Obesity

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.

Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.

While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.

To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m²), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m²), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m²), and 11-20 pounds in the obese category (≥ 30 kg/m²).

Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.

The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”

In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”

The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.

In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
 

Implementing these interventions could be challenging

D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”

“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.

Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.

In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”

Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.

While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.

“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.

This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.

The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.

Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.

While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.

To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m²), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m²), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m²), and 11-20 pounds in the obese category (≥ 30 kg/m²).

Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.

The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”

In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”

The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.

In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
 

Implementing these interventions could be challenging

D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”

“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.

Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.

In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”

Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.

While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.

“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.

This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.

The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.

Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.

While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.

To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m²), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m²), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m²), and 11-20 pounds in the obese category (≥ 30 kg/m²).

Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.

The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”

In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”

The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.

In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
 

Implementing these interventions could be challenging

D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”

“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.

Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.

In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”

Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.

While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.

“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.

This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

A peripherally-acting substance that boosts energy expenditure and reduces fat mass has the potential to become an obesity treatment that doesn’t produce cardiovascular or psychiatric side effects, scientists say.

The agent, BIBO3304, is a selective antagonist of the neuropeptide Y1 receptor, which is elevated in the fat tissue of individuals with obesity, resulting in reduced fat accumulation. It was originally developed more than 25 years ago by scientists at Boehringer Ingelheim, who had thought that it would reduce appetite by targeting Y1 receptors in the brain. But when it didn’t cross the blood-brain barrier as an oral drug, the company abandoned it.

Now a series of experiments by Chenxu Yan, of the Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, and colleagues have shown that “BIBO” works directly on Y1 receptors in the periphery to turn fat-storing white fat cells into heat-generating brown-like fat tissue, thereby enhancing energy expenditure.

The data were published online May 11 in Nature Communications.
 

Drug’s lack of effect on the brain turns out to be a positive

“Rather than just having the cells store fat, we change their characteristics so that most of the excess energy gets burned and produces heat instead of being stored as fat. BIBO programs the cell toward a more heat-producing cell rather than a fat-storing cell,” study coauthor Herbert Herzog, PhD, of the Garvan Institute, said in an interview.

Importantly, he said, the lack of effect on the brain that caused the drug’s initial developer to abandon it turns out to be a positive.

“As we looked at fat specifically, and we didn’t want to have any interference with the brain, this seems to work out as a real advantage … It has the desired effect of blocking fat accumulation but has the enormous benefit of not interfering with any brain function. That’s why so many of the obesity drugs that were on the market were taken off, because of the side effects they caused in the brain on mood and cardiovascular control. It’s a completely different ball game.”

The problem now, he said, is that because BIBO is off-patent, no pharmaceutical company is currently willing to invest in its development as a peripherally acting weight-loss drug, despite its potential advantages.

“We’re trying to find some interested party to help us get this to the clinical setting. We’re basic scientists. We need big money. We can do small-scale studies to get proof of principle. Hopefully, if that’s interesting, some bigger company will come along,” said Dr. Herzog.
 

Experiments in mice, human tissues demonstrate principle

In the series of studies, investigators fed genetically inbred mice a high-fat, high-sugar diet while giving BIBO to half of them. Over 8 weeks, the mice given BIBO had 40% less gain in fat mass compared to those overfed without the drug, despite them all eating the same amount.

Using a noninvasive infrared camera to measure skin surface temperature above brown adipose tissue, they found that the temperature was significantly increased with BIBO, independent of the weight of the brown fat.

This suggests that the thermogenesis of the brown fat is significantly contributing to whole-body energy expenditure. “With the drug, the mice have far greater energy expenditure measured by heat production,” Dr. Herzog explained.

In vitro experiments showed that Y1R blockade by BIBO induced “beigeing” of white fat deposits into more heat-producing brown fat. The body temperature increase is about 0.1-0.2ºC. “That’s a tiny amount, but it actually requires quite a lot of energy,” he said.

Experiments using fat tissue taken from obese and normal-weight humans showed the same thermogenesis with BIBO. “It’s such a fundamental process [that] you wouldn’t expect it to differ. The same mechanism is even found in flies and primitive worms,” he noted.
 

Neuropeptide Y receptor blockage: A treatment for many ills?

Previously, Dr. Herzog and colleagues found that blockade of the neuropeptide Y1 receptor also increases bone mass in mice.

“It’s a modest effect, but there’s nothing out there at the moment that really improves bone mass. If you can stop osteoporosis, that’s a benefit on its own,” he said.

Now they hope to study BIBO’s vasodilatory properties as a potential treatment for hypertension, if they get the funding.

Dr. Herzog is hopeful, as obesity, osteoporosis, and hypertension are all chronic conditions. “Having one drug that benefits them all would surely be of interest to clinicians and drug companies,” he observed.  

Dr. Yan and Dr. Herzog have reported no relevant financial relationships.

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

A peripherally-acting substance that boosts energy expenditure and reduces fat mass has the potential to become an obesity treatment that doesn’t produce cardiovascular or psychiatric side effects, scientists say.

The agent, BIBO3304, is a selective antagonist of the neuropeptide Y1 receptor, which is elevated in the fat tissue of individuals with obesity, resulting in reduced fat accumulation. It was originally developed more than 25 years ago by scientists at Boehringer Ingelheim, who had thought that it would reduce appetite by targeting Y1 receptors in the brain. But when it didn’t cross the blood-brain barrier as an oral drug, the company abandoned it.

Now a series of experiments by Chenxu Yan, of the Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, and colleagues have shown that “BIBO” works directly on Y1 receptors in the periphery to turn fat-storing white fat cells into heat-generating brown-like fat tissue, thereby enhancing energy expenditure.

The data were published online May 11 in Nature Communications.
 

Drug’s lack of effect on the brain turns out to be a positive

“Rather than just having the cells store fat, we change their characteristics so that most of the excess energy gets burned and produces heat instead of being stored as fat. BIBO programs the cell toward a more heat-producing cell rather than a fat-storing cell,” study coauthor Herbert Herzog, PhD, of the Garvan Institute, said in an interview.

Importantly, he said, the lack of effect on the brain that caused the drug’s initial developer to abandon it turns out to be a positive.

“As we looked at fat specifically, and we didn’t want to have any interference with the brain, this seems to work out as a real advantage … It has the desired effect of blocking fat accumulation but has the enormous benefit of not interfering with any brain function. That’s why so many of the obesity drugs that were on the market were taken off, because of the side effects they caused in the brain on mood and cardiovascular control. It’s a completely different ball game.”

The problem now, he said, is that because BIBO is off-patent, no pharmaceutical company is currently willing to invest in its development as a peripherally acting weight-loss drug, despite its potential advantages.

“We’re trying to find some interested party to help us get this to the clinical setting. We’re basic scientists. We need big money. We can do small-scale studies to get proof of principle. Hopefully, if that’s interesting, some bigger company will come along,” said Dr. Herzog.
 

Experiments in mice, human tissues demonstrate principle

In the series of studies, investigators fed genetically inbred mice a high-fat, high-sugar diet while giving BIBO to half of them. Over 8 weeks, the mice given BIBO had 40% less gain in fat mass compared to those overfed without the drug, despite them all eating the same amount.

Using a noninvasive infrared camera to measure skin surface temperature above brown adipose tissue, they found that the temperature was significantly increased with BIBO, independent of the weight of the brown fat.

This suggests that the thermogenesis of the brown fat is significantly contributing to whole-body energy expenditure. “With the drug, the mice have far greater energy expenditure measured by heat production,” Dr. Herzog explained.

In vitro experiments showed that Y1R blockade by BIBO induced “beigeing” of white fat deposits into more heat-producing brown fat. The body temperature increase is about 0.1-0.2ºC. “That’s a tiny amount, but it actually requires quite a lot of energy,” he said.

Experiments using fat tissue taken from obese and normal-weight humans showed the same thermogenesis with BIBO. “It’s such a fundamental process [that] you wouldn’t expect it to differ. The same mechanism is even found in flies and primitive worms,” he noted.
 

Neuropeptide Y receptor blockage: A treatment for many ills?

Previously, Dr. Herzog and colleagues found that blockade of the neuropeptide Y1 receptor also increases bone mass in mice.

“It’s a modest effect, but there’s nothing out there at the moment that really improves bone mass. If you can stop osteoporosis, that’s a benefit on its own,” he said.

Now they hope to study BIBO’s vasodilatory properties as a potential treatment for hypertension, if they get the funding.

Dr. Herzog is hopeful, as obesity, osteoporosis, and hypertension are all chronic conditions. “Having one drug that benefits them all would surely be of interest to clinicians and drug companies,” he observed.  

Dr. Yan and Dr. Herzog have reported no relevant financial relationships.

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

A peripherally-acting substance that boosts energy expenditure and reduces fat mass has the potential to become an obesity treatment that doesn’t produce cardiovascular or psychiatric side effects, scientists say.

The agent, BIBO3304, is a selective antagonist of the neuropeptide Y1 receptor, which is elevated in the fat tissue of individuals with obesity, resulting in reduced fat accumulation. It was originally developed more than 25 years ago by scientists at Boehringer Ingelheim, who had thought that it would reduce appetite by targeting Y1 receptors in the brain. But when it didn’t cross the blood-brain barrier as an oral drug, the company abandoned it.

Now a series of experiments by Chenxu Yan, of the Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, and colleagues have shown that “BIBO” works directly on Y1 receptors in the periphery to turn fat-storing white fat cells into heat-generating brown-like fat tissue, thereby enhancing energy expenditure.

The data were published online May 11 in Nature Communications.
 

Drug’s lack of effect on the brain turns out to be a positive

“Rather than just having the cells store fat, we change their characteristics so that most of the excess energy gets burned and produces heat instead of being stored as fat. BIBO programs the cell toward a more heat-producing cell rather than a fat-storing cell,” study coauthor Herbert Herzog, PhD, of the Garvan Institute, said in an interview.

Importantly, he said, the lack of effect on the brain that caused the drug’s initial developer to abandon it turns out to be a positive.

“As we looked at fat specifically, and we didn’t want to have any interference with the brain, this seems to work out as a real advantage … It has the desired effect of blocking fat accumulation but has the enormous benefit of not interfering with any brain function. That’s why so many of the obesity drugs that were on the market were taken off, because of the side effects they caused in the brain on mood and cardiovascular control. It’s a completely different ball game.”

The problem now, he said, is that because BIBO is off-patent, no pharmaceutical company is currently willing to invest in its development as a peripherally acting weight-loss drug, despite its potential advantages.

“We’re trying to find some interested party to help us get this to the clinical setting. We’re basic scientists. We need big money. We can do small-scale studies to get proof of principle. Hopefully, if that’s interesting, some bigger company will come along,” said Dr. Herzog.
 

Experiments in mice, human tissues demonstrate principle

In the series of studies, investigators fed genetically inbred mice a high-fat, high-sugar diet while giving BIBO to half of them. Over 8 weeks, the mice given BIBO had 40% less gain in fat mass compared to those overfed without the drug, despite them all eating the same amount.

Using a noninvasive infrared camera to measure skin surface temperature above brown adipose tissue, they found that the temperature was significantly increased with BIBO, independent of the weight of the brown fat.

This suggests that the thermogenesis of the brown fat is significantly contributing to whole-body energy expenditure. “With the drug, the mice have far greater energy expenditure measured by heat production,” Dr. Herzog explained.

In vitro experiments showed that Y1R blockade by BIBO induced “beigeing” of white fat deposits into more heat-producing brown fat. The body temperature increase is about 0.1-0.2ºC. “That’s a tiny amount, but it actually requires quite a lot of energy,” he said.

Experiments using fat tissue taken from obese and normal-weight humans showed the same thermogenesis with BIBO. “It’s such a fundamental process [that] you wouldn’t expect it to differ. The same mechanism is even found in flies and primitive worms,” he noted.
 

Neuropeptide Y receptor blockage: A treatment for many ills?

Previously, Dr. Herzog and colleagues found that blockade of the neuropeptide Y1 receptor also increases bone mass in mice.

“It’s a modest effect, but there’s nothing out there at the moment that really improves bone mass. If you can stop osteoporosis, that’s a benefit on its own,” he said.

Now they hope to study BIBO’s vasodilatory properties as a potential treatment for hypertension, if they get the funding.

Dr. Herzog is hopeful, as obesity, osteoporosis, and hypertension are all chronic conditions. “Having one drug that benefits them all would surely be of interest to clinicians and drug companies,” he observed.  

Dr. Yan and Dr. Herzog have reported no relevant financial relationships.

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

Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.

To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
 

Diagnosis in adults and adolescence

Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.

For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.

Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
 

The metabolic connection

A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.

Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.

The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
 

A genetic link

Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).

Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
 

Reproductive and gynecologic management

Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.

PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.

The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m². (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.

Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.

Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
 

Metabolic/gynecologic management

Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.

The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).

Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.

No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
 

Conclusion

PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.

Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.

Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.

To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
 

Diagnosis in adults and adolescence

Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.

For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.

Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
 

The metabolic connection

A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.

Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.

The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
 

A genetic link

Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).

Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
 

Reproductive and gynecologic management

Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.

PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.

The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m². (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.

Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.

Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
 

Metabolic/gynecologic management

Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.

The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).

Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.

No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
 

Conclusion

PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.

Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.

Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.

To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
 

Diagnosis in adults and adolescence

Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.

For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.

Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
 

The metabolic connection

A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.

Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.

The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
 

A genetic link

Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).

Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
 

Reproductive and gynecologic management

Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.

PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.

The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m². (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.

Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.

Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
 

Metabolic/gynecologic management

Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.

The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).

Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.

No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
 

Conclusion

PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.

Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

Evidence summary

No difference in overall hypoglycemia risk between glargine and NPH

A 2015 systematic review and meta-analysis of 28 RCTs compared efficacy and safety outcomes for insulin glargine, NPH insulin, premixed insulin preparations, and insulin detemir in 12,669 adults with type 2 ­diabetes (T2D) who were also taking an oral antidiabetic drug (OAD).¹ In the comparison of glargine to NPH, there was no difference in risk for hypoglycemia (5 trials; N not provided; risk ratio [RR] = 0.92; 0.84-1.001).

Symptomatic hypoglycemia (6 RCTs; RR = 0.89; 0.83-0.96) and nocturnal hypoglycemia (6 RCTs; RR = 0.63; 0.51-0.77) occurred significantly less frequently in those treated with glargine and an OAD compared to NPH and an OAD. The risk for severe hypoglycemia was not different between regimens (5 RCTs; RR = 0.76; 0.47-1.23). Weight gain was also similar (6 RCTs; weighted mean difference [WMD] = 0.36 kg [–0.12 to 0.84]). This review was limited by the fact that many of the trials were of moderate quality, the majority were funded by pharmaceutical companies, fasting glucose goals varied between trials, and some trials had a short duration (6 months).

There may be some advantages of glargine over NPH

A 2008 meta-analysis of 12 RCTs (5 of which were not included in the 2015 review) with 4385 patients with T2D compared fasting plasma glucose (FPG), A1C, hypoglycemia, and body weight for patients treated with NPH vs with glargine.² Researchers found a significant difference in patient-reported hypoglycemia (10 trials; N not provided; 59% vs 53%; P < .001), symptomatic hypoglycemia (6 trials; 51% vs 43%; P < .0001), and nocturnal hypoglycemia (8 trials; 33% vs 19%; P < .001), favoring glargine over NPH. However, there was no difference between these 2 groups in confirmed hypoglycemia (2 trials; 10% vs 6.3%; P = .11) or severe hypoglycemia (7 trials; 2.4% vs 1.4%; P = .07). Of note, there was no difference between groups in FPG or A1C and a smaller weight gain in the NPH group (6 trials; WMD = 0.33 kg; 95% CI, –0.61 to –0.06). This review did not assess potential biases in the included trials.

Other results indicate a significant benefit from glargine

A 2014 RCT (published after the systematic review search date) compared hypoglycemia risk between NPH and glargine in 1017 adults ages 30 to 70 years who’d had T2D for at least 1 year.³ Patients were randomized to receive an OAD paired with either once-daily glargine or twice-daily NPH. Insulin doses were titrated over the first 3 years of the study to achieve standard glycemic control (described as FPG < 120 mg/dL; this goal was changed to < 100 mg/dL after the first year).

Over 5 years, once-daily glargine resulted in a significantly lower risk for all symptomatic hypoglycemia (odds ratio [OR] = 0.71; 95% CI, 0.52-0.98) and for any severe event (OR = 0.62; 95% CI, 0.41-0.95) compared to NPH. Using a logistic regression model, the authors predicted that if 25 patients were treated with NPH instead of glargine, 1 additional patient would experience at least 1 severe hypoglycemic event. This trial was funded by a pharmaceutical company.

Hypoglycemia requiring hospital care was similar for basal insulin and NPH

A 2018 retrospective observational study (N = 25,489) analyzed the association between the initiation of basal insulin analogs vs NPH with hypoglycemia-related ED visits or hospital admissions.⁴ Adults older than 19 years with clinically recognized diabetes were identified using electronic medical records; those included in the analysis had newly initiated basal insulin therapy during the prior 12 months. Data was gathered via chart review.

The difference in ED visits or hospital admissions was not different between groups (mean difference = 3.1 events per 100 person-years; 95% CI, –1.5 to 7.7). Among 4428 patients matched by propensity score, there was again no difference for hypoglycemia-related ED visits or hospital admissions with insulin analog use (adjusted hazard ratio = 1.16; 95% CI, 0.71-1.78).

Editor’s takeaway

Meta-analysis of large RCTs shows the glargine insulin adverse effects profile, specifically nonsevere hypoglycemia, to be inconsistently better than NPH. These small differences, plus once-daily dosing, may encourage prescribing of analog basal insulin, but price and the need for more than once-daily dosing remain worthy considerations.

Evidence summary

No difference in overall hypoglycemia risk between glargine and NPH

A 2015 systematic review and meta-analysis of 28 RCTs compared efficacy and safety outcomes for insulin glargine, NPH insulin, premixed insulin preparations, and insulin detemir in 12,669 adults with type 2 ­diabetes (T2D) who were also taking an oral antidiabetic drug (OAD).¹ In the comparison of glargine to NPH, there was no difference in risk for hypoglycemia (5 trials; N not provided; risk ratio [RR] = 0.92; 0.84-1.001).

Symptomatic hypoglycemia (6 RCTs; RR = 0.89; 0.83-0.96) and nocturnal hypoglycemia (6 RCTs; RR = 0.63; 0.51-0.77) occurred significantly less frequently in those treated with glargine and an OAD compared to NPH and an OAD. The risk for severe hypoglycemia was not different between regimens (5 RCTs; RR = 0.76; 0.47-1.23). Weight gain was also similar (6 RCTs; weighted mean difference [WMD] = 0.36 kg [–0.12 to 0.84]). This review was limited by the fact that many of the trials were of moderate quality, the majority were funded by pharmaceutical companies, fasting glucose goals varied between trials, and some trials had a short duration (6 months).

There may be some advantages of glargine over NPH

A 2008 meta-analysis of 12 RCTs (5 of which were not included in the 2015 review) with 4385 patients with T2D compared fasting plasma glucose (FPG), A1C, hypoglycemia, and body weight for patients treated with NPH vs with glargine.² Researchers found a significant difference in patient-reported hypoglycemia (10 trials; N not provided; 59% vs 53%; P < .001), symptomatic hypoglycemia (6 trials; 51% vs 43%; P < .0001), and nocturnal hypoglycemia (8 trials; 33% vs 19%; P < .001), favoring glargine over NPH. However, there was no difference between these 2 groups in confirmed hypoglycemia (2 trials; 10% vs 6.3%; P = .11) or severe hypoglycemia (7 trials; 2.4% vs 1.4%; P = .07). Of note, there was no difference between groups in FPG or A1C and a smaller weight gain in the NPH group (6 trials; WMD = 0.33 kg; 95% CI, –0.61 to –0.06). This review did not assess potential biases in the included trials.

Other results indicate a significant benefit from glargine

A 2014 RCT (published after the systematic review search date) compared hypoglycemia risk between NPH and glargine in 1017 adults ages 30 to 70 years who’d had T2D for at least 1 year.³ Patients were randomized to receive an OAD paired with either once-daily glargine or twice-daily NPH. Insulin doses were titrated over the first 3 years of the study to achieve standard glycemic control (described as FPG < 120 mg/dL; this goal was changed to < 100 mg/dL after the first year).

Over 5 years, once-daily glargine resulted in a significantly lower risk for all symptomatic hypoglycemia (odds ratio [OR] = 0.71; 95% CI, 0.52-0.98) and for any severe event (OR = 0.62; 95% CI, 0.41-0.95) compared to NPH. Using a logistic regression model, the authors predicted that if 25 patients were treated with NPH instead of glargine, 1 additional patient would experience at least 1 severe hypoglycemic event. This trial was funded by a pharmaceutical company.

Hypoglycemia requiring hospital care was similar for basal insulin and NPH

A 2018 retrospective observational study (N = 25,489) analyzed the association between the initiation of basal insulin analogs vs NPH with hypoglycemia-related ED visits or hospital admissions.⁴ Adults older than 19 years with clinically recognized diabetes were identified using electronic medical records; those included in the analysis had newly initiated basal insulin therapy during the prior 12 months. Data was gathered via chart review.

The difference in ED visits or hospital admissions was not different between groups (mean difference = 3.1 events per 100 person-years; 95% CI, –1.5 to 7.7). Among 4428 patients matched by propensity score, there was again no difference for hypoglycemia-related ED visits or hospital admissions with insulin analog use (adjusted hazard ratio = 1.16; 95% CI, 0.71-1.78).

Editor’s takeaway

Meta-analysis of large RCTs shows the glargine insulin adverse effects profile, specifically nonsevere hypoglycemia, to be inconsistently better than NPH. These small differences, plus once-daily dosing, may encourage prescribing of analog basal insulin, but price and the need for more than once-daily dosing remain worthy considerations.

Evidence summary

No difference in overall hypoglycemia risk between glargine and NPH

A 2015 systematic review and meta-analysis of 28 RCTs compared efficacy and safety outcomes for insulin glargine, NPH insulin, premixed insulin preparations, and insulin detemir in 12,669 adults with type 2 ­diabetes (T2D) who were also taking an oral antidiabetic drug (OAD).¹ In the comparison of glargine to NPH, there was no difference in risk for hypoglycemia (5 trials; N not provided; risk ratio [RR] = 0.92; 0.84-1.001).

Symptomatic hypoglycemia (6 RCTs; RR = 0.89; 0.83-0.96) and nocturnal hypoglycemia (6 RCTs; RR = 0.63; 0.51-0.77) occurred significantly less frequently in those treated with glargine and an OAD compared to NPH and an OAD. The risk for severe hypoglycemia was not different between regimens (5 RCTs; RR = 0.76; 0.47-1.23). Weight gain was also similar (6 RCTs; weighted mean difference [WMD] = 0.36 kg [–0.12 to 0.84]). This review was limited by the fact that many of the trials were of moderate quality, the majority were funded by pharmaceutical companies, fasting glucose goals varied between trials, and some trials had a short duration (6 months).

There may be some advantages of glargine over NPH

A 2008 meta-analysis of 12 RCTs (5 of which were not included in the 2015 review) with 4385 patients with T2D compared fasting plasma glucose (FPG), A1C, hypoglycemia, and body weight for patients treated with NPH vs with glargine.² Researchers found a significant difference in patient-reported hypoglycemia (10 trials; N not provided; 59% vs 53%; P < .001), symptomatic hypoglycemia (6 trials; 51% vs 43%; P < .0001), and nocturnal hypoglycemia (8 trials; 33% vs 19%; P < .001), favoring glargine over NPH. However, there was no difference between these 2 groups in confirmed hypoglycemia (2 trials; 10% vs 6.3%; P = .11) or severe hypoglycemia (7 trials; 2.4% vs 1.4%; P = .07). Of note, there was no difference between groups in FPG or A1C and a smaller weight gain in the NPH group (6 trials; WMD = 0.33 kg; 95% CI, –0.61 to –0.06). This review did not assess potential biases in the included trials.

Other results indicate a significant benefit from glargine

A 2014 RCT (published after the systematic review search date) compared hypoglycemia risk between NPH and glargine in 1017 adults ages 30 to 70 years who’d had T2D for at least 1 year.³ Patients were randomized to receive an OAD paired with either once-daily glargine or twice-daily NPH. Insulin doses were titrated over the first 3 years of the study to achieve standard glycemic control (described as FPG < 120 mg/dL; this goal was changed to < 100 mg/dL after the first year).

Over 5 years, once-daily glargine resulted in a significantly lower risk for all symptomatic hypoglycemia (odds ratio [OR] = 0.71; 95% CI, 0.52-0.98) and for any severe event (OR = 0.62; 95% CI, 0.41-0.95) compared to NPH. Using a logistic regression model, the authors predicted that if 25 patients were treated with NPH instead of glargine, 1 additional patient would experience at least 1 severe hypoglycemic event. This trial was funded by a pharmaceutical company.

Hypoglycemia requiring hospital care was similar for basal insulin and NPH

A 2018 retrospective observational study (N = 25,489) analyzed the association between the initiation of basal insulin analogs vs NPH with hypoglycemia-related ED visits or hospital admissions.⁴ Adults older than 19 years with clinically recognized diabetes were identified using electronic medical records; those included in the analysis had newly initiated basal insulin therapy during the prior 12 months. Data was gathered via chart review.

The difference in ED visits or hospital admissions was not different between groups (mean difference = 3.1 events per 100 person-years; 95% CI, –1.5 to 7.7). Among 4428 patients matched by propensity score, there was again no difference for hypoglycemia-related ED visits or hospital admissions with insulin analog use (adjusted hazard ratio = 1.16; 95% CI, 0.71-1.78).

Editor’s takeaway

Meta-analysis of large RCTs shows the glargine insulin adverse effects profile, specifically nonsevere hypoglycemia, to be inconsistently better than NPH. These small differences, plus once-daily dosing, may encourage prescribing of analog basal insulin, but price and the need for more than once-daily dosing remain worthy considerations.