr. Cicuttini

In an interview, Dr. Cicuttini noted the selection of methotrexate for this trial was intentional. “We considered the evidence and decided to test methotrexate because we know it is effective in inflammatory arthritis, and its mode of action is broader than the more selective anti-TNF [tumor necrosis factor] agents,” which she noted have failed in prior hand OA trials. She also noted that the only previous randomized controlled trial of MTX tested a dose of 10 mg/week, rather than the 20 mg/week dose used in METHODS. 
 

Study details and results

METHODS was a randomized, double-blind, placebo-controlled trial at multiple sites within Australia. Patients were recruited from 2017 to 2022, with a temporary pause in 2020 during the COVID-19 pandemic because of safety concerns regarding MTX use. Participants included in this study were aged 40-75 years, had pain in hand joints for most days in the past 3 months, and a pain score of at least 40 mm on a 100-mm VAS in the past 7 days.

The participants’ hand OA fulfilled American College of Rheumatology criteria, radiographic osteoarthritis (Kellgren and Lawrence grade 2 or more) in at least one joint, and MRI-detected synovitis of grade 1 or more in at least one joint. They excluded patients with concomitant rheumatic disease, gout, psoriasis, positive rheumatoid factor or anti-cyclic citrullinated peptides, or elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein), as well as those with contraindication to methotrexate or MRI.

The trials’ 97 participants were assigned 1:1 to MTX or placebo using block randomization. The MTX group started on oral MTX 10 mg weekly for the first 4 weeks, followed by 20 mg weekly for the remainder of the study. Participants took folic acid 5 mg once a day to reduce risk of MTX-related side effects.

The mean age of the participants was 61 years, with 70% female. Baseline characteristics were generally well-balanced, except for higher mean BMI in the MTX group. At 6 months, the MTX group had a greater reduction in mean VAS pain than the placebo group (–15.2 mm vs. –7.7 mm; adjusted between-group difference, –9.9 mm). The minimally clinically important difference for OA trials is a 15-mm change (out of 100) in VAS pain.

The MTX group also had greater reduction in mean Australian Canadian OA Hand Index (AUSCAN) score for pain and stiffness at 6 months, compared with placebo, but there were no differences in other secondary outcomes (mean AUSCAN, Functional Index for Hand Osteoarthritis, Health Assessment Questionnaire, Michigan Hand Outcomes Questionnaire, or grip strength).

MTX was well-tolerated with no serious adverse events related to treatment; only 5 of 50 participants in the MTX group and 4 of 47 in the placebo group discontinued study medication. Incidence of adverse events was similar in the two groups throughout the trial, including mild leukopenia, elevated liver enzymes, mild reduction of hemoglobin, and raised creatinine. None of the laboratory abnormalities required change in medication dosage or affected ability to continue in the study. 
 

Qualifications and considerations for MTX use

Commenting on the study, OA researcher Amanda E. Nelson, MD, MSCR, associate professor of medicine at the University of North Carolina at Chapel Hill’s Thurston Arthritis Research Center, said that its overall design was “excellent,” including appropriate masking, controls, randomization, and power and sample size calculations, contributing to “the trial’s relatively positive, although still modest, results.” Dr. Nelson was not involved with the METHODS study.

Dr. Nelson

Several factors may have contributed to the study’s success, including the broader mechanism of action of methotrexate and higher dose used, Ida K. Haugen, MD, PhD, senior researcher at Diakonhjemmet Hospital’s Center for Treatment of Rheumatic and Musculoskeletal Diseases in Oslo, Norway, told this news organization.

She noted that the MTX 20 mg/week dosage is similar to what is used in treatment of RA and may be key to better targeting inflammation.

Nicolas Tourrenc

“Furthermore, the study included individuals with hand OA and synovitis by MRI, and thus may have found the right patient population in comparison to prior studies,” Dr. Haugen said.

Dr. Cicuttini agreed, noting that “previous trials [of MTX] did not target the inflammatory phenotype of hand osteoarthritis that would be expected to respond.” In the previous randomized controlled trial of MTX in hand OA, only 29 of a total 1024 joints had synovitis, she explained. “Their inclusion criteria were individuals with severe erosive hand osteoarthritis, suggesting that this later-stage disease is less likely to respond.”

Dr. Cicuttini said that she saw no specific issues in regard to potential use of MTX in the OA population in the clinic. “The data we have, together with the large experience we have with using methotrexate and the fact that treatments for hand OA are not very effective, means that it would be reasonable to offer this to patients with hand OA and inflammation,” she said. “The level of evidence for an effect of methotrexate would need to be discussed with the patient. The discussion around the use of methotrexate would then need to proceed in the same way we discuss the use of methotrexate with patients when used for other inflammatory joint diseases, and the decision is then made with the patient.”

In contrast, Dr. Nelson expressed some concerns regarding the immediate use of MTX for this population. “Many individuals with hand OA have multiple medical comorbidities and polypharmacy, which are important when considering additional treatments, particularly those with modest benefit and potential adverse effects over the long term,” she said. “I do not think this single study provides enough evidence to suggest that all such patients should be treated with methotrexate, and more data, particularly about long-term use and optimal risk stratification, is needed.” 

While MTX use in refractory inflammatory hand OA is not yet recommended in international guidelines, Dr. Haugen believes this study supports use of MTX in this patient population. Given that MRI and ultrasound may not always be available to identify synovitis, Dr. Nelson and Dr. Haugen suggested identifying patients who may benefit through careful history and clinical examination for evidence of swollen joints. In addition, Dr. Cicuttini explained that she would not necessarily use MTX in patients with erosive OA radiographically because it may be a later stage of disease that is less likely to respond.

The authors highlighted potential limitations of the METHODS trial. They initially planned to study whether MTX reduced pain and improved radiographic progression at 2 years, but since they paused the study for 7 months during the COVID-19 pandemic, they amended the trial protocol and focused on pain reduction at 6 months as the primary endpoint instead.

Tender and swollen joint counts were initially going to be included, but this was modified given the use of virtual telemedicine visits during the pandemic. Dr. Cicuttini said that further studies are underway to identify potential subpopulations who may benefit from immunosuppression, and others are needed to determine whether MTX reduces joint damage and slows disease progression in hand OA with inflammation.

Dr. Cicuttini said her research group is interested to see whether women who develop hand OA around the time of menopause (“menopausal OA”) are a group that could benefit. Dr. Haugen noted that she is involved in a study testing MTX in erosive hand OA (the MERINO trial). 

The study was funded by a project grant from the National Health and Medical Research Council of Australia. The authors reported no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Patients with hand osteoarthritis (OA) and MRI-detected synovitis who took methotrexate (MTX) 20 mg weekly over a 6-month period had a significant and potentially clinically meaningful reduction in pain and stiffness over those who received placebo in the first randomized controlled trial of its kind to show positive results with the drug.

Patients who were randomly assigned to MTX took 10 mg orally for the first 4 weeks then increased to 20 mg for the rest of the trial, with differences in the primary outcome of pain measured by visual analog scale (VAS) first becoming significant over placebo at 3 months.

Senior author of the METHODS study (Methotrexate to Treat Hand Osteoarthritis with Synovitis), Flavia Cicuttini, PhD, MSc, head of the musculoskeletal unit at Monash University and head of rheumatology at Alfred Hospital, Melbourne, Australia, noted that the effect of MTX was higher than effect sizes that have been reported for NSAIDs on pain in hip or knee OA.

Astrid Gast/Thinkstock

The study was published online October 12 in The Lancet.

METHODS makes improvements on past studies

While OA is traditionally categorized as a noninflammatory process, it’s known that there are some patients who have a clinical phenotype characterized by joint swelling (synovitis) and others develop erosive disease. MTX is one of the most common therapies for inflammatory arthritis and standard of care for rheumatoid arthritis (RA) management. Previous studies of methotrexate showed lack of efficacy in hand OA but may have been because of the use of a low dose, poor power due to moderate sample size, and failure to target the specific inflammatory OA phenotype.

Dr. Cicuttini

In an interview, Dr. Cicuttini noted the selection of methotrexate for this trial was intentional. “We considered the evidence and decided to test methotrexate because we know it is effective in inflammatory arthritis, and its mode of action is broader than the more selective anti-TNF [tumor necrosis factor] agents,” which she noted have failed in prior hand OA trials. She also noted that the only previous randomized controlled trial of MTX tested a dose of 10 mg/week, rather than the 20 mg/week dose used in METHODS. 
 

Study details and results

METHODS was a randomized, double-blind, placebo-controlled trial at multiple sites within Australia. Patients were recruited from 2017 to 2022, with a temporary pause in 2020 during the COVID-19 pandemic because of safety concerns regarding MTX use. Participants included in this study were aged 40-75 years, had pain in hand joints for most days in the past 3 months, and a pain score of at least 40 mm on a 100-mm VAS in the past 7 days.

The participants’ hand OA fulfilled American College of Rheumatology criteria, radiographic osteoarthritis (Kellgren and Lawrence grade 2 or more) in at least one joint, and MRI-detected synovitis of grade 1 or more in at least one joint. They excluded patients with concomitant rheumatic disease, gout, psoriasis, positive rheumatoid factor or anti-cyclic citrullinated peptides, or elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein), as well as those with contraindication to methotrexate or MRI.

The trials’ 97 participants were assigned 1:1 to MTX or placebo using block randomization. The MTX group started on oral MTX 10 mg weekly for the first 4 weeks, followed by 20 mg weekly for the remainder of the study. Participants took folic acid 5 mg once a day to reduce risk of MTX-related side effects.

The mean age of the participants was 61 years, with 70% female. Baseline characteristics were generally well-balanced, except for higher mean BMI in the MTX group. At 6 months, the MTX group had a greater reduction in mean VAS pain than the placebo group (–15.2 mm vs. –7.7 mm; adjusted between-group difference, –9.9 mm). The minimally clinically important difference for OA trials is a 15-mm change (out of 100) in VAS pain.

The MTX group also had greater reduction in mean Australian Canadian OA Hand Index (AUSCAN) score for pain and stiffness at 6 months, compared with placebo, but there were no differences in other secondary outcomes (mean AUSCAN, Functional Index for Hand Osteoarthritis, Health Assessment Questionnaire, Michigan Hand Outcomes Questionnaire, or grip strength).

MTX was well-tolerated with no serious adverse events related to treatment; only 5 of 50 participants in the MTX group and 4 of 47 in the placebo group discontinued study medication. Incidence of adverse events was similar in the two groups throughout the trial, including mild leukopenia, elevated liver enzymes, mild reduction of hemoglobin, and raised creatinine. None of the laboratory abnormalities required change in medication dosage or affected ability to continue in the study. 
 

Qualifications and considerations for MTX use

Commenting on the study, OA researcher Amanda E. Nelson, MD, MSCR, associate professor of medicine at the University of North Carolina at Chapel Hill’s Thurston Arthritis Research Center, said that its overall design was “excellent,” including appropriate masking, controls, randomization, and power and sample size calculations, contributing to “the trial’s relatively positive, although still modest, results.” Dr. Nelson was not involved with the METHODS study.

Dr. Nelson

Several factors may have contributed to the study’s success, including the broader mechanism of action of methotrexate and higher dose used, Ida K. Haugen, MD, PhD, senior researcher at Diakonhjemmet Hospital’s Center for Treatment of Rheumatic and Musculoskeletal Diseases in Oslo, Norway, told this news organization.

She noted that the MTX 20 mg/week dosage is similar to what is used in treatment of RA and may be key to better targeting inflammation.

Nicolas Tourrenc

“Furthermore, the study included individuals with hand OA and synovitis by MRI, and thus may have found the right patient population in comparison to prior studies,” Dr. Haugen said.

Dr. Cicuttini agreed, noting that “previous trials [of MTX] did not target the inflammatory phenotype of hand osteoarthritis that would be expected to respond.” In the previous randomized controlled trial of MTX in hand OA, only 29 of a total 1024 joints had synovitis, she explained. “Their inclusion criteria were individuals with severe erosive hand osteoarthritis, suggesting that this later-stage disease is less likely to respond.”

Dr. Cicuttini said that she saw no specific issues in regard to potential use of MTX in the OA population in the clinic. “The data we have, together with the large experience we have with using methotrexate and the fact that treatments for hand OA are not very effective, means that it would be reasonable to offer this to patients with hand OA and inflammation,” she said. “The level of evidence for an effect of methotrexate would need to be discussed with the patient. The discussion around the use of methotrexate would then need to proceed in the same way we discuss the use of methotrexate with patients when used for other inflammatory joint diseases, and the decision is then made with the patient.”

In contrast, Dr. Nelson expressed some concerns regarding the immediate use of MTX for this population. “Many individuals with hand OA have multiple medical comorbidities and polypharmacy, which are important when considering additional treatments, particularly those with modest benefit and potential adverse effects over the long term,” she said. “I do not think this single study provides enough evidence to suggest that all such patients should be treated with methotrexate, and more data, particularly about long-term use and optimal risk stratification, is needed.” 

While MTX use in refractory inflammatory hand OA is not yet recommended in international guidelines, Dr. Haugen believes this study supports use of MTX in this patient population. Given that MRI and ultrasound may not always be available to identify synovitis, Dr. Nelson and Dr. Haugen suggested identifying patients who may benefit through careful history and clinical examination for evidence of swollen joints. In addition, Dr. Cicuttini explained that she would not necessarily use MTX in patients with erosive OA radiographically because it may be a later stage of disease that is less likely to respond.

The authors highlighted potential limitations of the METHODS trial. They initially planned to study whether MTX reduced pain and improved radiographic progression at 2 years, but since they paused the study for 7 months during the COVID-19 pandemic, they amended the trial protocol and focused on pain reduction at 6 months as the primary endpoint instead.

Tender and swollen joint counts were initially going to be included, but this was modified given the use of virtual telemedicine visits during the pandemic. Dr. Cicuttini said that further studies are underway to identify potential subpopulations who may benefit from immunosuppression, and others are needed to determine whether MTX reduces joint damage and slows disease progression in hand OA with inflammation.

Dr. Cicuttini said her research group is interested to see whether women who develop hand OA around the time of menopause (“menopausal OA”) are a group that could benefit. Dr. Haugen noted that she is involved in a study testing MTX in erosive hand OA (the MERINO trial). 

The study was funded by a project grant from the National Health and Medical Research Council of Australia. The authors reported no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Patients with hand osteoarthritis (OA) and MRI-detected synovitis who took methotrexate (MTX) 20 mg weekly over a 6-month period had a significant and potentially clinically meaningful reduction in pain and stiffness over those who received placebo in the first randomized controlled trial of its kind to show positive results with the drug.

Patients who were randomly assigned to MTX took 10 mg orally for the first 4 weeks then increased to 20 mg for the rest of the trial, with differences in the primary outcome of pain measured by visual analog scale (VAS) first becoming significant over placebo at 3 months.

Senior author of the METHODS study (Methotrexate to Treat Hand Osteoarthritis with Synovitis), Flavia Cicuttini, PhD, MSc, head of the musculoskeletal unit at Monash University and head of rheumatology at Alfred Hospital, Melbourne, Australia, noted that the effect of MTX was higher than effect sizes that have been reported for NSAIDs on pain in hip or knee OA.

Astrid Gast/Thinkstock

The study was published online October 12 in The Lancet.

METHODS makes improvements on past studies

While OA is traditionally categorized as a noninflammatory process, it’s known that there are some patients who have a clinical phenotype characterized by joint swelling (synovitis) and others develop erosive disease. MTX is one of the most common therapies for inflammatory arthritis and standard of care for rheumatoid arthritis (RA) management. Previous studies of methotrexate showed lack of efficacy in hand OA but may have been because of the use of a low dose, poor power due to moderate sample size, and failure to target the specific inflammatory OA phenotype.

Dr. Cicuttini

In an interview, Dr. Cicuttini noted the selection of methotrexate for this trial was intentional. “We considered the evidence and decided to test methotrexate because we know it is effective in inflammatory arthritis, and its mode of action is broader than the more selective anti-TNF [tumor necrosis factor] agents,” which she noted have failed in prior hand OA trials. She also noted that the only previous randomized controlled trial of MTX tested a dose of 10 mg/week, rather than the 20 mg/week dose used in METHODS. 
 

Study details and results

METHODS was a randomized, double-blind, placebo-controlled trial at multiple sites within Australia. Patients were recruited from 2017 to 2022, with a temporary pause in 2020 during the COVID-19 pandemic because of safety concerns regarding MTX use. Participants included in this study were aged 40-75 years, had pain in hand joints for most days in the past 3 months, and a pain score of at least 40 mm on a 100-mm VAS in the past 7 days.

The participants’ hand OA fulfilled American College of Rheumatology criteria, radiographic osteoarthritis (Kellgren and Lawrence grade 2 or more) in at least one joint, and MRI-detected synovitis of grade 1 or more in at least one joint. They excluded patients with concomitant rheumatic disease, gout, psoriasis, positive rheumatoid factor or anti-cyclic citrullinated peptides, or elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein), as well as those with contraindication to methotrexate or MRI.

The trials’ 97 participants were assigned 1:1 to MTX or placebo using block randomization. The MTX group started on oral MTX 10 mg weekly for the first 4 weeks, followed by 20 mg weekly for the remainder of the study. Participants took folic acid 5 mg once a day to reduce risk of MTX-related side effects.

The mean age of the participants was 61 years, with 70% female. Baseline characteristics were generally well-balanced, except for higher mean BMI in the MTX group. At 6 months, the MTX group had a greater reduction in mean VAS pain than the placebo group (–15.2 mm vs. –7.7 mm; adjusted between-group difference, –9.9 mm). The minimally clinically important difference for OA trials is a 15-mm change (out of 100) in VAS pain.

The MTX group also had greater reduction in mean Australian Canadian OA Hand Index (AUSCAN) score for pain and stiffness at 6 months, compared with placebo, but there were no differences in other secondary outcomes (mean AUSCAN, Functional Index for Hand Osteoarthritis, Health Assessment Questionnaire, Michigan Hand Outcomes Questionnaire, or grip strength).

MTX was well-tolerated with no serious adverse events related to treatment; only 5 of 50 participants in the MTX group and 4 of 47 in the placebo group discontinued study medication. Incidence of adverse events was similar in the two groups throughout the trial, including mild leukopenia, elevated liver enzymes, mild reduction of hemoglobin, and raised creatinine. None of the laboratory abnormalities required change in medication dosage or affected ability to continue in the study. 
 

Qualifications and considerations for MTX use

Commenting on the study, OA researcher Amanda E. Nelson, MD, MSCR, associate professor of medicine at the University of North Carolina at Chapel Hill’s Thurston Arthritis Research Center, said that its overall design was “excellent,” including appropriate masking, controls, randomization, and power and sample size calculations, contributing to “the trial’s relatively positive, although still modest, results.” Dr. Nelson was not involved with the METHODS study.

Dr. Nelson

Several factors may have contributed to the study’s success, including the broader mechanism of action of methotrexate and higher dose used, Ida K. Haugen, MD, PhD, senior researcher at Diakonhjemmet Hospital’s Center for Treatment of Rheumatic and Musculoskeletal Diseases in Oslo, Norway, told this news organization.

She noted that the MTX 20 mg/week dosage is similar to what is used in treatment of RA and may be key to better targeting inflammation.

Nicolas Tourrenc

“Furthermore, the study included individuals with hand OA and synovitis by MRI, and thus may have found the right patient population in comparison to prior studies,” Dr. Haugen said.

Dr. Cicuttini agreed, noting that “previous trials [of MTX] did not target the inflammatory phenotype of hand osteoarthritis that would be expected to respond.” In the previous randomized controlled trial of MTX in hand OA, only 29 of a total 1024 joints had synovitis, she explained. “Their inclusion criteria were individuals with severe erosive hand osteoarthritis, suggesting that this later-stage disease is less likely to respond.”

Dr. Cicuttini said that she saw no specific issues in regard to potential use of MTX in the OA population in the clinic. “The data we have, together with the large experience we have with using methotrexate and the fact that treatments for hand OA are not very effective, means that it would be reasonable to offer this to patients with hand OA and inflammation,” she said. “The level of evidence for an effect of methotrexate would need to be discussed with the patient. The discussion around the use of methotrexate would then need to proceed in the same way we discuss the use of methotrexate with patients when used for other inflammatory joint diseases, and the decision is then made with the patient.”

In contrast, Dr. Nelson expressed some concerns regarding the immediate use of MTX for this population. “Many individuals with hand OA have multiple medical comorbidities and polypharmacy, which are important when considering additional treatments, particularly those with modest benefit and potential adverse effects over the long term,” she said. “I do not think this single study provides enough evidence to suggest that all such patients should be treated with methotrexate, and more data, particularly about long-term use and optimal risk stratification, is needed.” 

While MTX use in refractory inflammatory hand OA is not yet recommended in international guidelines, Dr. Haugen believes this study supports use of MTX in this patient population. Given that MRI and ultrasound may not always be available to identify synovitis, Dr. Nelson and Dr. Haugen suggested identifying patients who may benefit through careful history and clinical examination for evidence of swollen joints. In addition, Dr. Cicuttini explained that she would not necessarily use MTX in patients with erosive OA radiographically because it may be a later stage of disease that is less likely to respond.

The authors highlighted potential limitations of the METHODS trial. They initially planned to study whether MTX reduced pain and improved radiographic progression at 2 years, but since they paused the study for 7 months during the COVID-19 pandemic, they amended the trial protocol and focused on pain reduction at 6 months as the primary endpoint instead.

Tender and swollen joint counts were initially going to be included, but this was modified given the use of virtual telemedicine visits during the pandemic. Dr. Cicuttini said that further studies are underway to identify potential subpopulations who may benefit from immunosuppression, and others are needed to determine whether MTX reduces joint damage and slows disease progression in hand OA with inflammation.

Dr. Cicuttini said her research group is interested to see whether women who develop hand OA around the time of menopause (“menopausal OA”) are a group that could benefit. Dr. Haugen noted that she is involved in a study testing MTX in erosive hand OA (the MERINO trial). 

The study was funded by a project grant from the National Health and Medical Research Council of Australia. The authors reported no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the biologic tezepelumab (Tezspire, Amgen) had similar efficacy at reducing exacerbations, improving lung function, and symptom control as observed in patients with asthma alone, according to a new post-hoc analysis of the phase 2b PATHWAY and phase 3 NAVIGATOR clinical trials.

GERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.

The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.

Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.

Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.

TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.

The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).

Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).

There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).

The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.

The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.

Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the biologic tezepelumab (Tezspire, Amgen) had similar efficacy at reducing exacerbations, improving lung function, and symptom control as observed in patients with asthma alone, according to a new post-hoc analysis of the phase 2b PATHWAY and phase 3 NAVIGATOR clinical trials.

GERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.

The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.

Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.

Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.

TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.

The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).

Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).

There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).

The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.

The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.

Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the biologic tezepelumab (Tezspire, Amgen) had similar efficacy at reducing exacerbations, improving lung function, and symptom control as observed in patients with asthma alone, according to a new post-hoc analysis of the phase 2b PATHWAY and phase 3 NAVIGATOR clinical trials.

GERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.

The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.

Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.

Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.

TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.

The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).

Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).

There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).

The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.

The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome back to another GI Common Concerns.

Today, I want to highlight some information about menopause.

Approximately 1.5 million women in the United States per year enter into menopause. Hysterectomy is also one of the most common surgeries for women worldwide, with an estimated 20%-40% undergoing this procedure by the age of 60.

Therefore, whether it’s because of biologic onset with age or surgical induction, menopause is a very common condition, and it’s important that we understand its symptoms and the latest information around it.
 

Impact on GI motility

One of the clearest functional symptoms to be aware of with menopause relates to alterations in hormonal balance. This has an impact on gastrointestinal (GI) motility by increasing abdominal muscle stimulation related to different patterns of secretion and can result in a number of symptomatic changes.

One such change that can occur is food intolerance. It is believed that menopause-associated food intolerance has multiple possible causes and may be related more to alterations to the microbiome, which can be contributed to by diet, activity, sleep cycle, and other factors.

When food intolerances are triggered in the perimenopausal or menopausal patient, it may lead you to recommend the well-established FODMAP diet, which is known to reduce symptoms. But the answer for every patient is not simply placing them on a FODMAP diet and telling them they have irritable bowel syndrome.

Other approaches can be considered for addressing food intolerance in these patients. The data are quite strong that adjunctive use of a dietitian is tremendously helpful in this particular population.

When it comes to menopausal patients, however, we need to consider other changes in their activity or adverse contributors to their mental health, such as stress or anxiety. These all contribute to more of a multifactorial composite in this population, for which irritable bowel syndrome serves as a similar example.

This means that we may need to expand our horizons rather than to focus on solely on antispasmodic or diet-related interventions.

Instead, we can start to consider more of a multidimensional treatment approach consisting of education, relaxation, cognitive-behavioral therapy, and physical activity. Certainly, there are now behavioral interventions using Internet-based digital formats to increase the acceptability and sustainability among patients.

Choosing such a multidisciplinary approach can be quite helpful.
 

The metabolic consequences of altering hormonal balance

Recent data from a rat model study investigated the metabolic impact of changing hormonal balance.

Investigators looked at ovariectomized rats and found that there was a biologic change in the diversity of the general GI biome. There were also noteworthy associations with weight fluctuations and dramatic changes in the spatial memory and cognitive performance characteristics of these rats, which was subsequently improved by supplemental estrogen.

This indicates that we may be able to remediate these effects with the similar use of supplemental hormone replacement treatments.

Another recent study looked at nonalcoholic fatty liver disease, which is very common in the general population and has a > 20% worldwide prevalence in postmenopausal women. Albeit small in numbers, this was a very interesting study.

Investigators looked at the delivery method for menopausal hormone therapy, which was transdermal for 75 patients and oral for 293 patients. Then, they looked at ultrasound definition of nonalcoholic fatty liver disease after 1 year as the endpoint. They found an approximate 7% reduction in the patients who received the transdermal administration compared with a 4% increase in the patients who received it orally.

Again, we have to remember this is a relatively small study, but the results indicate that the route of estrogen administration may be an important consideration in nonalcoholic fatty liver disease.
 

Sleep disturbances: fragmentation, duration, and quality

Sleep is something that’s near and dear to my heart and is the focus of a lot of our research.

Sleep disturbances are really part and parcel of menopause and are observed with hormonal imbalances and temperature intolerances. Disturbances such as sleep fragmentation, shorter sleep duration, and poorer sleep quality have a dramatic effect not only on the biome but also on sensory thresholds.

Therefore, as we start to look at mitigating strategies here, we need to focus on sleep and ask the right questions.

In my own practice, I try not to just ask, “How did you sleep last night?” That’s because sleep can be somewhat amnestic. You may have a cognitive awakening or a noncognitive awakening but still have experienced fragmentation.

As a result, my focus is on next-day function. I ask my patients, “When you get up in the morning, are you refreshed? Do you have the ability to perform daytime activities? Do you experience early fatigue or cognitive changes that occur?”

These questions can provide good insights into the sleep efficiency of the previous night.
 

The effect of the microbiome on osteoporosis

One final topic I found very interesting pertains to the effects of menopause on osteoporosis.

We certainly know that postmenopausal women have a very high prevalence of osteopenia, and that osteoporosis is a progression of that, as well as that increased bone-related disease affects fractures and related morbidity and mortality.

However, there’s accumulating evidence on the osteoporotic effects of biomarker changes in menopause, which shows that the biome regulates the pathophysiologic process of at least a large degree of osteoporosis.

This starts to make sense when you look at the pro-inflammatory factors that increase with changes in biome diversity, in particular tumor necrosis factor alpha (which is something we also see in inflammatory bowel disease), interleukin-1, and increased activated osteoclasts.

Therefore, when it comes to decreasing bone loss among patients who are perimenopausal or postmenopausal, we don’t yet have a clear answer. Hormone therapy, diet, activity, vitamin D supplementation, and other things may positively change the biome. They are worthy topics for patients to bring up with their ob.gyns. or primary care doctors.

Although it may be a little bit outside the scope of gastroenterology, in my opinion there are a number of new findings relating to menopause that we as a field need to be more proactive in addressing.

Ask the right questions when these people come in to you, irrespective of why they’re there. Start to ask about the quality of their sleep. What are their other functional symptoms? What are their other potential osteoporosis-related risks?

We must do a better job about individualizing care. Rather than treating patients as disease states, we must start to do specific patient-focused care.

I hope this gives you some provocative thoughts when you have your next session with a patient in the perimenopausal or menopausal state. There are lots of things that we continue to learn.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Va., and a past president of the American College of Gastroenterology. He serves as an adviser to ISOThrive and Johnson & Johnson.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome back to another GI Common Concerns.

Today, I want to highlight some information about menopause.

Approximately 1.5 million women in the United States per year enter into menopause. Hysterectomy is also one of the most common surgeries for women worldwide, with an estimated 20%-40% undergoing this procedure by the age of 60.

Therefore, whether it’s because of biologic onset with age or surgical induction, menopause is a very common condition, and it’s important that we understand its symptoms and the latest information around it.
 

Impact on GI motility

One of the clearest functional symptoms to be aware of with menopause relates to alterations in hormonal balance. This has an impact on gastrointestinal (GI) motility by increasing abdominal muscle stimulation related to different patterns of secretion and can result in a number of symptomatic changes.

One such change that can occur is food intolerance. It is believed that menopause-associated food intolerance has multiple possible causes and may be related more to alterations to the microbiome, which can be contributed to by diet, activity, sleep cycle, and other factors.

When food intolerances are triggered in the perimenopausal or menopausal patient, it may lead you to recommend the well-established FODMAP diet, which is known to reduce symptoms. But the answer for every patient is not simply placing them on a FODMAP diet and telling them they have irritable bowel syndrome.

Other approaches can be considered for addressing food intolerance in these patients. The data are quite strong that adjunctive use of a dietitian is tremendously helpful in this particular population.

When it comes to menopausal patients, however, we need to consider other changes in their activity or adverse contributors to their mental health, such as stress or anxiety. These all contribute to more of a multifactorial composite in this population, for which irritable bowel syndrome serves as a similar example.

This means that we may need to expand our horizons rather than to focus on solely on antispasmodic or diet-related interventions.

Instead, we can start to consider more of a multidimensional treatment approach consisting of education, relaxation, cognitive-behavioral therapy, and physical activity. Certainly, there are now behavioral interventions using Internet-based digital formats to increase the acceptability and sustainability among patients.

Choosing such a multidisciplinary approach can be quite helpful.
 

The metabolic consequences of altering hormonal balance

Recent data from a rat model study investigated the metabolic impact of changing hormonal balance.

Investigators looked at ovariectomized rats and found that there was a biologic change in the diversity of the general GI biome. There were also noteworthy associations with weight fluctuations and dramatic changes in the spatial memory and cognitive performance characteristics of these rats, which was subsequently improved by supplemental estrogen.

This indicates that we may be able to remediate these effects with the similar use of supplemental hormone replacement treatments.

Another recent study looked at nonalcoholic fatty liver disease, which is very common in the general population and has a > 20% worldwide prevalence in postmenopausal women. Albeit small in numbers, this was a very interesting study.

Investigators looked at the delivery method for menopausal hormone therapy, which was transdermal for 75 patients and oral for 293 patients. Then, they looked at ultrasound definition of nonalcoholic fatty liver disease after 1 year as the endpoint. They found an approximate 7% reduction in the patients who received the transdermal administration compared with a 4% increase in the patients who received it orally.

Again, we have to remember this is a relatively small study, but the results indicate that the route of estrogen administration may be an important consideration in nonalcoholic fatty liver disease.
 

Sleep disturbances: fragmentation, duration, and quality

Sleep is something that’s near and dear to my heart and is the focus of a lot of our research.

Sleep disturbances are really part and parcel of menopause and are observed with hormonal imbalances and temperature intolerances. Disturbances such as sleep fragmentation, shorter sleep duration, and poorer sleep quality have a dramatic effect not only on the biome but also on sensory thresholds.

Therefore, as we start to look at mitigating strategies here, we need to focus on sleep and ask the right questions.

In my own practice, I try not to just ask, “How did you sleep last night?” That’s because sleep can be somewhat amnestic. You may have a cognitive awakening or a noncognitive awakening but still have experienced fragmentation.

As a result, my focus is on next-day function. I ask my patients, “When you get up in the morning, are you refreshed? Do you have the ability to perform daytime activities? Do you experience early fatigue or cognitive changes that occur?”

These questions can provide good insights into the sleep efficiency of the previous night.
 

The effect of the microbiome on osteoporosis

One final topic I found very interesting pertains to the effects of menopause on osteoporosis.

We certainly know that postmenopausal women have a very high prevalence of osteopenia, and that osteoporosis is a progression of that, as well as that increased bone-related disease affects fractures and related morbidity and mortality.

However, there’s accumulating evidence on the osteoporotic effects of biomarker changes in menopause, which shows that the biome regulates the pathophysiologic process of at least a large degree of osteoporosis.

This starts to make sense when you look at the pro-inflammatory factors that increase with changes in biome diversity, in particular tumor necrosis factor alpha (which is something we also see in inflammatory bowel disease), interleukin-1, and increased activated osteoclasts.

Therefore, when it comes to decreasing bone loss among patients who are perimenopausal or postmenopausal, we don’t yet have a clear answer. Hormone therapy, diet, activity, vitamin D supplementation, and other things may positively change the biome. They are worthy topics for patients to bring up with their ob.gyns. or primary care doctors.

Although it may be a little bit outside the scope of gastroenterology, in my opinion there are a number of new findings relating to menopause that we as a field need to be more proactive in addressing.

Ask the right questions when these people come in to you, irrespective of why they’re there. Start to ask about the quality of their sleep. What are their other functional symptoms? What are their other potential osteoporosis-related risks?

We must do a better job about individualizing care. Rather than treating patients as disease states, we must start to do specific patient-focused care.

I hope this gives you some provocative thoughts when you have your next session with a patient in the perimenopausal or menopausal state. There are lots of things that we continue to learn.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Va., and a past president of the American College of Gastroenterology. He serves as an adviser to ISOThrive and Johnson & Johnson.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome back to another GI Common Concerns.

Today, I want to highlight some information about menopause.

Approximately 1.5 million women in the United States per year enter into menopause. Hysterectomy is also one of the most common surgeries for women worldwide, with an estimated 20%-40% undergoing this procedure by the age of 60.

Therefore, whether it’s because of biologic onset with age or surgical induction, menopause is a very common condition, and it’s important that we understand its symptoms and the latest information around it.
 

Impact on GI motility

One of the clearest functional symptoms to be aware of with menopause relates to alterations in hormonal balance. This has an impact on gastrointestinal (GI) motility by increasing abdominal muscle stimulation related to different patterns of secretion and can result in a number of symptomatic changes.

One such change that can occur is food intolerance. It is believed that menopause-associated food intolerance has multiple possible causes and may be related more to alterations to the microbiome, which can be contributed to by diet, activity, sleep cycle, and other factors.

When food intolerances are triggered in the perimenopausal or menopausal patient, it may lead you to recommend the well-established FODMAP diet, which is known to reduce symptoms. But the answer for every patient is not simply placing them on a FODMAP diet and telling them they have irritable bowel syndrome.

Other approaches can be considered for addressing food intolerance in these patients. The data are quite strong that adjunctive use of a dietitian is tremendously helpful in this particular population.

When it comes to menopausal patients, however, we need to consider other changes in their activity or adverse contributors to their mental health, such as stress or anxiety. These all contribute to more of a multifactorial composite in this population, for which irritable bowel syndrome serves as a similar example.

This means that we may need to expand our horizons rather than to focus on solely on antispasmodic or diet-related interventions.

Instead, we can start to consider more of a multidimensional treatment approach consisting of education, relaxation, cognitive-behavioral therapy, and physical activity. Certainly, there are now behavioral interventions using Internet-based digital formats to increase the acceptability and sustainability among patients.

Choosing such a multidisciplinary approach can be quite helpful.
 

The metabolic consequences of altering hormonal balance

Recent data from a rat model study investigated the metabolic impact of changing hormonal balance.

Investigators looked at ovariectomized rats and found that there was a biologic change in the diversity of the general GI biome. There were also noteworthy associations with weight fluctuations and dramatic changes in the spatial memory and cognitive performance characteristics of these rats, which was subsequently improved by supplemental estrogen.

This indicates that we may be able to remediate these effects with the similar use of supplemental hormone replacement treatments.

Another recent study looked at nonalcoholic fatty liver disease, which is very common in the general population and has a > 20% worldwide prevalence in postmenopausal women. Albeit small in numbers, this was a very interesting study.

Investigators looked at the delivery method for menopausal hormone therapy, which was transdermal for 75 patients and oral for 293 patients. Then, they looked at ultrasound definition of nonalcoholic fatty liver disease after 1 year as the endpoint. They found an approximate 7% reduction in the patients who received the transdermal administration compared with a 4% increase in the patients who received it orally.

Again, we have to remember this is a relatively small study, but the results indicate that the route of estrogen administration may be an important consideration in nonalcoholic fatty liver disease.
 

Sleep disturbances: fragmentation, duration, and quality

Sleep is something that’s near and dear to my heart and is the focus of a lot of our research.

Sleep disturbances are really part and parcel of menopause and are observed with hormonal imbalances and temperature intolerances. Disturbances such as sleep fragmentation, shorter sleep duration, and poorer sleep quality have a dramatic effect not only on the biome but also on sensory thresholds.

Therefore, as we start to look at mitigating strategies here, we need to focus on sleep and ask the right questions.

In my own practice, I try not to just ask, “How did you sleep last night?” That’s because sleep can be somewhat amnestic. You may have a cognitive awakening or a noncognitive awakening but still have experienced fragmentation.

As a result, my focus is on next-day function. I ask my patients, “When you get up in the morning, are you refreshed? Do you have the ability to perform daytime activities? Do you experience early fatigue or cognitive changes that occur?”

These questions can provide good insights into the sleep efficiency of the previous night.
 

The effect of the microbiome on osteoporosis

One final topic I found very interesting pertains to the effects of menopause on osteoporosis.

We certainly know that postmenopausal women have a very high prevalence of osteopenia, and that osteoporosis is a progression of that, as well as that increased bone-related disease affects fractures and related morbidity and mortality.

However, there’s accumulating evidence on the osteoporotic effects of biomarker changes in menopause, which shows that the biome regulates the pathophysiologic process of at least a large degree of osteoporosis.

This starts to make sense when you look at the pro-inflammatory factors that increase with changes in biome diversity, in particular tumor necrosis factor alpha (which is something we also see in inflammatory bowel disease), interleukin-1, and increased activated osteoclasts.

Therefore, when it comes to decreasing bone loss among patients who are perimenopausal or postmenopausal, we don’t yet have a clear answer. Hormone therapy, diet, activity, vitamin D supplementation, and other things may positively change the biome. They are worthy topics for patients to bring up with their ob.gyns. or primary care doctors.

Although it may be a little bit outside the scope of gastroenterology, in my opinion there are a number of new findings relating to menopause that we as a field need to be more proactive in addressing.

Ask the right questions when these people come in to you, irrespective of why they’re there. Start to ask about the quality of their sleep. What are their other functional symptoms? What are their other potential osteoporosis-related risks?

We must do a better job about individualizing care. Rather than treating patients as disease states, we must start to do specific patient-focused care.

I hope this gives you some provocative thoughts when you have your next session with a patient in the perimenopausal or menopausal state. There are lots of things that we continue to learn.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Va., and a past president of the American College of Gastroenterology. He serves as an adviser to ISOThrive and Johnson & Johnson.

A version of this article first appeared on Medscape.com.

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

A version of this article first appeared on Medscape.com.

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

A version of this article first appeared on Medscape.com.

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

A version of this article first appeared on Medscape.com.

TOPLINE:

Close adherence to the Portfolio dietary pattern, including foods that have been shown to actively lower cholesterol (for example, plant proteins, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) is associated with a 14% lower risk for total cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, pooled results from three large observational studies suggest.

METHODOLOGY:

• The study included 73,924 women from the Nurses’ Health Study (NHS), 92,346 women from the Nurses’ Health Study II (NHSII), and 43,970 men from the Health Professionals Follow-Up Study (HPFS) without CVD at baseline who were followed biennially on lifestyle, medical history, and other health-related factors.
• From food-frequency questionnaires (FFQs) completed every 4 years, researchers categorized foods into the six components of the Portfolio diet:
• Plant protein such as legumes, beans, tofu, peas, and soymilk
• Nuts and seeds
• Fiber sources such as bran, oats, berries, and eggplant
• Phytosterols
• Monounsaturated fat (MUFA) sources such as olive oil and avocado
• High saturated fat and cholesterol sources such as whole-fat dairy and red and processed meats
• They scored each from 1 (least adherent) to 5 (most adherent), with a higher score indicating higher consumption.
• Researchers examined the association of this Portfolio Diet Score (PDS) with total CVD, CHD, and stroke, in the three cohorts, and associations with plasma levels of lipid and inflammatory biomarkers in a subpopulation of the cohorts.

TAKEAWAY:

• During up to 30 years of follow-up, there were 16,917 incident CVD cases, including 10,666 CHD cases and 6,473 strokes.
• In a pooled analysis of the three cohorts, the fully adjusted hazard ratio for total CVD comparing the highest with the lowest quintile of the PDS was 0.86 (95% confidence interval, 0.81-0.92; P for trend < .001).
• Also comparing extreme quintiles, the pooled HR for CHD was 0.86 (95% CI, 0.80-0.93; P for trend = .0001) and for stroke, it was 0.86 (95% CI, 0.78-0.95; P for trend = .0003).
• A higher PDS was also associated with a more favorable lipid profile and lower levels of inflammation.

IN PRACTICE:

“This study provides additional evidence to support the use of the plant-based Portfolio dietary pattern for reducing the risk of CVD,” which aligns with American Heart Association guidelines promoting consumption of whole grains, fruits and vegetables, plant-based proteins, minimally processed foods, and healthy unsaturated plant oils, the authors conclude.

SOURCE:

The study was conducted by Andrea J. Glenn, PhD, RD, department of nutrition, Harvard T.H. Chan School of Public Health, Boston, and colleagues. It was published online in the journal Circulation.

LIMITATIONS:

As the study was observational, residual confounding can’t be ruled out. Diet was self-reported, which may have resulted in measurement errors. Consumption of some recommended foods was low, even in the top quintiles, so the association with CVD risk may be underestimated. Information on a few key Portfolio diet foods, including barley and okra, was unavailable, potentially leading to underestimation of intake, which may also attenuate the findings.

DISCLOSURES:

The study was supported by the Diabetes Canada End Diabetes 100 Award. The NH and HPFS studies are supported by the National Institutes of Health. Dr. Glenn is supported by a Canadian Institutes of Health Research fellowship; she has received honoraria or travel support from the Soy Nutrition Institute Global, Vinasoy, and the Academy of Nutrition and Dietetics. See original article for disclosures of other authors.

A version of this article first appeared on Medscape.com.

TOPLINE:

Close adherence to the Portfolio dietary pattern, including foods that have been shown to actively lower cholesterol (for example, plant proteins, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) is associated with a 14% lower risk for total cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, pooled results from three large observational studies suggest.

METHODOLOGY:

• The study included 73,924 women from the Nurses’ Health Study (NHS), 92,346 women from the Nurses’ Health Study II (NHSII), and 43,970 men from the Health Professionals Follow-Up Study (HPFS) without CVD at baseline who were followed biennially on lifestyle, medical history, and other health-related factors.
• From food-frequency questionnaires (FFQs) completed every 4 years, researchers categorized foods into the six components of the Portfolio diet:
• Plant protein such as legumes, beans, tofu, peas, and soymilk
• Nuts and seeds
• Fiber sources such as bran, oats, berries, and eggplant
• Phytosterols
• Monounsaturated fat (MUFA) sources such as olive oil and avocado
• High saturated fat and cholesterol sources such as whole-fat dairy and red and processed meats
• They scored each from 1 (least adherent) to 5 (most adherent), with a higher score indicating higher consumption.
• Researchers examined the association of this Portfolio Diet Score (PDS) with total CVD, CHD, and stroke, in the three cohorts, and associations with plasma levels of lipid and inflammatory biomarkers in a subpopulation of the cohorts.

TAKEAWAY:

• During up to 30 years of follow-up, there were 16,917 incident CVD cases, including 10,666 CHD cases and 6,473 strokes.
• In a pooled analysis of the three cohorts, the fully adjusted hazard ratio for total CVD comparing the highest with the lowest quintile of the PDS was 0.86 (95% confidence interval, 0.81-0.92; P for trend < .001).
• Also comparing extreme quintiles, the pooled HR for CHD was 0.86 (95% CI, 0.80-0.93; P for trend = .0001) and for stroke, it was 0.86 (95% CI, 0.78-0.95; P for trend = .0003).
• A higher PDS was also associated with a more favorable lipid profile and lower levels of inflammation.

IN PRACTICE:

“This study provides additional evidence to support the use of the plant-based Portfolio dietary pattern for reducing the risk of CVD,” which aligns with American Heart Association guidelines promoting consumption of whole grains, fruits and vegetables, plant-based proteins, minimally processed foods, and healthy unsaturated plant oils, the authors conclude.

SOURCE:

The study was conducted by Andrea J. Glenn, PhD, RD, department of nutrition, Harvard T.H. Chan School of Public Health, Boston, and colleagues. It was published online in the journal Circulation.

LIMITATIONS:

As the study was observational, residual confounding can’t be ruled out. Diet was self-reported, which may have resulted in measurement errors. Consumption of some recommended foods was low, even in the top quintiles, so the association with CVD risk may be underestimated. Information on a few key Portfolio diet foods, including barley and okra, was unavailable, potentially leading to underestimation of intake, which may also attenuate the findings.

DISCLOSURES:

The study was supported by the Diabetes Canada End Diabetes 100 Award. The NH and HPFS studies are supported by the National Institutes of Health. Dr. Glenn is supported by a Canadian Institutes of Health Research fellowship; she has received honoraria or travel support from the Soy Nutrition Institute Global, Vinasoy, and the Academy of Nutrition and Dietetics. See original article for disclosures of other authors.

A version of this article first appeared on Medscape.com.

TOPLINE:

Close adherence to the Portfolio dietary pattern, including foods that have been shown to actively lower cholesterol (for example, plant proteins, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) is associated with a 14% lower risk for total cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, pooled results from three large observational studies suggest.

METHODOLOGY:

• The study included 73,924 women from the Nurses’ Health Study (NHS), 92,346 women from the Nurses’ Health Study II (NHSII), and 43,970 men from the Health Professionals Follow-Up Study (HPFS) without CVD at baseline who were followed biennially on lifestyle, medical history, and other health-related factors.
• From food-frequency questionnaires (FFQs) completed every 4 years, researchers categorized foods into the six components of the Portfolio diet:
• Plant protein such as legumes, beans, tofu, peas, and soymilk
• Nuts and seeds
• Fiber sources such as bran, oats, berries, and eggplant
• Phytosterols
• Monounsaturated fat (MUFA) sources such as olive oil and avocado
• High saturated fat and cholesterol sources such as whole-fat dairy and red and processed meats
• They scored each from 1 (least adherent) to 5 (most adherent), with a higher score indicating higher consumption.
• Researchers examined the association of this Portfolio Diet Score (PDS) with total CVD, CHD, and stroke, in the three cohorts, and associations with plasma levels of lipid and inflammatory biomarkers in a subpopulation of the cohorts.

TAKEAWAY:

• During up to 30 years of follow-up, there were 16,917 incident CVD cases, including 10,666 CHD cases and 6,473 strokes.
• In a pooled analysis of the three cohorts, the fully adjusted hazard ratio for total CVD comparing the highest with the lowest quintile of the PDS was 0.86 (95% confidence interval, 0.81-0.92; P for trend < .001).
• Also comparing extreme quintiles, the pooled HR for CHD was 0.86 (95% CI, 0.80-0.93; P for trend = .0001) and for stroke, it was 0.86 (95% CI, 0.78-0.95; P for trend = .0003).
• A higher PDS was also associated with a more favorable lipid profile and lower levels of inflammation.

IN PRACTICE:

“This study provides additional evidence to support the use of the plant-based Portfolio dietary pattern for reducing the risk of CVD,” which aligns with American Heart Association guidelines promoting consumption of whole grains, fruits and vegetables, plant-based proteins, minimally processed foods, and healthy unsaturated plant oils, the authors conclude.

SOURCE:

The study was conducted by Andrea J. Glenn, PhD, RD, department of nutrition, Harvard T.H. Chan School of Public Health, Boston, and colleagues. It was published online in the journal Circulation.

LIMITATIONS:

As the study was observational, residual confounding can’t be ruled out. Diet was self-reported, which may have resulted in measurement errors. Consumption of some recommended foods was low, even in the top quintiles, so the association with CVD risk may be underestimated. Information on a few key Portfolio diet foods, including barley and okra, was unavailable, potentially leading to underestimation of intake, which may also attenuate the findings.

DISCLOSURES:

The study was supported by the Diabetes Canada End Diabetes 100 Award. The NH and HPFS studies are supported by the National Institutes of Health. Dr. Glenn is supported by a Canadian Institutes of Health Research fellowship; she has received honoraria or travel support from the Soy Nutrition Institute Global, Vinasoy, and the Academy of Nutrition and Dietetics. See original article for disclosures of other authors.

A version of this article first appeared on Medscape.com.

A new global analysis highlights the substantial burden of premature deaths from cancer around the world – a burden that could potentially be averted through prevention, early detection, and timely treatment.

According to the analysis, in 2020, over half of all cancer deaths – 5.28 million of 9.96 million – occurred prematurely (before age 70), leading to a loss of roughly 183 million life-years from the disease worldwide.

More than two-thirds of premature cancer-related deaths – 3.6 million, or 68% – were potentially preventable through lifestyle changes or early detection efforts, such as cancer screening, dietary changes, or smoking cessation, and about one-third – 1.65 million, or 31% – may have been treatable.

But two biostatisticians not involved in the study who took a deep dive into it urged caution in interpreting the data.

Nilanjan Chatterjee, PhD, Bloomberg Distinguished Professor, Bloomberg School of Public Health at Johns Hopkins University, Baltimore, said the study does a “great job in bringing a lot of diverse data together to show there is very high potential for preventing premature deaths due to cancer worldwide.”

However, for a variety of reasons, Dr. Chatterjee explained, one should not “overinterpret” the high percentage of potentially preventable cancer deaths.

Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong, in Australia, agreed.

“It’s likely many cancer deaths are, in theory, preventable, but the numbers around just how many are necessarily vague,” said Dr. Meyerowitz-Katz. “Also, ‘in theory preventable’ doesn’t necessarily mean that we can actually do it in practice.”
 

Invest in cancer prevention

The study, led by researchers from the World Health Organization’s International Agency for Research on Cancer and partners, provides estimates of premature deaths from 36 cancers across 185 countries.

The findings, published in The Lancet Global Health along with a new Lancet Commission report – “Women, Power, and Cancer” also highlighted the “underrecognized” cancer burden among women around the world.

Cancer ranks in the top three causes of premature mortality among women in almost all countries worldwide, but it is often “deprioritized,” the Lancet Commission report explained.

Of the nearly 5.3 million premature cancer deaths in 2020, 2.9 million occurred in men, and 2.3 million occurred in women, the investigators found. Of the premature deaths among women, 1.5 million could have potentially been avoided through prevention or detection efforts, while the remaining 800,000 might have been averted “if all women everywhere could access optimal cancer care,” the authors said.

Lung cancer was the leading contributor to preventable premature years of life lost in countries that have medium to very high scores on the Human Development Index (HDI), whereas cervical cancer was the leading contributor in low-HDI countries. HDI rankings are based on life expectancy, education, and gross national income.

Among women, as many as 72% of cancer death were premature in low-HDI countries, vs 36% in very high-HDI countries.

Overall, across all four tiers of HDI, colorectal and breast cancers represented the major treatable cancers.

Reducing exposure to four main risk factors – tobacco smoking, alcohol consumption, high body weight, and infections – would go a long way toward reducing potentially preventable premature cancer-related deaths, the authors said.

“Globally, there are marked inequalities between countries in reaching the target of reducing premature mortality from noncommunicable diseases, including cancer,” author Isabelle Soerjomataram, MD, PhD, deputy head of cancer surveillance at the International Agency for Research on Cancer, said in a press release.

“Greater investments in cancer prevention programs can reduce the prevalence of key risk factors for cancer, and increased coverage of vaccination alongside early diagnosis and screening linked to timely treatment can and must address the current cancer inequalities that are seen worldwide,” she added.
 

Caveats and cautionary notes

The authors acknowledge that the study has limitations related to its methodology and underlying assumptions. For instance, some premature cancer deaths that were classified as preventable may have been averted through curative therapy as well.

The findings also represent a snapshot of premature mortality in 2020 but do not necessarily predict progress in cancer control over time.

In Dr. Chatterjee’s view, this is “an excellent descriptive study that gives a good overall picture about the potential for saving a very large fraction of premature death due to cancer by implementing what is now known about primary and secondary interventions, and treatments.”

However, estimates for the effects of various risk factors and interventions are often derived from observational nonrandomized studies, which can have various types of biases, he said.

“Additionally, availability of data, observational or randomized, are often limited from many countries in Africa, Latin America, and Asia, where the cancer burdens are increasing,” Dr. Chatterjee told this news organization. “Therefore, extrapolating evidence generated mostly from North America and European countries to other understudied settings could be problematic due to difference in background in genetics, environment, socioeconomic, and cultural differences.”

Dr. Meyerowitz-Katz said the issue with this “very complex” article is that it includes “models built upon models, all of which include layers of assumptions that aren’t always obvious and may be wrong.”

On top of that, he said, “there are questions over whether the modifiable risk factors are really modifiable. Can we really get rid of 100% of ‘lack of physical exercise’? What would that even look like?”

Overall, Dr. Meyerowitz-Katz noted, “Yes, some proportion of these cancers could be prevented, and that percentage may be large, but the exact 70% estimate is very uncertain in my opinion.”

The study had no commercial funding. The authors, Dr. Chatterjee, and Dr. Meyerowitz-Katz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new global analysis highlights the substantial burden of premature deaths from cancer around the world – a burden that could potentially be averted through prevention, early detection, and timely treatment.

According to the analysis, in 2020, over half of all cancer deaths – 5.28 million of 9.96 million – occurred prematurely (before age 70), leading to a loss of roughly 183 million life-years from the disease worldwide.

More than two-thirds of premature cancer-related deaths – 3.6 million, or 68% – were potentially preventable through lifestyle changes or early detection efforts, such as cancer screening, dietary changes, or smoking cessation, and about one-third – 1.65 million, or 31% – may have been treatable.

But two biostatisticians not involved in the study who took a deep dive into it urged caution in interpreting the data.

Nilanjan Chatterjee, PhD, Bloomberg Distinguished Professor, Bloomberg School of Public Health at Johns Hopkins University, Baltimore, said the study does a “great job in bringing a lot of diverse data together to show there is very high potential for preventing premature deaths due to cancer worldwide.”

However, for a variety of reasons, Dr. Chatterjee explained, one should not “overinterpret” the high percentage of potentially preventable cancer deaths.

Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong, in Australia, agreed.

“It’s likely many cancer deaths are, in theory, preventable, but the numbers around just how many are necessarily vague,” said Dr. Meyerowitz-Katz. “Also, ‘in theory preventable’ doesn’t necessarily mean that we can actually do it in practice.”
 

Invest in cancer prevention

The study, led by researchers from the World Health Organization’s International Agency for Research on Cancer and partners, provides estimates of premature deaths from 36 cancers across 185 countries.

The findings, published in The Lancet Global Health along with a new Lancet Commission report – “Women, Power, and Cancer” also highlighted the “underrecognized” cancer burden among women around the world.

Cancer ranks in the top three causes of premature mortality among women in almost all countries worldwide, but it is often “deprioritized,” the Lancet Commission report explained.

Of the nearly 5.3 million premature cancer deaths in 2020, 2.9 million occurred in men, and 2.3 million occurred in women, the investigators found. Of the premature deaths among women, 1.5 million could have potentially been avoided through prevention or detection efforts, while the remaining 800,000 might have been averted “if all women everywhere could access optimal cancer care,” the authors said.

Lung cancer was the leading contributor to preventable premature years of life lost in countries that have medium to very high scores on the Human Development Index (HDI), whereas cervical cancer was the leading contributor in low-HDI countries. HDI rankings are based on life expectancy, education, and gross national income.

Among women, as many as 72% of cancer death were premature in low-HDI countries, vs 36% in very high-HDI countries.

Overall, across all four tiers of HDI, colorectal and breast cancers represented the major treatable cancers.

Reducing exposure to four main risk factors – tobacco smoking, alcohol consumption, high body weight, and infections – would go a long way toward reducing potentially preventable premature cancer-related deaths, the authors said.

“Globally, there are marked inequalities between countries in reaching the target of reducing premature mortality from noncommunicable diseases, including cancer,” author Isabelle Soerjomataram, MD, PhD, deputy head of cancer surveillance at the International Agency for Research on Cancer, said in a press release.

“Greater investments in cancer prevention programs can reduce the prevalence of key risk factors for cancer, and increased coverage of vaccination alongside early diagnosis and screening linked to timely treatment can and must address the current cancer inequalities that are seen worldwide,” she added.
 

Caveats and cautionary notes

The authors acknowledge that the study has limitations related to its methodology and underlying assumptions. For instance, some premature cancer deaths that were classified as preventable may have been averted through curative therapy as well.

The findings also represent a snapshot of premature mortality in 2020 but do not necessarily predict progress in cancer control over time.

In Dr. Chatterjee’s view, this is “an excellent descriptive study that gives a good overall picture about the potential for saving a very large fraction of premature death due to cancer by implementing what is now known about primary and secondary interventions, and treatments.”

However, estimates for the effects of various risk factors and interventions are often derived from observational nonrandomized studies, which can have various types of biases, he said.

“Additionally, availability of data, observational or randomized, are often limited from many countries in Africa, Latin America, and Asia, where the cancer burdens are increasing,” Dr. Chatterjee told this news organization. “Therefore, extrapolating evidence generated mostly from North America and European countries to other understudied settings could be problematic due to difference in background in genetics, environment, socioeconomic, and cultural differences.”

Dr. Meyerowitz-Katz said the issue with this “very complex” article is that it includes “models built upon models, all of which include layers of assumptions that aren’t always obvious and may be wrong.”

On top of that, he said, “there are questions over whether the modifiable risk factors are really modifiable. Can we really get rid of 100% of ‘lack of physical exercise’? What would that even look like?”

Overall, Dr. Meyerowitz-Katz noted, “Yes, some proportion of these cancers could be prevented, and that percentage may be large, but the exact 70% estimate is very uncertain in my opinion.”

The study had no commercial funding. The authors, Dr. Chatterjee, and Dr. Meyerowitz-Katz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new global analysis highlights the substantial burden of premature deaths from cancer around the world – a burden that could potentially be averted through prevention, early detection, and timely treatment.

According to the analysis, in 2020, over half of all cancer deaths – 5.28 million of 9.96 million – occurred prematurely (before age 70), leading to a loss of roughly 183 million life-years from the disease worldwide.

More than two-thirds of premature cancer-related deaths – 3.6 million, or 68% – were potentially preventable through lifestyle changes or early detection efforts, such as cancer screening, dietary changes, or smoking cessation, and about one-third – 1.65 million, or 31% – may have been treatable.

But two biostatisticians not involved in the study who took a deep dive into it urged caution in interpreting the data.

Nilanjan Chatterjee, PhD, Bloomberg Distinguished Professor, Bloomberg School of Public Health at Johns Hopkins University, Baltimore, said the study does a “great job in bringing a lot of diverse data together to show there is very high potential for preventing premature deaths due to cancer worldwide.”

However, for a variety of reasons, Dr. Chatterjee explained, one should not “overinterpret” the high percentage of potentially preventable cancer deaths.

Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong, in Australia, agreed.

“It’s likely many cancer deaths are, in theory, preventable, but the numbers around just how many are necessarily vague,” said Dr. Meyerowitz-Katz. “Also, ‘in theory preventable’ doesn’t necessarily mean that we can actually do it in practice.”
 

Invest in cancer prevention

The study, led by researchers from the World Health Organization’s International Agency for Research on Cancer and partners, provides estimates of premature deaths from 36 cancers across 185 countries.

The findings, published in The Lancet Global Health along with a new Lancet Commission report – “Women, Power, and Cancer” also highlighted the “underrecognized” cancer burden among women around the world.

Cancer ranks in the top three causes of premature mortality among women in almost all countries worldwide, but it is often “deprioritized,” the Lancet Commission report explained.

Of the nearly 5.3 million premature cancer deaths in 2020, 2.9 million occurred in men, and 2.3 million occurred in women, the investigators found. Of the premature deaths among women, 1.5 million could have potentially been avoided through prevention or detection efforts, while the remaining 800,000 might have been averted “if all women everywhere could access optimal cancer care,” the authors said.

Lung cancer was the leading contributor to preventable premature years of life lost in countries that have medium to very high scores on the Human Development Index (HDI), whereas cervical cancer was the leading contributor in low-HDI countries. HDI rankings are based on life expectancy, education, and gross national income.

Among women, as many as 72% of cancer death were premature in low-HDI countries, vs 36% in very high-HDI countries.

Overall, across all four tiers of HDI, colorectal and breast cancers represented the major treatable cancers.

Reducing exposure to four main risk factors – tobacco smoking, alcohol consumption, high body weight, and infections – would go a long way toward reducing potentially preventable premature cancer-related deaths, the authors said.

“Globally, there are marked inequalities between countries in reaching the target of reducing premature mortality from noncommunicable diseases, including cancer,” author Isabelle Soerjomataram, MD, PhD, deputy head of cancer surveillance at the International Agency for Research on Cancer, said in a press release.

“Greater investments in cancer prevention programs can reduce the prevalence of key risk factors for cancer, and increased coverage of vaccination alongside early diagnosis and screening linked to timely treatment can and must address the current cancer inequalities that are seen worldwide,” she added.
 

Caveats and cautionary notes

The authors acknowledge that the study has limitations related to its methodology and underlying assumptions. For instance, some premature cancer deaths that were classified as preventable may have been averted through curative therapy as well.

The findings also represent a snapshot of premature mortality in 2020 but do not necessarily predict progress in cancer control over time.

In Dr. Chatterjee’s view, this is “an excellent descriptive study that gives a good overall picture about the potential for saving a very large fraction of premature death due to cancer by implementing what is now known about primary and secondary interventions, and treatments.”

However, estimates for the effects of various risk factors and interventions are often derived from observational nonrandomized studies, which can have various types of biases, he said.

“Additionally, availability of data, observational or randomized, are often limited from many countries in Africa, Latin America, and Asia, where the cancer burdens are increasing,” Dr. Chatterjee told this news organization. “Therefore, extrapolating evidence generated mostly from North America and European countries to other understudied settings could be problematic due to difference in background in genetics, environment, socioeconomic, and cultural differences.”

Dr. Meyerowitz-Katz said the issue with this “very complex” article is that it includes “models built upon models, all of which include layers of assumptions that aren’t always obvious and may be wrong.”

On top of that, he said, “there are questions over whether the modifiable risk factors are really modifiable. Can we really get rid of 100% of ‘lack of physical exercise’? What would that even look like?”

Overall, Dr. Meyerowitz-Katz noted, “Yes, some proportion of these cancers could be prevented, and that percentage may be large, but the exact 70% estimate is very uncertain in my opinion.”

The study had no commercial funding. The authors, Dr. Chatterjee, and Dr. Meyerowitz-Katz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.

How accurate are these claims? According to six experts who talked with this news organization, not very.

“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.

“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. But when you look at the scientific data, outside of libido, it’s difficult to recommend testosterone therapy,” she added by phone.

“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”

Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.

“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.

“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.

According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.

Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
 

Postmenopausal testosterone recommended for libido only

“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.

“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”

“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”

“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”

Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.

She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
 

TRT for non-libido issues may sometimes be appropriate

“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”

In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.

“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.

“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”

“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”

All contributors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.

How accurate are these claims? According to six experts who talked with this news organization, not very.

“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.

“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. But when you look at the scientific data, outside of libido, it’s difficult to recommend testosterone therapy,” she added by phone.

“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”

Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.

“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.

“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.

According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.

Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
 

Postmenopausal testosterone recommended for libido only

“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.

“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”

“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”

“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”

Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.

She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
 

TRT for non-libido issues may sometimes be appropriate

“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”

In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.

“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.

“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”

“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”

All contributors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.

How accurate are these claims? According to six experts who talked with this news organization, not very.

“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.

“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. But when you look at the scientific data, outside of libido, it’s difficult to recommend testosterone therapy,” she added by phone.

“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”

Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.

“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.

“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.

According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.

Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
 

Postmenopausal testosterone recommended for libido only

“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.

“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”

“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”

“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”

Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.

She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
 

TRT for non-libido issues may sometimes be appropriate

“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”

In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.

“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.

“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”

“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”

All contributors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.