Marlene Busko

Time-restricted eating – where caloric intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories – has “generated impressive [animal] data in preventing or reversing metabolic diseases associated with obesity,” and “more rigorous human studies are needed,” conclude the authors of a new review.

“Time-restricted eating is an easy-to-follow and effective dietary strategy that requires less mental math than counting calories,” said senior author Satchidananda Panda, PhD, of the Panda Lab at the Salk Institute for Biological Studies, La Jolla, Calif.

It “can improve sleep and a person’s quality of life as well as reduce the risk of obesity, diabetes, and heart disease,” he noted in a press release from the Endocrine Society.

“People who are trying to lose weight and live a healthier lifestyle should pay more attention to when they eat as well as what they eat,” Dr. Panda advised.

Moreover, “eating at random times breaks the synchrony of our internal program [circadian clock] and make us prone to diseases,” so it is important to eat at consistent times.

Furthermore, time-restricted eating, a type of intermittent fasting, “is a lifestyle that anyone can adopt,” he noted, which “can help eliminate health disparities and lets everyone live a healthy and fulfilling life.”

The article, by Emily N. Manoogian, PhD, a postdoctoral fellow in the same lab, and colleagues was published online Sept. 22 in Endocrine Reviews.

The authors suggest that health care providers should encourage high-risk patients (such as those with obesity) to monitor their eating and sleeping times and make easy-to-implement behavior changes, such as decreasing after-dinner snacking and going to bed at the same time each day.
 

Animal experiments, early studies in humans

In animal experiments, time-restricted feeding without reducing caloric intake prevented or attenuated the severity of metabolic diseases including obesity, glucose intolerance, hepatic steatosis, dyslipidemia, and age-related decline in cardiac function, Dr. Manoogian and colleagues report.

In pilot human studies, time-restricted eating with or without explicit calorie reduction was associated with reductions in body weight, glucose intolerance, hypertension, and dyslipidemia.

Most studies did not restrict calories or provide dietary recommendations, yet participants commonly reduced their caloric intake by 7%-22%.
 

39 published clinical trials, many upcoming ones

The authors identified 39 clinical trials of time-restricted eating, which were mostly published in the past 2 years, with the earliest one published in 2013.

Most studies were short and small (4-12 weeks, 10-20 participants) and were of people with obesity, healthy adults, and athletes. Most of the trials had an 8- to 10-hour daily “eating window.”

Body weight decreased in 24 of 39 studies, and “importantly,” time-restricted eating was feasible and safe in all studies, the authors note.

“Larger randomized controlled trials are needed as many of the studies to date are smaller pre-post or crossover trials,” Dr. Manoogian and colleagues summarize. “Yet, the replication of findings, even in diverse patient populations, speaks to the potential impact of [time-restricted eating] as a health intervention.”

The many ongoing international clinical trials of time-restricted eating that are listed on clinicaltrials.gov should improve our understanding of time-restricted eating, they add.

Some of the larger trials are in participants with prediabetes (344 participants, NCT03504683), diabetes (144 participants, NCT04155619), metabolic syndrome (118 participants, NCT04057339), and firefighters on 24-hour shifts (150 participants, NCT03533023). There are also smaller pilot studies in participants with cancer (NCT04243512) and polycystic ovary syndrome (NCT03792282).
 

Be consistent; do not eat within 3 hours of bedtime

In the meantime, the review authors offer several tips:

• Because high melatonin levels (late at night or early morning) can inhibit proper response to food, choose a time to eat that starts at least an hour after waking and stops at least 3 hours before bedtime. If you sleep 8 hours, that leaves 12 hours for the time-restricted eating window.
• Try to eat within the same time window each day.
• Some research suggests eating earlier in the eating phase is better than eating later.

The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Cancer Institute, the Larry l. Hillblom Foundation, the Wu Tsai Human Performance Alliance, the U.S. Department of Defense, and the Federal Emergency Management Agency. Dr. Panda has reported receiving royalties from his book, The Circadian Code. The other authors have reported no relevant financial disclosures.

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

Time-restricted eating – where caloric intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories – has “generated impressive [animal] data in preventing or reversing metabolic diseases associated with obesity,” and “more rigorous human studies are needed,” conclude the authors of a new review.

“Time-restricted eating is an easy-to-follow and effective dietary strategy that requires less mental math than counting calories,” said senior author Satchidananda Panda, PhD, of the Panda Lab at the Salk Institute for Biological Studies, La Jolla, Calif.

It “can improve sleep and a person’s quality of life as well as reduce the risk of obesity, diabetes, and heart disease,” he noted in a press release from the Endocrine Society.

“People who are trying to lose weight and live a healthier lifestyle should pay more attention to when they eat as well as what they eat,” Dr. Panda advised.

Moreover, “eating at random times breaks the synchrony of our internal program [circadian clock] and make us prone to diseases,” so it is important to eat at consistent times.

Furthermore, time-restricted eating, a type of intermittent fasting, “is a lifestyle that anyone can adopt,” he noted, which “can help eliminate health disparities and lets everyone live a healthy and fulfilling life.”

The article, by Emily N. Manoogian, PhD, a postdoctoral fellow in the same lab, and colleagues was published online Sept. 22 in Endocrine Reviews.

The authors suggest that health care providers should encourage high-risk patients (such as those with obesity) to monitor their eating and sleeping times and make easy-to-implement behavior changes, such as decreasing after-dinner snacking and going to bed at the same time each day.
 

Animal experiments, early studies in humans

In animal experiments, time-restricted feeding without reducing caloric intake prevented or attenuated the severity of metabolic diseases including obesity, glucose intolerance, hepatic steatosis, dyslipidemia, and age-related decline in cardiac function, Dr. Manoogian and colleagues report.

In pilot human studies, time-restricted eating with or without explicit calorie reduction was associated with reductions in body weight, glucose intolerance, hypertension, and dyslipidemia.

Most studies did not restrict calories or provide dietary recommendations, yet participants commonly reduced their caloric intake by 7%-22%.
 

39 published clinical trials, many upcoming ones

The authors identified 39 clinical trials of time-restricted eating, which were mostly published in the past 2 years, with the earliest one published in 2013.

Most studies were short and small (4-12 weeks, 10-20 participants) and were of people with obesity, healthy adults, and athletes. Most of the trials had an 8- to 10-hour daily “eating window.”

Body weight decreased in 24 of 39 studies, and “importantly,” time-restricted eating was feasible and safe in all studies, the authors note.

“Larger randomized controlled trials are needed as many of the studies to date are smaller pre-post or crossover trials,” Dr. Manoogian and colleagues summarize. “Yet, the replication of findings, even in diverse patient populations, speaks to the potential impact of [time-restricted eating] as a health intervention.”

The many ongoing international clinical trials of time-restricted eating that are listed on clinicaltrials.gov should improve our understanding of time-restricted eating, they add.

Some of the larger trials are in participants with prediabetes (344 participants, NCT03504683), diabetes (144 participants, NCT04155619), metabolic syndrome (118 participants, NCT04057339), and firefighters on 24-hour shifts (150 participants, NCT03533023). There are also smaller pilot studies in participants with cancer (NCT04243512) and polycystic ovary syndrome (NCT03792282).
 

Be consistent; do not eat within 3 hours of bedtime

In the meantime, the review authors offer several tips:

• Because high melatonin levels (late at night or early morning) can inhibit proper response to food, choose a time to eat that starts at least an hour after waking and stops at least 3 hours before bedtime. If you sleep 8 hours, that leaves 12 hours for the time-restricted eating window.
• Try to eat within the same time window each day.
• Some research suggests eating earlier in the eating phase is better than eating later.

The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Cancer Institute, the Larry l. Hillblom Foundation, the Wu Tsai Human Performance Alliance, the U.S. Department of Defense, and the Federal Emergency Management Agency. Dr. Panda has reported receiving royalties from his book, The Circadian Code. The other authors have reported no relevant financial disclosures.

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

Time-restricted eating – where caloric intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories – has “generated impressive [animal] data in preventing or reversing metabolic diseases associated with obesity,” and “more rigorous human studies are needed,” conclude the authors of a new review.

“Time-restricted eating is an easy-to-follow and effective dietary strategy that requires less mental math than counting calories,” said senior author Satchidananda Panda, PhD, of the Panda Lab at the Salk Institute for Biological Studies, La Jolla, Calif.

It “can improve sleep and a person’s quality of life as well as reduce the risk of obesity, diabetes, and heart disease,” he noted in a press release from the Endocrine Society.

“People who are trying to lose weight and live a healthier lifestyle should pay more attention to when they eat as well as what they eat,” Dr. Panda advised.

Moreover, “eating at random times breaks the synchrony of our internal program [circadian clock] and make us prone to diseases,” so it is important to eat at consistent times.

Furthermore, time-restricted eating, a type of intermittent fasting, “is a lifestyle that anyone can adopt,” he noted, which “can help eliminate health disparities and lets everyone live a healthy and fulfilling life.”

The article, by Emily N. Manoogian, PhD, a postdoctoral fellow in the same lab, and colleagues was published online Sept. 22 in Endocrine Reviews.

The authors suggest that health care providers should encourage high-risk patients (such as those with obesity) to monitor their eating and sleeping times and make easy-to-implement behavior changes, such as decreasing after-dinner snacking and going to bed at the same time each day.
 

Animal experiments, early studies in humans

In animal experiments, time-restricted feeding without reducing caloric intake prevented or attenuated the severity of metabolic diseases including obesity, glucose intolerance, hepatic steatosis, dyslipidemia, and age-related decline in cardiac function, Dr. Manoogian and colleagues report.

In pilot human studies, time-restricted eating with or without explicit calorie reduction was associated with reductions in body weight, glucose intolerance, hypertension, and dyslipidemia.

Most studies did not restrict calories or provide dietary recommendations, yet participants commonly reduced their caloric intake by 7%-22%.
 

39 published clinical trials, many upcoming ones

The authors identified 39 clinical trials of time-restricted eating, which were mostly published in the past 2 years, with the earliest one published in 2013.

Most studies were short and small (4-12 weeks, 10-20 participants) and were of people with obesity, healthy adults, and athletes. Most of the trials had an 8- to 10-hour daily “eating window.”

Body weight decreased in 24 of 39 studies, and “importantly,” time-restricted eating was feasible and safe in all studies, the authors note.

“Larger randomized controlled trials are needed as many of the studies to date are smaller pre-post or crossover trials,” Dr. Manoogian and colleagues summarize. “Yet, the replication of findings, even in diverse patient populations, speaks to the potential impact of [time-restricted eating] as a health intervention.”

The many ongoing international clinical trials of time-restricted eating that are listed on clinicaltrials.gov should improve our understanding of time-restricted eating, they add.

Some of the larger trials are in participants with prediabetes (344 participants, NCT03504683), diabetes (144 participants, NCT04155619), metabolic syndrome (118 participants, NCT04057339), and firefighters on 24-hour shifts (150 participants, NCT03533023). There are also smaller pilot studies in participants with cancer (NCT04243512) and polycystic ovary syndrome (NCT03792282).
 

Be consistent; do not eat within 3 hours of bedtime

In the meantime, the review authors offer several tips:

• Because high melatonin levels (late at night or early morning) can inhibit proper response to food, choose a time to eat that starts at least an hour after waking and stops at least 3 hours before bedtime. If you sleep 8 hours, that leaves 12 hours for the time-restricted eating window.
• Try to eat within the same time window each day.
• Some research suggests eating earlier in the eating phase is better than eating later.

The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Cancer Institute, the Larry l. Hillblom Foundation, the Wu Tsai Human Performance Alliance, the U.S. Department of Defense, and the Federal Emergency Management Agency. Dr. Panda has reported receiving royalties from his book, The Circadian Code. The other authors have reported no relevant financial disclosures.

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

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.

Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension. 

verbaska_studio/thinkstockphotos

The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.

“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization. 

“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”

However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.

“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”

According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”

“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.

He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.

The statement is aimed at both primary care providers and specialists.
 

Diet, physical activity help, but weight regain common

Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.

To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.  

The effect of intermittent fasting on blood pressure control is not clear, the statement noted.

It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.

“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
 

Other options to address obesity, hypertension

Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.

The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).

The long-term effects of antiobesity medications on blood pressure are mixed.

However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.

Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.

In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.

Unanswered questions, future research directions

In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.

Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”

They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:

• What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
• Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
• What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?

“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.

Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension. 

verbaska_studio/thinkstockphotos

The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.

“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization. 

“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”

However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.

“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”

According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”

“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.

He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.

The statement is aimed at both primary care providers and specialists.
 

Diet, physical activity help, but weight regain common

Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.

To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.  

The effect of intermittent fasting on blood pressure control is not clear, the statement noted.

It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.

“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
 

Other options to address obesity, hypertension

Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.

The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).

The long-term effects of antiobesity medications on blood pressure are mixed.

However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.

Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.

In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.

Unanswered questions, future research directions

In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.

Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”

They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:

• What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
• Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
• What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?

“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.

Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension. 

verbaska_studio/thinkstockphotos

The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.

“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization. 

“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”

However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.

“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”

According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”

“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.

He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.

The statement is aimed at both primary care providers and specialists.
 

Diet, physical activity help, but weight regain common

Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.

To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.  

The effect of intermittent fasting on blood pressure control is not clear, the statement noted.

It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.

“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
 

Other options to address obesity, hypertension

Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.

The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).

The long-term effects of antiobesity medications on blood pressure are mixed.

However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.

Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.

In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.

Unanswered questions, future research directions

In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.

Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”

They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:

• What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
• Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
• What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?

“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.

Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

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

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

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

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

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

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

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

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

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

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

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

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

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

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

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

The U.S. Food and Drug Administration has approved lonapegsomatropin (Skytrofa, Ascendis Pharma), the first weekly subcutaneous injectable growth hormone for children with growth hormone deficiency (GHD).

The approval was based on the findings of the 52-week, phase 3 heiGHt trial in 161 treatment-naive pediatric patients with GHD, which was recently published in the Journal of Clinical Endocrinology & Metabolism.

Since 1987, the standard treatment for pediatric GHD, in which the pituitary gland does not produce enough growth hormone, has been a daily injection of somatropin (recombinant DNA human growth hormone).

“I am excited to be able to reduce the number of shots for some children requiring growth hormone therapy” with this new dosing option, Bradley S. Miller, MD, PhD, who was not involved with the research, said in an email.

“I am hopeful that a once-weekly growth hormone option will improve adherence to growth hormone therapy, leading to improved growth and metabolic outcomes,” added Dr. Miller, professor and division director, pediatric endocrinology, at the University of Minnesota Masonic Children’s Hospital, Minneapolis.

Lonapegsomatropin is approved for the treatment of pediatric patients age 1 year and older who weigh at least 11.5 kg (25.4 pounds) and have short stature due to inadequate secretion of endogenous growth hormone, according to the prescribing information.

The drug molecule consists of a prodrug of somatropin that is inactive when it is bound to a proprietary TransCon (transient conjugation) inert carrier using a TransCon linker. The three-part molecule breaks apart after injection, exposing the active somatropin that is slowly released.

The heiGHt trial demonstrated noninferiority of lonapegsomatropin to somatropin daily injections. Children who received weekly lonapegsomatropin grew 11.2 cm (4.4 inches) per year, whereas those who received an equivalent total dose of somatropin daily injections grew 10.3 cm (4.1 inches) per year.

Safety outcomes – the ratio of bone age to chronologic age, adverse events, tolerability, and immunogenicity – were similar in both groups.
 

Anticipated uptake, other drugs on horizon

Lonapegsomatropin is expected to be available shortly in the United States along with a suite of patient support programs, according to a company press release.

“The impact of the approval of lonapegsomatropin on clinical practice will depend upon its availability, coverage by insurance providers, and patient/provider comfort with using a new product,” Dr. Miller said.

For most pediatric endocrinologists, daily growth hormone has been available their entire careers, so he expects it will take some time for the pediatric endocrinology community to be comfortable prescribing long-acting growth hormone (LAGH), the name given to the once-weekly products.

In the meantime, an FDA decision on another once-weekly growth hormone, somatrogon (OPKO Health/Pfizer) for children with GHD is expected very soon, in October 2021.

And a weekly injectable somapacitan (Sogroya, Novo Nordisk), approved by the FDA in September last year for adults with GHD, is also being studied in children, with estimated study completion in 2024.

“Approval of more LAGH molecules, approval of LAGH for more indications, real-world evidence of safety, efficacy, and improved adherence, and personal experience with LAGH will all likely lead to increased LAGH use over time,” Dr. Miller speculated.

“Over the long-term, I expect insurance providers will cover LAGH products,” he surmised, “but that the price will be similar to or slightly higher than daily growth hormone.”

However, if improved adherence with LAGH is demonstrated and associated with better treatment outcomes, the price of LAGH will likely increase and use of daily growth hormone will decrease, he predicts.

Paul Saenger, MD, who was not involved with the research, believes “all three long-acting growth hormone drugs will eventually be approved for GHD in children.”

“The price will be the same or may be at most 10% more than daily growth hormone replacement,” Dr. Saenger, a pediatric endocrinologist and clinical assistant professor at NYU Long Island School of Medicine, New York, said in an email.

However, daily subcutaneous injections will still be warranted for certain children with GHD, Dr. Miller noted.

“Daily growth hormone may be better than LAGH for a small number of children who have severe GHD associated with hypoglycemia,” he said. “The low levels of growth hormone at the end of the weekly interval of LAGH may allow hypoglycemia to occur in this population.”
 

Phase 3 trial in 161 treatment-naive children with GHD

The heiGHt trial randomized treatment-naive prepubertal children with GHD 2:1 to weekly lonapegsomatropin or daily somatropin (Genotropin, Pfizer) at 73 sites in 15 countries.

The children were a mean age of 8.5 years (range, 3.2-13.1 years), 82% were boys, and 94% were White.

There were no reported serious adverse events or discontinuations related to lonapegsomatropin.

The most common adverse reactions in ≥5% of these pediatric patients were viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).

Both study groups reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.

Trial limitations include the fact the study was not blinded (as patients received a weekly or daily injection) and drug doses were fixed at 0.24 mg human growth hormone/kg/week, although in real-world clinical practice, doses may be titrated.

Lonapegsomatropin has been studied in more than 300 children with GHD in the phase 3 program in the heiGHt trial (treatment-naive patients), fliGHt trial (treatment-experienced patients), and enliGHten trial (an ongoing long-term extension trial that includes some patients who have been taking lonapegsomatropin for more than 4 years).

The study was sponsored by Ascendis Pharma. Some of the phase 3 study authors are company employees.

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

Having a “high normal” serum sodium level in midlife, which reflects less than optimal fluid intake, is associated with an increased risk for left ventricular hypertrophy – a heart failure (HF) precursor – and for HF itself, in older age, a new study suggests.

Georges Lievre / Fotolia.com

Compared with middle-aged adults in the Atherosclerosis Risk in Communities (ARIC) study with normal serum sodium, those with levels of 142-146 mmol/L were more likely to have left ventricular hypertrophy or HF when they were in their 70s and 80s, independent of other risk factors.  

Natalia Dmitrieva, PhD, a research scientist at the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md., presented the study findings in an e-poster on Aug. 27 at the European Society of Cardiology (ESC) Congress 2021.

“Our study suggests that maintaining good hydration can prevent or at least slow down the changes within the heart that lead to heart failure,” she said in a statement from the ESC.

It “suggests that all adults should aim for eight to ten glasses of liquid [daily] and keep salt intake low,” Dr. Dmitrieva said in an interview.

However, people should not rely completely on thirst, she cautioned, especially in middle age, when thirst sensation starts to deteriorate. And too much fluid intake can be harmful and even dangerous.

Normal serum sodium is usually defined as 135-146 mmol/L, Dr. Dmitrieva explained, and this study involved only patients in ARIC with sodium levels in this range, to try to exclude patients with genetic or water-salt balance diseases.

The findings suggest that a serum sodium level of 142-146 mmol/L, which would not be flagged as abnormal by a test lab, “can be used by clinicians as a warning sign” for a patient’s increased risk for HF, she noted.

Clinicians should explain this risk to patients and advise them to drink at least 2 L per day. However, people should not try to reduce their sodium levels by drinking more than 2 to 3 L per day, she cautioned, which can be harmful and even deadly, and they should consult their doctors.
 

Watch hydration

“An important finding of this study is that sodium values considered ‘normal’ may also be deleterious,” Jacob Joseph, MD, director, heart failure program, VA Boston Healthcare System, who was not involved with this study, said in an interview.

“These results are similar to studies we have conducted in heart failure with preserved ejection fraction,” noted Dr. Joseph, associate professor of medicine at Harvard Medical School, Boston.

Their studies showed a U-shaped relationship between serum sodium values and adverse outcomes, “indicating an ‘optimal’ range of serum sodium value that was narrower than the accepted normal laboratory value range,” he noted.

The study by Dmitrieva et al. was observational and the findings would need to be verified in a randomized controlled trial, Dr. Joseph pointed out; however, the research “supports the idea that even a high normal sodium level may indicate risk of future heart failure.

“Hence, patients should pay attention to hydration,” he continued, and “clinicians should not assume that a sodium level of 142 mmol/L is appropriate and should ensure that patients are paying attention to hydration.

“In today’s busy and stress-filled lifestyle, it is easy to forget about adequate fluid intake,” Dr. Joseph added. 
 

More than 15,000 adults followed for 25 Years

To investigate the relationship between serum sodium, hydration, and future heart failure, Dr. Dmitrieva and colleagues analyzed data from 15,792 adults in ARIC who were 44-66 years of age at study entry, with serum sodium levels from 135 to 146 mmol/L.

The participants were evaluated over five visits until they reached 70-90 years.

They were divided into four groups based on their average serum sodium concentrations at study visits one and two (conducted in the first 3 years): 135 -139.5 mmol/L, 140-141.5 mmol/L, 142-143.5 mmol/L, and 144-146 mmol/L.

The researchers determined the percentage of people in each group who developed HF and left ventricular hypertrophy at visit five (25 years after study enrollment).

Patients with higher serum sodium levels had a significantly higher risk for HF and left ventricular hypertrophy, after adjustment for other risk factors, including age, blood pressure, kidney function, blood cholesterol, blood glucose, body mass index, sex, and smoking status.

Every 1 mmol/L increase in serum sodium concentration in midlife was associated with 1.20 and 1.11 increased odds of developing left ventricular hypertrophy and HF, respectively, 25 years later.

“More studies are needed to find out what proportion of people with serum sodium 142 mmol/L and higher have this [serum sodium] level because they do not drink enough and will be able to reduce it by making sure they consistently drink 2 to 2.5 L per day,” said Dr. Dmitrieva.

“It is likely that for some people, other factors that are related to genetics or diseases affecting water-salt balance could be causing their increased serum sodium levels,” she speculated.

The study was funded by the Intramural Program of the National Heart, Lung, and Blood Institute. The authors and Dr. Joseph have no relevant financial disclosures.

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

Having a “high normal” serum sodium level in midlife, which reflects less than optimal fluid intake, is associated with an increased risk for left ventricular hypertrophy – a heart failure (HF) precursor – and for HF itself, in older age, a new study suggests.

Georges Lievre / Fotolia.com

Compared with middle-aged adults in the Atherosclerosis Risk in Communities (ARIC) study with normal serum sodium, those with levels of 142-146 mmol/L were more likely to have left ventricular hypertrophy or HF when they were in their 70s and 80s, independent of other risk factors.  

Natalia Dmitrieva, PhD, a research scientist at the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md., presented the study findings in an e-poster on Aug. 27 at the European Society of Cardiology (ESC) Congress 2021.

“Our study suggests that maintaining good hydration can prevent or at least slow down the changes within the heart that lead to heart failure,” she said in a statement from the ESC.

It “suggests that all adults should aim for eight to ten glasses of liquid [daily] and keep salt intake low,” Dr. Dmitrieva said in an interview.

However, people should not rely completely on thirst, she cautioned, especially in middle age, when thirst sensation starts to deteriorate. And too much fluid intake can be harmful and even dangerous.

Normal serum sodium is usually defined as 135-146 mmol/L, Dr. Dmitrieva explained, and this study involved only patients in ARIC with sodium levels in this range, to try to exclude patients with genetic or water-salt balance diseases.

The findings suggest that a serum sodium level of 142-146 mmol/L, which would not be flagged as abnormal by a test lab, “can be used by clinicians as a warning sign” for a patient’s increased risk for HF, she noted.

Clinicians should explain this risk to patients and advise them to drink at least 2 L per day. However, people should not try to reduce their sodium levels by drinking more than 2 to 3 L per day, she cautioned, which can be harmful and even deadly, and they should consult their doctors.
 

Watch hydration

“An important finding of this study is that sodium values considered ‘normal’ may also be deleterious,” Jacob Joseph, MD, director, heart failure program, VA Boston Healthcare System, who was not involved with this study, said in an interview.

“These results are similar to studies we have conducted in heart failure with preserved ejection fraction,” noted Dr. Joseph, associate professor of medicine at Harvard Medical School, Boston.

Their studies showed a U-shaped relationship between serum sodium values and adverse outcomes, “indicating an ‘optimal’ range of serum sodium value that was narrower than the accepted normal laboratory value range,” he noted.

The study by Dmitrieva et al. was observational and the findings would need to be verified in a randomized controlled trial, Dr. Joseph pointed out; however, the research “supports the idea that even a high normal sodium level may indicate risk of future heart failure.

“Hence, patients should pay attention to hydration,” he continued, and “clinicians should not assume that a sodium level of 142 mmol/L is appropriate and should ensure that patients are paying attention to hydration.

“In today’s busy and stress-filled lifestyle, it is easy to forget about adequate fluid intake,” Dr. Joseph added. 
 

More than 15,000 adults followed for 25 Years

To investigate the relationship between serum sodium, hydration, and future heart failure, Dr. Dmitrieva and colleagues analyzed data from 15,792 adults in ARIC who were 44-66 years of age at study entry, with serum sodium levels from 135 to 146 mmol/L.

The participants were evaluated over five visits until they reached 70-90 years.

They were divided into four groups based on their average serum sodium concentrations at study visits one and two (conducted in the first 3 years): 135 -139.5 mmol/L, 140-141.5 mmol/L, 142-143.5 mmol/L, and 144-146 mmol/L.

The researchers determined the percentage of people in each group who developed HF and left ventricular hypertrophy at visit five (25 years after study enrollment).

Patients with higher serum sodium levels had a significantly higher risk for HF and left ventricular hypertrophy, after adjustment for other risk factors, including age, blood pressure, kidney function, blood cholesterol, blood glucose, body mass index, sex, and smoking status.

Every 1 mmol/L increase in serum sodium concentration in midlife was associated with 1.20 and 1.11 increased odds of developing left ventricular hypertrophy and HF, respectively, 25 years later.

“More studies are needed to find out what proportion of people with serum sodium 142 mmol/L and higher have this [serum sodium] level because they do not drink enough and will be able to reduce it by making sure they consistently drink 2 to 2.5 L per day,” said Dr. Dmitrieva.

“It is likely that for some people, other factors that are related to genetics or diseases affecting water-salt balance could be causing their increased serum sodium levels,” she speculated.

The study was funded by the Intramural Program of the National Heart, Lung, and Blood Institute. The authors and Dr. Joseph have no relevant financial disclosures.

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

Having a “high normal” serum sodium level in midlife, which reflects less than optimal fluid intake, is associated with an increased risk for left ventricular hypertrophy – a heart failure (HF) precursor – and for HF itself, in older age, a new study suggests.

Georges Lievre / Fotolia.com

Compared with middle-aged adults in the Atherosclerosis Risk in Communities (ARIC) study with normal serum sodium, those with levels of 142-146 mmol/L were more likely to have left ventricular hypertrophy or HF when they were in their 70s and 80s, independent of other risk factors.  

Natalia Dmitrieva, PhD, a research scientist at the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md., presented the study findings in an e-poster on Aug. 27 at the European Society of Cardiology (ESC) Congress 2021.

“Our study suggests that maintaining good hydration can prevent or at least slow down the changes within the heart that lead to heart failure,” she said in a statement from the ESC.

It “suggests that all adults should aim for eight to ten glasses of liquid [daily] and keep salt intake low,” Dr. Dmitrieva said in an interview.

However, people should not rely completely on thirst, she cautioned, especially in middle age, when thirst sensation starts to deteriorate. And too much fluid intake can be harmful and even dangerous.

Normal serum sodium is usually defined as 135-146 mmol/L, Dr. Dmitrieva explained, and this study involved only patients in ARIC with sodium levels in this range, to try to exclude patients with genetic or water-salt balance diseases.

The findings suggest that a serum sodium level of 142-146 mmol/L, which would not be flagged as abnormal by a test lab, “can be used by clinicians as a warning sign” for a patient’s increased risk for HF, she noted.

Clinicians should explain this risk to patients and advise them to drink at least 2 L per day. However, people should not try to reduce their sodium levels by drinking more than 2 to 3 L per day, she cautioned, which can be harmful and even deadly, and they should consult their doctors.
 

Watch hydration

“An important finding of this study is that sodium values considered ‘normal’ may also be deleterious,” Jacob Joseph, MD, director, heart failure program, VA Boston Healthcare System, who was not involved with this study, said in an interview.

“These results are similar to studies we have conducted in heart failure with preserved ejection fraction,” noted Dr. Joseph, associate professor of medicine at Harvard Medical School, Boston.

Their studies showed a U-shaped relationship between serum sodium values and adverse outcomes, “indicating an ‘optimal’ range of serum sodium value that was narrower than the accepted normal laboratory value range,” he noted.

The study by Dmitrieva et al. was observational and the findings would need to be verified in a randomized controlled trial, Dr. Joseph pointed out; however, the research “supports the idea that even a high normal sodium level may indicate risk of future heart failure.

“Hence, patients should pay attention to hydration,” he continued, and “clinicians should not assume that a sodium level of 142 mmol/L is appropriate and should ensure that patients are paying attention to hydration.

“In today’s busy and stress-filled lifestyle, it is easy to forget about adequate fluid intake,” Dr. Joseph added. 
 

More than 15,000 adults followed for 25 Years

To investigate the relationship between serum sodium, hydration, and future heart failure, Dr. Dmitrieva and colleagues analyzed data from 15,792 adults in ARIC who were 44-66 years of age at study entry, with serum sodium levels from 135 to 146 mmol/L.

The participants were evaluated over five visits until they reached 70-90 years.

They were divided into four groups based on their average serum sodium concentrations at study visits one and two (conducted in the first 3 years): 135 -139.5 mmol/L, 140-141.5 mmol/L, 142-143.5 mmol/L, and 144-146 mmol/L.

The researchers determined the percentage of people in each group who developed HF and left ventricular hypertrophy at visit five (25 years after study enrollment).

Patients with higher serum sodium levels had a significantly higher risk for HF and left ventricular hypertrophy, after adjustment for other risk factors, including age, blood pressure, kidney function, blood cholesterol, blood glucose, body mass index, sex, and smoking status.

Every 1 mmol/L increase in serum sodium concentration in midlife was associated with 1.20 and 1.11 increased odds of developing left ventricular hypertrophy and HF, respectively, 25 years later.

“More studies are needed to find out what proportion of people with serum sodium 142 mmol/L and higher have this [serum sodium] level because they do not drink enough and will be able to reduce it by making sure they consistently drink 2 to 2.5 L per day,” said Dr. Dmitrieva.

“It is likely that for some people, other factors that are related to genetics or diseases affecting water-salt balance could be causing their increased serum sodium levels,” she speculated.

The study was funded by the Intramural Program of the National Heart, Lung, and Blood Institute. The authors and Dr. Joseph have no relevant financial disclosures.

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Among middle-aged people without heart disease, drinking up to three cups of coffee per day was linked with a lower risk for stroke or death over the next decade, along with better heart structure and function, in a large, observational study.

S_Bachstroem/Getty Images

Specifically, light-to-moderate coffee drinking, defined as 0.5 to 3 cups per day, was associated with a 21% lower risk for stroke, a 17% lower risk for death from cardiovascular disease (CVD), and a 12% lower risk for death from all causes, as well as more favorable cardiac MRI findings, compared with nondrinkers (< 0.5 cup per day) during a median 11-year follow-up.

Heavy coffee drinkers, defined as those consuming more than three cups per day, on the other hand, likewise had more favorable cardiac MRI findings, but with similar (not lower) rates of stroke and CVD or all-cause mortality compared with nondrinkers.

Judit Simon, MD, presented these findings, from close to 500,000 participants in the UK Biobank study, at a press conference before an e-poster session at the virtual annual congress of the European Society of Cardiology.

“To our knowledge, this is the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” Dr. Simon, a PhD student at the Heart and Vascular Centre, Semmelweis University, Budapest, Hungary, said in an ESC press release.

The results “suggest that regular coffee consumption is safe, as even high daily intake was not associated with adverse cardiovascular outcomes and all-cause mortality after a follow-up of 10 to 15 years,” she said.

The imaging analysis showed that “compared with participants who did not drink coffee regularly, daily consumers had healthier sized and better functioning hearts,” Dr. Simon continued, “consistent with reversing the detrimental effects of aging on the heart.”

“The observed benefits might be partly explained by positive alterations in cardiac structure and function,” she speculated, adding that further studies are needed to explain the underlying mechanisms.

Instant coffee most popular

In this population, the coffee drinkers mostly drank instant coffee (55%), followed by filtered/ground (23%), decaffeinated (20%), or other types of coffee (2%), Dr. Simon said in an interview.

Risk for myocardial infarction (MI) or heart failure did not significantly differ for different categories of coffee intake, she added. The researchers did not study the effect of coffee consumption on atrial fibrillation (AF), she noted. 

Study limitations, Dr. Simon acknowledged, include that it was observational, so it cannot show causation, and that coffee consumption was self-reported in a questionnaire.

Invited to comment, Alice H. Lichtenstein, DSc, who was not involved with the research, said, “Consistent with prior data, this new study indicates there is no adverse effect of coffee consumption on cardiovascular health and there may be a benefit.”

However, “because of the nature of the data, it would not be recommended that an individual starting drinking coffee to improve cardiovascular health,” added Dr. Lichtenstein, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston.

But if people already drink coffee, “it is fine to continue, assuming that the coffee drinks are not high in added sugar and cream,” she said in an interview.
 

Coffee intake, CVD outcomes, and heart structure

To study the relationship between coffee intake and incident MI, stroke, and death, as well as heart structure, the researchers examined data from the UK Biobank, which recruited 500,000 people aged 40-69 years in 2006-2010 from across the United Kingdom.

They identified 468,629 participants with no signs of heart disease at recruitment and an average age of 56 years, of whom 56% were women.

The participants were divided into three groups based on usual coffee intake: none (22% of participants), light-to-moderate (58%), and high (20%).

Median tea intake was three cups per day overall, four cups per day in noncoffee drinkers, three cups per day in light-to-moderate coffee drinkers, and one cup per day in high coffee drinkers.

Compared to not drinking coffee, light-to-moderate coffee consumption was associated with lower risks for all-cause death (hazard ratio [HR], 0.88; P < .001), CVD death (HR, 0.83; P = .006), and stroke (HR, 0.79; P = .037), over a median follow-up of 11 years, after adjustment for sex; weight; height; smoking status; physical activity; high blood pressure; diabetes; cholesterol level; socioeconomic status; and usual intake of alcohol, meat, tea, fruit, and vegetables.  

In the 30,650 participants who had cardiac MRI data, the study found that compared with not drinking coffee, both light-to-moderate and high coffee consumption were associated with significantly increased left and right ventricular end-systolic and end-diastolic volumes, and with greater left ventricular mass (all P < .001).

These differences were small but significant, Dr. Simon stressed, because this was a cohort of healthy patients who did not have CVD (heart failure, MI, stroke, AF) at baseline, although some had hypertension or diabetes.

Press conference chairperson, Steen Dalby Kristensen, MD, professor and cardiologist, Aarhus University Hospital, Denmark, a coffee lover himself, wanted to know if an amount such as two, three, or four cups of coffee was optimal to see these heart benefits, and whether there were differences in benefits seen with drinking different types of coffee.

The analysis did not identify an optimal coffee intake, Dr. Simon said. Compared with not drinking coffee, she continued, drinking instant coffee was associated with a lower risk for all-cause mortality, but not CVD mortality or stroke.

Drinking filtered coffee was associated with lower risks for all three outcomes, but there was no significant difference in risk for MI. Drinking decaffeinated coffee was associated with a lower risk for all-cause and CVD mortality.

“Decaffeinated coffee contains a small amount of caffeine,” Dr. Simon pointed out. “Something other than caffeine might have this protective impact,” she suggested.

The researchers and Dr. Lichtenstein declared having no relevant financial disclosures.  

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

Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.  

Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.

The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.

This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.

The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”

Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.

The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.

“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.

This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.

ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
 

Aim for 3.5 hours a week

A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.

And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.

ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.

The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.

Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.

The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.

“We certainly cautioned against far exceeding this level,” he added.

Patients in the usual care group received exercise advice but no active intervention.

All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.

The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.

At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).

This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.

Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.

“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.

Cost was not a barrier since the sessions with an exercise physiologist were free.

Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.

Most patients liked the variety of physical activity options.

The researchers plan to determine any gender differences in ACTIVE-AF.

Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.

The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.  

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

Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.  

Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.

The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.

This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.

The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”

Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.

The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.

“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.

This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.

ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
 

Aim for 3.5 hours a week

A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.

And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.

ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.

The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.

Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.

The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.

“We certainly cautioned against far exceeding this level,” he added.

Patients in the usual care group received exercise advice but no active intervention.

All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.

The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.

At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).

This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.

Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.

“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.

Cost was not a barrier since the sessions with an exercise physiologist were free.

Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.

Most patients liked the variety of physical activity options.

The researchers plan to determine any gender differences in ACTIVE-AF.

Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.

The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.  

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

Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.  

Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.

The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.

This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.

The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”

Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.

The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.

“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.

This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.

ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
 

Aim for 3.5 hours a week

A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.

And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.

ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.

The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.

Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.

The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.

“We certainly cautioned against far exceeding this level,” he added.

Patients in the usual care group received exercise advice but no active intervention.

All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.

The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.

At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).

This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.

Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.

“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.

Cost was not a barrier since the sessions with an exercise physiologist were free.

Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.

Most patients liked the variety of physical activity options.

The researchers plan to determine any gender differences in ACTIVE-AF.

Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.

The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.  

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