expert roundtables

Comparative Effectiveness of FDA-Approved Treatments for Chronic Weight Management

by Caroline M. Apovian, MD, FACP, FTOS, DABOM, George A. Bray, MD, F. Xavier Pi-Sunyer, MD

Overview

For motivated patients with a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with comorbidities, treatment guidelines recommend that US Food and Drug Administration–approved medications be used as an adjunct to lifestyle modification to help achieve weight-loss and health goals. Further, guidelines have suggested that physicians use the product information to weigh the potential risks of the medications against the possible benefits for each individual patient. Currently, there are no head-to-head studies comparing the efficacy and tolerability of the medications approved for use in chronic weight management, but a 2016 meta-analysis of 28 randomized clinical trials with 29,018 patients demonstrated that orlistat, lorcaserin, naltrexone/bupropion, phentermine/topiramate, and liraglutide 3.0 mg were all associated with significant weight loss at 1 year compared with placebo. A median 23% of patients receiving placebo in the analysis had at least 5% weight loss, compared with 75% of participants taking phentermine/topiramate, 63% of participants taking liraglutide 3.0 mg, 55% taking naltrexone/bupropion, 49% taking lorcaserin, and 44% taking orlistat. The analysis also demonstrated that all active treatments were well tolerated, with 1.3 to 2.9 higher odds of being associated with discontinuation due to adverse events compared with placebo. Lorcaserin had the lowest odds of being discontinued due to adverse events, and liraglutide and naltrexone/bupropion had the highest odds. In addition to weight loss, another meta-analysis concluded that treatment with orlistat, lorcaserin, naltrexone/bupropion, phentermine/topiramate, and liraglutide is also associated with decreases in fasting blood glucose and waist circumference in patients with obesity. Finally, a 2017 quantitative study of the 5 FDA-approved weight-loss medications was also conducted to assess the differences in efficacy in 43,443 patients. Rates of body weight regain (measured in kg/year) were 0.51 for orlistat, 0.48 for lorcaserin, 0.91 for naltrexone/bupropion, 1.27 for phentermine/topiramate, and 0.43 for liraglutide, and the 1-year dropout rates ranged from 24.3% for liraglutide to 49.1% for naltrexone/bupropion. Our featured experts in the field discuss how the different FDA-approved medications for chronic weight management compare with regard to effectiveness.

Q: How do the different FDA-approved treatments compare with regard to effectiveness? 

Caroline Apovian, MD, FACP, FTOS, DABOM

Director, Nutrition and Weight Management
Section of Endocrinology, Diabetes, and Nutrition
Boston Medical Center
Professor of Medicine, Boston University School of Medicine
Boston, MA

“The average weight-loss results seen in meta-analyses and clinical trials average a total population, so those results do not really help much in clinical practice. Physicians still have to look at individual patients and make an informed treatment decision based on history and physical examination.” 

Caroline M. Apovian, MD

There are 5 medications currently approved for chronic weight management—6 if you include phentermine used alone. The clinical trials on the efficacy and safety of these drugs show different average weight loss, ranging from between 3% and 5% placebo-subtracted weight loss and going up to 12%. If you only consider absolute average weight loss for comparison, certain drugs, such as the combination of phentermine/topiramate, are associated with a 9% weight loss and others, such as lorcaserin, are associated with a 3% to 5% weight loss. Then there are others in the middle of the range, such as naltrexone/bupropion at 6% to 7% weight loss, liraglutide with a larger 8% weight loss, and phentermine alone. Because it was first approved in 1959, the trials of phentermine were completed a long time ago and are not the same kind of trials that are done now for drugs going through the FDA approval process. Therefore, phentermine alone cannot be compared as critically as the other 5 FDA-approved medications. If you look at waterfall plots for comparison, the weight losses within each trial are very different in terms of intersubject variation. Therefore, the averages really do not tell you enough to make treatment decisions based on individual patients seen in clinical practice. Even though the combination of phentermine/topiramate may, on average, provide more weight loss than the average weight loss seen with lorcaserin, that does not mean that every single patient is going to do better on phentermine/topiramate. There are patients who are on the other extreme of the waterfall plot for lorcaserin and do very well on lorcaserin and do not do as well on phentermine/topiramate. The average weight-loss results seen in meta-analyses and clinical trials average a total population, so those results do not really help much in clinical practice. Physicians still have to look at individual patients and make an informed treatment decision based on history and physical examination. 



F. Xavier Pi-Sunyer, MD

Professor of Medicine, Institute of Human Nutrition
Co-Director, Columbia Obesity/Nutrition Research Center
Columbia University
New York, NY

“As for the 5 FDA-approved medications, orlistat has not been very successful primarily because of its side effects, so it is not commonly used. The other 4 medications are similar in terms of efficacy, with slight differences in weight loss based on the individual patient response. Liraglutide is the 1 medication that is a little different because it gets good weight-loss results, but it is an injectable.”

F. Xavier Pi-Sunyer, MD

I agree and will add a couple of additional thoughts. First, phentermine is currently the most commonly prescribed obesity drug in the United States, despite being the drug that the FDA has warned is addictive. Although I believe that it is not addictive, the use of phentermine has diminished because some patients fear that they will become addicted. Nevertheless, it is safe and less costly because it is generic, and it is used very widely in the United States. The concern is that we have little long-term clinical data because it was only tested as a short-term drug back in the days when the FDA only allowed 3 months’ treatment duration. As for the 5 FDA-approved medications, orlistat has not been very successful primarily because of its side effects, so it is not commonly used. The other 4 medications are similar in terms of efficacy, with slight differences in weight loss based on the individual patient response. Liraglutide is the 1 medication that is a little different because it gets good weight-loss results, but it is an injectable. Despite its efficacy, liraglutide is not used as much as it should be because its cost is quite high. The FDA has improved treatment by approving a number of drugs for chronic weight management, but the limitations of the drugs, side effects, and costs really affect their day-to-day use by primary care physicians, endocrinologists, cardiologists, and other clinicians.

George A. Bray, MD

Boyd Professor Emeritus, LSU, 
Pennington Biomedical Research Center, 
Louisiana State University, 
New Orleans, LA

“There is considerable variability in individual treatment response with these drugs, with some individuals losing a lot of weight and others actually gaining weight. However, we still have to make some kind of qualitative comparison between the medications.” 

George A. Bray, MD

There is considerable variability in individual treatment response with these drugs, with some individuals losing a lot of weight and others actually gaining weight. However, we still have to make some kind of qualitative comparison between the medications. A very interesting quantitative analysis of the weight-loss medications by Dong and colleagues used a modeling technique to compare drugs. The authors modeled the rate of weight loss for each drug. They included 31 trials with orlistat, and 3 to 6 trials each for the other drugs. The analysis resulted in a maximum weight loss and the time to half maximum weight loss. The placebo treatment produced a weight loss of approximately -2.7 kg. For orlistat, the weight loss was -6.65 kg, which was a little better than lorcaserin (-5.39 kg) and a little less than liraglutide (-7.68 kg). Both phentermine/topiramate and naltrexone/bupropion were considerably better, with a modeled average weight loss of -15.6 kg and -13.2 kg, respectively. Equally interesting was the time to half maximum weight loss, which varied between 12.7 weeks for liraglutide and approximately 35 weeks for naltrexone/bupropion and orlistat. This quantitative analysis is an interesting analytical approach to treatment comparisons that may be more generally utilized.

References

Apovian CM, Aronne LJ, Bessesen DH, et al; Endocrine Society. Pharmacological management of obesity: an Endocrine Society Clinical Practice Guideline [published correction appears in J Clin Endocrinol Metab. 2015;100(5):2135-2136]. J Clin Endocrinol Metab. 2015;100(2):342-362.

Bray GA, Heisel WE, Afshin A, et al. The science of obesity management: an Endocrine Society Scientific Statement. Endocr Rev. 2018;39(2):79-132.

Dong Z, Xu L, Liu H, Lv Y, Zheng Q, Li L. Comparative efficacy of five long-term weight loss drugs: quantitative information for medication guidelines. Obes Rev. 2017;18(12):1377-1385.

Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients With Obesity. Endocr Pract. 2016;22 Suppl 3:1-203.

Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society [published correction appears in Circulation. 2014;129(25 Suppl 2):S139-S140]. Circulation. 2014;129(25 Suppl 2):S102-S138.

Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis [published correction appears in JAMA. 2016;316(9):995]. JAMA. 2016;315(22):2424-2434.

Khera R, Pandey A, Chandar AK, et al. Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis. Gastroenterology. 2018;154(5):1309-1319.e7.

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