Obesity Week 2016

NEW ORLEANS – Severely obese patients who undergo Roux-en-Y gastric bypass surgery are subsequently at sharply increased risk for new-onset alcohol use disorder as well as for treatment of substance use disorder, compared with others who opt for a laparoscopic adjustable banding procedure for weight loss, Wendy C. King, PhD, reported at a meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

This new finding from the NIH-sponsored Longitudinal Assessment of Bariatric Surgery–2 study (LABS-2) has important implications for clinical practice.

“Patients considering bariatric surgery really should be informed of this surgery-specific risk. Also, alcohol use disorder screening, evaluation, intervention, and referral should be incorporated as part of regular presurgical and definitely also postoperative care. And because many patients don’t return to their surgeon for long-term postoperative care, it’s important that clinicians in primary care and other specialties are really looking for this problem in long-term follow-up,” said Dr. King, an epidemiologist at the University of Pittsburgh.

LABS-2 is an observational cohort study of patients undergoing first-time bariatric surgery at 10 participating U.S. hospitals, all of which have academic ties and are rated as bariatric surgery centers of excellence. Dr. King presented 5-year postsurgical follow-up data on 1,481 patients who had Roux-en-Y gastric bypass (RYGB) and 522 with laparoscopic adjustable gastric banding (LAGB). Independently of their regular clinical care visits, participants were assessed annually for their alcohol use and its consequences using the Alcohol Use Disorders Identification Test (AUDIT), use of illicit drugs within the past year, and whether they had undergone hospitalization or counseling for alcohol or drug problems. A score of 8 or more points on the AUDIT was deemed an indication of symptoms of alcohol use disorder (AUD),

After eliminating from consideration the 7% of patients with AUD symptoms at baseline, the cumulative incidence of AUD symptoms in the RYGB patients climbed from zero to 20.8% by the end of the fifth year of follow-up. Treatment for a substance use disorder occurred in 3.5% of RYGB patients during their first 5 years postsurgery, and 7.5% admitted to illicit drug use, said Dr. King.

In contrast, the cumulative incidence of AUD symptoms through 5 years in the LAGB patients was only 11.3%, less than 1% underwent treatment for a substance use disorder, and 4.9% said they had used illicit drugs.

But LABS-2 is not a randomized trial. Patients chose their bariatric procedure together with their surgeon. For this reason, it was important to perform a multivariate regression analysis adjusted for sociodemographics, social support, psychiatric treatment, lifetime history of psychiatric hospitalization, baseline smoking and alcohol consumption, and other potential confounders.

After performing this statistical exercise, the RYGB patients remained at an adjusted 2.05-fold increased risk of AUD symptoms, compared with the LAGB patients, as well as at 3.83-fold greater risk of treatment for a substance use disorder.

The 1.6-fold increased rate of illicit drug use in the RYGB group didn’t achieve statistical significance. Moreover, on closer examination, most of this illicit drug use involved marijuana, and its use in the post–bariatric surgery population appeared to mirror secular trends in the United States as a whole, according to Dr. King.

With her coinvestigators, Dr. King searched for presurgical risk factors that might predict postsurgical substance misuse. Perhaps the most interesting finding concerned the factors that weren’t predictive, including education, unemployment, score on the Beck Depression Inventory, SF-36 mental component summary score, race, marital status, binge eating, loss of control eating, and body mass index.

Lower social support prior to surgery was associated with increased risk for developing AUD symptoms during the first 5 years after bariatric surgery. Younger age and smoking at baseline were associated with increased rates of postoperative AUD symptoms, substance use disorder treatment, and illicit drug use. A history of psychiatric treatment was associated with increased rates of substance use disorder treatment and illicit drug use.

“That could indicate greater medical surveillance among those patients or greater willingness to get treatment, since they’d had treatment for other psychiatric issues in the past,” Dr. King speculated.

She described the study’s strengths as its large size, geographically diverse patient population, unusually high retention over time, compared with other bariatric surgery studies, and the use of AUDIT, a validated and reliable screening tool. The major limitations are that investigators didn’t inquire about illicit use of opioids and benzodiazepines, and recipients of gastric sleeve procedures weren’t included in the long-term follow-up analysis because LABS-2 began before the gastric sleeve boomed in popularity.

John M. Morton, MD, a former president of the American Society for Metabolic and Bariatric Surgery, predicted that a similar study that included gastric sleeve patients would show them to have the same unremarkable postoperative rates of substance misuse as the LAGB group.

“I want to emphasize that this increased incidence of alcohol problems in the Roux-en-Y gastric bypass patients is maybe not so much a psychological issue as it is a physiologic one,” added Dr. Morton, chief of bariatric and minimally invasive surgery at Stanford (Calif.) School of Medicine.

Dr. King agreed. “Just in the last year and a half there have been some great pharmacokinetic studies showing that the Roux-en-Y affects alcohol metabolism and absorption, as well as studies in rodent models that suggest alcohol produces increased neurobiologic reward,” she noted.

The LABS-2 study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. King reported having no relevant financial interests.
 

[email protected]
 

NEW ORLEANS – Severely obese patients who undergo Roux-en-Y gastric bypass surgery are subsequently at sharply increased risk for new-onset alcohol use disorder as well as for treatment of substance use disorder, compared with others who opt for a laparoscopic adjustable banding procedure for weight loss, Wendy C. King, PhD, reported at a meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

This new finding from the NIH-sponsored Longitudinal Assessment of Bariatric Surgery–2 study (LABS-2) has important implications for clinical practice.

“Patients considering bariatric surgery really should be informed of this surgery-specific risk. Also, alcohol use disorder screening, evaluation, intervention, and referral should be incorporated as part of regular presurgical and definitely also postoperative care. And because many patients don’t return to their surgeon for long-term postoperative care, it’s important that clinicians in primary care and other specialties are really looking for this problem in long-term follow-up,” said Dr. King, an epidemiologist at the University of Pittsburgh.

LABS-2 is an observational cohort study of patients undergoing first-time bariatric surgery at 10 participating U.S. hospitals, all of which have academic ties and are rated as bariatric surgery centers of excellence. Dr. King presented 5-year postsurgical follow-up data on 1,481 patients who had Roux-en-Y gastric bypass (RYGB) and 522 with laparoscopic adjustable gastric banding (LAGB). Independently of their regular clinical care visits, participants were assessed annually for their alcohol use and its consequences using the Alcohol Use Disorders Identification Test (AUDIT), use of illicit drugs within the past year, and whether they had undergone hospitalization or counseling for alcohol or drug problems. A score of 8 or more points on the AUDIT was deemed an indication of symptoms of alcohol use disorder (AUD),

After eliminating from consideration the 7% of patients with AUD symptoms at baseline, the cumulative incidence of AUD symptoms in the RYGB patients climbed from zero to 20.8% by the end of the fifth year of follow-up. Treatment for a substance use disorder occurred in 3.5% of RYGB patients during their first 5 years postsurgery, and 7.5% admitted to illicit drug use, said Dr. King.

In contrast, the cumulative incidence of AUD symptoms through 5 years in the LAGB patients was only 11.3%, less than 1% underwent treatment for a substance use disorder, and 4.9% said they had used illicit drugs.

But LABS-2 is not a randomized trial. Patients chose their bariatric procedure together with their surgeon. For this reason, it was important to perform a multivariate regression analysis adjusted for sociodemographics, social support, psychiatric treatment, lifetime history of psychiatric hospitalization, baseline smoking and alcohol consumption, and other potential confounders.

After performing this statistical exercise, the RYGB patients remained at an adjusted 2.05-fold increased risk of AUD symptoms, compared with the LAGB patients, as well as at 3.83-fold greater risk of treatment for a substance use disorder.

The 1.6-fold increased rate of illicit drug use in the RYGB group didn’t achieve statistical significance. Moreover, on closer examination, most of this illicit drug use involved marijuana, and its use in the post–bariatric surgery population appeared to mirror secular trends in the United States as a whole, according to Dr. King.

With her coinvestigators, Dr. King searched for presurgical risk factors that might predict postsurgical substance misuse. Perhaps the most interesting finding concerned the factors that weren’t predictive, including education, unemployment, score on the Beck Depression Inventory, SF-36 mental component summary score, race, marital status, binge eating, loss of control eating, and body mass index.

Lower social support prior to surgery was associated with increased risk for developing AUD symptoms during the first 5 years after bariatric surgery. Younger age and smoking at baseline were associated with increased rates of postoperative AUD symptoms, substance use disorder treatment, and illicit drug use. A history of psychiatric treatment was associated with increased rates of substance use disorder treatment and illicit drug use.

“That could indicate greater medical surveillance among those patients or greater willingness to get treatment, since they’d had treatment for other psychiatric issues in the past,” Dr. King speculated.

She described the study’s strengths as its large size, geographically diverse patient population, unusually high retention over time, compared with other bariatric surgery studies, and the use of AUDIT, a validated and reliable screening tool. The major limitations are that investigators didn’t inquire about illicit use of opioids and benzodiazepines, and recipients of gastric sleeve procedures weren’t included in the long-term follow-up analysis because LABS-2 began before the gastric sleeve boomed in popularity.

John M. Morton, MD, a former president of the American Society for Metabolic and Bariatric Surgery, predicted that a similar study that included gastric sleeve patients would show them to have the same unremarkable postoperative rates of substance misuse as the LAGB group.

“I want to emphasize that this increased incidence of alcohol problems in the Roux-en-Y gastric bypass patients is maybe not so much a psychological issue as it is a physiologic one,” added Dr. Morton, chief of bariatric and minimally invasive surgery at Stanford (Calif.) School of Medicine.

Dr. King agreed. “Just in the last year and a half there have been some great pharmacokinetic studies showing that the Roux-en-Y affects alcohol metabolism and absorption, as well as studies in rodent models that suggest alcohol produces increased neurobiologic reward,” she noted.

The LABS-2 study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. King reported having no relevant financial interests.
 

[email protected]
 

NEW ORLEANS – Severely obese patients who undergo Roux-en-Y gastric bypass surgery are subsequently at sharply increased risk for new-onset alcohol use disorder as well as for treatment of substance use disorder, compared with others who opt for a laparoscopic adjustable banding procedure for weight loss, Wendy C. King, PhD, reported at a meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

This new finding from the NIH-sponsored Longitudinal Assessment of Bariatric Surgery–2 study (LABS-2) has important implications for clinical practice.

“Patients considering bariatric surgery really should be informed of this surgery-specific risk. Also, alcohol use disorder screening, evaluation, intervention, and referral should be incorporated as part of regular presurgical and definitely also postoperative care. And because many patients don’t return to their surgeon for long-term postoperative care, it’s important that clinicians in primary care and other specialties are really looking for this problem in long-term follow-up,” said Dr. King, an epidemiologist at the University of Pittsburgh.

LABS-2 is an observational cohort study of patients undergoing first-time bariatric surgery at 10 participating U.S. hospitals, all of which have academic ties and are rated as bariatric surgery centers of excellence. Dr. King presented 5-year postsurgical follow-up data on 1,481 patients who had Roux-en-Y gastric bypass (RYGB) and 522 with laparoscopic adjustable gastric banding (LAGB). Independently of their regular clinical care visits, participants were assessed annually for their alcohol use and its consequences using the Alcohol Use Disorders Identification Test (AUDIT), use of illicit drugs within the past year, and whether they had undergone hospitalization or counseling for alcohol or drug problems. A score of 8 or more points on the AUDIT was deemed an indication of symptoms of alcohol use disorder (AUD),

After eliminating from consideration the 7% of patients with AUD symptoms at baseline, the cumulative incidence of AUD symptoms in the RYGB patients climbed from zero to 20.8% by the end of the fifth year of follow-up. Treatment for a substance use disorder occurred in 3.5% of RYGB patients during their first 5 years postsurgery, and 7.5% admitted to illicit drug use, said Dr. King.

In contrast, the cumulative incidence of AUD symptoms through 5 years in the LAGB patients was only 11.3%, less than 1% underwent treatment for a substance use disorder, and 4.9% said they had used illicit drugs.

But LABS-2 is not a randomized trial. Patients chose their bariatric procedure together with their surgeon. For this reason, it was important to perform a multivariate regression analysis adjusted for sociodemographics, social support, psychiatric treatment, lifetime history of psychiatric hospitalization, baseline smoking and alcohol consumption, and other potential confounders.

After performing this statistical exercise, the RYGB patients remained at an adjusted 2.05-fold increased risk of AUD symptoms, compared with the LAGB patients, as well as at 3.83-fold greater risk of treatment for a substance use disorder.

The 1.6-fold increased rate of illicit drug use in the RYGB group didn’t achieve statistical significance. Moreover, on closer examination, most of this illicit drug use involved marijuana, and its use in the post–bariatric surgery population appeared to mirror secular trends in the United States as a whole, according to Dr. King.

With her coinvestigators, Dr. King searched for presurgical risk factors that might predict postsurgical substance misuse. Perhaps the most interesting finding concerned the factors that weren’t predictive, including education, unemployment, score on the Beck Depression Inventory, SF-36 mental component summary score, race, marital status, binge eating, loss of control eating, and body mass index.

Lower social support prior to surgery was associated with increased risk for developing AUD symptoms during the first 5 years after bariatric surgery. Younger age and smoking at baseline were associated with increased rates of postoperative AUD symptoms, substance use disorder treatment, and illicit drug use. A history of psychiatric treatment was associated with increased rates of substance use disorder treatment and illicit drug use.

“That could indicate greater medical surveillance among those patients or greater willingness to get treatment, since they’d had treatment for other psychiatric issues in the past,” Dr. King speculated.

She described the study’s strengths as its large size, geographically diverse patient population, unusually high retention over time, compared with other bariatric surgery studies, and the use of AUDIT, a validated and reliable screening tool. The major limitations are that investigators didn’t inquire about illicit use of opioids and benzodiazepines, and recipients of gastric sleeve procedures weren’t included in the long-term follow-up analysis because LABS-2 began before the gastric sleeve boomed in popularity.

John M. Morton, MD, a former president of the American Society for Metabolic and Bariatric Surgery, predicted that a similar study that included gastric sleeve patients would show them to have the same unremarkable postoperative rates of substance misuse as the LAGB group.

“I want to emphasize that this increased incidence of alcohol problems in the Roux-en-Y gastric bypass patients is maybe not so much a psychological issue as it is a physiologic one,” added Dr. Morton, chief of bariatric and minimally invasive surgery at Stanford (Calif.) School of Medicine.

Dr. King agreed. “Just in the last year and a half there have been some great pharmacokinetic studies showing that the Roux-en-Y affects alcohol metabolism and absorption, as well as studies in rodent models that suggest alcohol produces increased neurobiologic reward,” she noted.

The LABS-2 study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. King reported having no relevant financial interests.
 

[email protected]
 

NEW ORLEANS – Early weight loss on liraglutide – specifically, dropping at least 4% of body weight at 16 weeks – is a strong and clinically useful identifier of patients with a high likelihood of significant weight loss 13 months into treatment, with an accompanying improvement in cardiometabolic risk factors, according to Ken Fujioka, MD.

Conversely, patients who aren’t early responders to subcutaneous liraglutide at 3 mg/day are unlikely to achieve at least 5% weight loss after a full year on the drug, the regulatory benchmark for clinically meaningful weight loss, added Dr. Fujioka, an internist and director of the center for weight management at the Scripps Clinic in La Jolla, Calif.

“Using this early response criterion at week 16 to predict long-term weight loss is to me a very valuable tool. Obesity is an odd disease because it has so many different causes. Finding the right drug is tough, and how long to keep trying with a particular medication is something we haven’t known. So I think the biggest change in obesity medicine is the creation of stopping rules that allow you to say, ‘OK, maybe this isn’t going to work. There’s some other reason you’re gaining weight, so let’s move on to something else,’” Dr. Fujioka said at the meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

“When you stop the medication, you improve the risk-benefit ratio by removing all risk. That’s a win-win to me, and I applaud the FDA for getting on the pharmaceutical companies to make sure they put stopping rules in their medication labels,” he added.

He presented a post hoc pooled analysis of two previously published large, double-blind phase III clinical trials of subcutaneous liraglutide at 3 mg/day (Saxenda) or placebo in combination with a diet and exercise intervention for weight loss: the 3,731-patient SCALE Obesity and Prediabetes trial and the 846-patient SCALE Diabetes trial. In both trials liraglutide was started at a dose of 0.6 mg and titrated to 3.0 mg by week 4. The lifestyle intervention entailed a 500-kcal/day deficit diet and a minimum of 150 minutes of physical activity per week.

The purpose of the pooled analysis was to identify the best early predictor of response status at 56 weeks by examining the impact of 3%, 4%, and 5% weight loss after 8, 12, and 16 weeks of treatment as cut points. This post hoc analysis was prespecified at the request of the Food and Drug Administration before the trials were completed.

The bottom line: The best predictor of long-term outcome on liraglutide, a glucagonlike peptide–1 analog, proved to be a weight loss of 4% or greater at 16 weeks. It had an 81% positive predictive value and a 76% negative predictive value for at least a 5% weight loss at 56 weeks. It correctly predicted weight outcomes at 56 weeks in 80.1% of patients, the highest success rate of all the combinations studied. This finding was the impetus for the current product labeling, which contains the stopping rule. Dr. Fujioka shared study data not included in the labeling; namely, the marked contrast in how early responders and early nonresponders fared at 56 weeks.

The mean weight loss at 56 weeks in nondiabetic early responders to liraglutide was 10.8%, compared with only 3% in early nondiabetic nonresponders. Diabetic early responders averaged an 8.5% weight loss at 56 weeks, while early nonresponders had a mean 3.1% weight loss.

In the SCALE Obesity and Prediabetes trial, 50% of early responders to liraglutide ended up with a greater than 10% weight loss at 56 weeks, and 21% had more than 15% weight loss, compared with rates of 6% and 2%, respectively, in early nonresponders.

In the SCALE Diabetes study, 38% of early responders had greater than 10% weight loss long term, a rate nearly fourfold higher than in early nonresponders. Moreover, 10% of early responder diabetic patients had greater than 15% weight loss, versus a mere 2% of early nonresponders, the internist continued.

The ratio of early responders to early nonresponders in the nondiabetic population was 77%:23%. In diabetic patients, it was 63%:37%.

Turning to cardiometabolic endpoints, Dr. Fujioka noted that early responders in the SCALE Obesity and Prediabetes trial went on to show a mean reduction in systolic blood pressure of 5.1 mm Hg at 56 weeks, compared with a 2–mm Hg decrease in early nonresponders. Early responders also averaged a 10.5-cm shrinkage in waist circumference from a baseline of 115 cm, which was more than twice that observed at 56 weeks in early nonresponders. HDL-cholesterol level rose by 3.9% in early responders but remained unchanged over time in early nonresponders.

Diabetic patients who were early responders to liraglutide 3.0 mg/day had a mean 44.2-mg/dL reduction in fasting plasma glucose at 56 weeks from a baseline of 158 mg/dL, compared with a 30.1-mg/dL decrease in early nonresponders.

“The drop in fasting blood glucose is very quick – within a matter of weeks – so if you already have diabetic patients on drugs that are going to bring their blood sugar down, you may have to back titrate those other drugs really quickly. You don’t want to make your patients hypoglycemic,” the physician said.

Mean hemoglobin A_1c values in early responder diabetic patients fell by 1.6% from a baseline of 7.9%, a full 0.5% greater reduction than in early nonresponders.

By far the most frequent adverse events in the two SCALE trials were gastrointestinal, with nausea leading the way. Rates were modestly higher in the early responders.

 

This analysis and the clinical trials on which it was based were sponsored by Novo Nordisk, which markets liraglutide under the brand names Saxenda and Voctoza. The presenter reported receiving research grants from and serving as a consultant to Novo Nordisk and other pharmaceutical companies.

NEW ORLEANS – Early weight loss on liraglutide – specifically, dropping at least 4% of body weight at 16 weeks – is a strong and clinically useful identifier of patients with a high likelihood of significant weight loss 13 months into treatment, with an accompanying improvement in cardiometabolic risk factors, according to Ken Fujioka, MD.

Conversely, patients who aren’t early responders to subcutaneous liraglutide at 3 mg/day are unlikely to achieve at least 5% weight loss after a full year on the drug, the regulatory benchmark for clinically meaningful weight loss, added Dr. Fujioka, an internist and director of the center for weight management at the Scripps Clinic in La Jolla, Calif.

“Using this early response criterion at week 16 to predict long-term weight loss is to me a very valuable tool. Obesity is an odd disease because it has so many different causes. Finding the right drug is tough, and how long to keep trying with a particular medication is something we haven’t known. So I think the biggest change in obesity medicine is the creation of stopping rules that allow you to say, ‘OK, maybe this isn’t going to work. There’s some other reason you’re gaining weight, so let’s move on to something else,’” Dr. Fujioka said at the meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

“When you stop the medication, you improve the risk-benefit ratio by removing all risk. That’s a win-win to me, and I applaud the FDA for getting on the pharmaceutical companies to make sure they put stopping rules in their medication labels,” he added.

He presented a post hoc pooled analysis of two previously published large, double-blind phase III clinical trials of subcutaneous liraglutide at 3 mg/day (Saxenda) or placebo in combination with a diet and exercise intervention for weight loss: the 3,731-patient SCALE Obesity and Prediabetes trial and the 846-patient SCALE Diabetes trial. In both trials liraglutide was started at a dose of 0.6 mg and titrated to 3.0 mg by week 4. The lifestyle intervention entailed a 500-kcal/day deficit diet and a minimum of 150 minutes of physical activity per week.

The purpose of the pooled analysis was to identify the best early predictor of response status at 56 weeks by examining the impact of 3%, 4%, and 5% weight loss after 8, 12, and 16 weeks of treatment as cut points. This post hoc analysis was prespecified at the request of the Food and Drug Administration before the trials were completed.

The bottom line: The best predictor of long-term outcome on liraglutide, a glucagonlike peptide–1 analog, proved to be a weight loss of 4% or greater at 16 weeks. It had an 81% positive predictive value and a 76% negative predictive value for at least a 5% weight loss at 56 weeks. It correctly predicted weight outcomes at 56 weeks in 80.1% of patients, the highest success rate of all the combinations studied. This finding was the impetus for the current product labeling, which contains the stopping rule. Dr. Fujioka shared study data not included in the labeling; namely, the marked contrast in how early responders and early nonresponders fared at 56 weeks.

The mean weight loss at 56 weeks in nondiabetic early responders to liraglutide was 10.8%, compared with only 3% in early nondiabetic nonresponders. Diabetic early responders averaged an 8.5% weight loss at 56 weeks, while early nonresponders had a mean 3.1% weight loss.

In the SCALE Obesity and Prediabetes trial, 50% of early responders to liraglutide ended up with a greater than 10% weight loss at 56 weeks, and 21% had more than 15% weight loss, compared with rates of 6% and 2%, respectively, in early nonresponders.

In the SCALE Diabetes study, 38% of early responders had greater than 10% weight loss long term, a rate nearly fourfold higher than in early nonresponders. Moreover, 10% of early responder diabetic patients had greater than 15% weight loss, versus a mere 2% of early nonresponders, the internist continued.

The ratio of early responders to early nonresponders in the nondiabetic population was 77%:23%. In diabetic patients, it was 63%:37%.

Turning to cardiometabolic endpoints, Dr. Fujioka noted that early responders in the SCALE Obesity and Prediabetes trial went on to show a mean reduction in systolic blood pressure of 5.1 mm Hg at 56 weeks, compared with a 2–mm Hg decrease in early nonresponders. Early responders also averaged a 10.5-cm shrinkage in waist circumference from a baseline of 115 cm, which was more than twice that observed at 56 weeks in early nonresponders. HDL-cholesterol level rose by 3.9% in early responders but remained unchanged over time in early nonresponders.

Diabetic patients who were early responders to liraglutide 3.0 mg/day had a mean 44.2-mg/dL reduction in fasting plasma glucose at 56 weeks from a baseline of 158 mg/dL, compared with a 30.1-mg/dL decrease in early nonresponders.

“The drop in fasting blood glucose is very quick – within a matter of weeks – so if you already have diabetic patients on drugs that are going to bring their blood sugar down, you may have to back titrate those other drugs really quickly. You don’t want to make your patients hypoglycemic,” the physician said.

Mean hemoglobin A_1c values in early responder diabetic patients fell by 1.6% from a baseline of 7.9%, a full 0.5% greater reduction than in early nonresponders.

By far the most frequent adverse events in the two SCALE trials were gastrointestinal, with nausea leading the way. Rates were modestly higher in the early responders.

 

This analysis and the clinical trials on which it was based were sponsored by Novo Nordisk, which markets liraglutide under the brand names Saxenda and Voctoza. The presenter reported receiving research grants from and serving as a consultant to Novo Nordisk and other pharmaceutical companies.

NEW ORLEANS – Early weight loss on liraglutide – specifically, dropping at least 4% of body weight at 16 weeks – is a strong and clinically useful identifier of patients with a high likelihood of significant weight loss 13 months into treatment, with an accompanying improvement in cardiometabolic risk factors, according to Ken Fujioka, MD.

Conversely, patients who aren’t early responders to subcutaneous liraglutide at 3 mg/day are unlikely to achieve at least 5% weight loss after a full year on the drug, the regulatory benchmark for clinically meaningful weight loss, added Dr. Fujioka, an internist and director of the center for weight management at the Scripps Clinic in La Jolla, Calif.

“Using this early response criterion at week 16 to predict long-term weight loss is to me a very valuable tool. Obesity is an odd disease because it has so many different causes. Finding the right drug is tough, and how long to keep trying with a particular medication is something we haven’t known. So I think the biggest change in obesity medicine is the creation of stopping rules that allow you to say, ‘OK, maybe this isn’t going to work. There’s some other reason you’re gaining weight, so let’s move on to something else,’” Dr. Fujioka said at the meeting presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.

“When you stop the medication, you improve the risk-benefit ratio by removing all risk. That’s a win-win to me, and I applaud the FDA for getting on the pharmaceutical companies to make sure they put stopping rules in their medication labels,” he added.

He presented a post hoc pooled analysis of two previously published large, double-blind phase III clinical trials of subcutaneous liraglutide at 3 mg/day (Saxenda) or placebo in combination with a diet and exercise intervention for weight loss: the 3,731-patient SCALE Obesity and Prediabetes trial and the 846-patient SCALE Diabetes trial. In both trials liraglutide was started at a dose of 0.6 mg and titrated to 3.0 mg by week 4. The lifestyle intervention entailed a 500-kcal/day deficit diet and a minimum of 150 minutes of physical activity per week.

The purpose of the pooled analysis was to identify the best early predictor of response status at 56 weeks by examining the impact of 3%, 4%, and 5% weight loss after 8, 12, and 16 weeks of treatment as cut points. This post hoc analysis was prespecified at the request of the Food and Drug Administration before the trials were completed.

The bottom line: The best predictor of long-term outcome on liraglutide, a glucagonlike peptide–1 analog, proved to be a weight loss of 4% or greater at 16 weeks. It had an 81% positive predictive value and a 76% negative predictive value for at least a 5% weight loss at 56 weeks. It correctly predicted weight outcomes at 56 weeks in 80.1% of patients, the highest success rate of all the combinations studied. This finding was the impetus for the current product labeling, which contains the stopping rule. Dr. Fujioka shared study data not included in the labeling; namely, the marked contrast in how early responders and early nonresponders fared at 56 weeks.

The mean weight loss at 56 weeks in nondiabetic early responders to liraglutide was 10.8%, compared with only 3% in early nondiabetic nonresponders. Diabetic early responders averaged an 8.5% weight loss at 56 weeks, while early nonresponders had a mean 3.1% weight loss.

In the SCALE Obesity and Prediabetes trial, 50% of early responders to liraglutide ended up with a greater than 10% weight loss at 56 weeks, and 21% had more than 15% weight loss, compared with rates of 6% and 2%, respectively, in early nonresponders.

In the SCALE Diabetes study, 38% of early responders had greater than 10% weight loss long term, a rate nearly fourfold higher than in early nonresponders. Moreover, 10% of early responder diabetic patients had greater than 15% weight loss, versus a mere 2% of early nonresponders, the internist continued.

The ratio of early responders to early nonresponders in the nondiabetic population was 77%:23%. In diabetic patients, it was 63%:37%.

Turning to cardiometabolic endpoints, Dr. Fujioka noted that early responders in the SCALE Obesity and Prediabetes trial went on to show a mean reduction in systolic blood pressure of 5.1 mm Hg at 56 weeks, compared with a 2–mm Hg decrease in early nonresponders. Early responders also averaged a 10.5-cm shrinkage in waist circumference from a baseline of 115 cm, which was more than twice that observed at 56 weeks in early nonresponders. HDL-cholesterol level rose by 3.9% in early responders but remained unchanged over time in early nonresponders.

Diabetic patients who were early responders to liraglutide 3.0 mg/day had a mean 44.2-mg/dL reduction in fasting plasma glucose at 56 weeks from a baseline of 158 mg/dL, compared with a 30.1-mg/dL decrease in early nonresponders.

“The drop in fasting blood glucose is very quick – within a matter of weeks – so if you already have diabetic patients on drugs that are going to bring their blood sugar down, you may have to back titrate those other drugs really quickly. You don’t want to make your patients hypoglycemic,” the physician said.

Mean hemoglobin A_1c values in early responder diabetic patients fell by 1.6% from a baseline of 7.9%, a full 0.5% greater reduction than in early nonresponders.

By far the most frequent adverse events in the two SCALE trials were gastrointestinal, with nausea leading the way. Rates were modestly higher in the early responders.

 

This analysis and the clinical trials on which it was based were sponsored by Novo Nordisk, which markets liraglutide under the brand names Saxenda and Voctoza. The presenter reported receiving research grants from and serving as a consultant to Novo Nordisk and other pharmaceutical companies.