Episode 61: Semaglutide for Obesity.  

Dr Arreaza discusses with Dr Carranza the results of the STEP trials: Semaglutide Treatment Effect in People with obesity, which allowed semaglutide gain FDA approval as a treatment for obesity.

By Hector Arreaza, MD, and Claudia Carranza, MD

This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. 

One of the major challenges of modern medicine is to find an effective treatment for obesity.

Obesity was considered a disease in 1998 by the National Institutes of Health[1].

In 2002, the Internal Revenue Service, AKA the feared IRS, issued a statement to make obesity treatment a deductible medical expense. Who would have known that obesity was tax deductible?

Later, in 2013 obesity was accepted as a complex, chronic disease by the American Medical Association[2]. Many other organizations have made statements in favor or against the definition of obesity as a disease.

We recently announced the exciting news of semaglutide as a new FDA-approved medication for the chronic treatment of obesity. Today we want to give you a very brief summary (brief-ísimo) of the trials that allowed semaglutide to gain that FDA-approval. 

Semaglutide was tested at different levels with the STEP trials. STEP stands for Semaglutide Treatment Effect in People with obesity (STEP). All these trials were done in 68 weeks, all patients received counseling about lifestyle modifications, 70-80% were women, ages averaging 40-50 years old.

STEP 1: Does semaglutide cause weight loss in patients without diabetes?

The focal point of this trial was weight management with semaglutide in patients without diabetes. This was a double-blind trial. There were 1961 participants enrolled. A group was assigned to placebo and another group was assigned to weekly injection of semaglutide. For the semaglutide group, the goal dose of semaglutide was 2.4 mg, starting with 0.25 mg, increasing every 4 weeks: 0.5 -> 1.0 -> 1.7 -> 2.4 (reaching the goal dose in 4 months), 3 out of 4 participants were Caucasians. 

Outcomes: after 68 weeks weight reduction was -16.9% in patients on semaglutide, more than 86% of participants had a weight loss >5%, 69% lost >10% of their weight, and 50% percent lost >15% of their body weight, and about 32% lost >20% of their weight. This may be comparable to bariatric surgery in some patients; however, the weight loss is not as dramatic. Other parameters improved were waist circumference, blood pressure, triglycerides. LDL and total cholesterol were not significantly affected. There was a clinical meaningful change in 40% of patients. 7 out of 100 could not complete trial for GI adverse effects, most commonly nausea, diarrhea, vomiting, constipation. Acute pancreatitis presented in 0.2% of the semaglutide group (all recovered during study) vs 0% in the placebo group[3]. 

STEP 2: Does semaglutide cause weight loss in patients with diabetes? 

The focal point of this study was weight management with semaglutide in type 2 diabetes mellitus. 1210 patients participated in 12 different countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly assigned to semaglutide 2.4 mg weekly, Semaglutide 1 mg weekly, or placebo. 

Weight loss was superior with semaglutide 2.4 mg, -9.6% of body weight with semaglutide vs -3.4% weight loss with placebo. As you can see, weight loss in individuals with diabetes is more difficult. The effect on diabetes control was about the same with semaglutide 1 mg vs 2.4 mg. The 1 mg dose reduced A1C -1.5%, and the reduction was -1.6% with semaglutide 2.4 mg. A1C reduction was about the same regardless of weight loss. 

STEP 3: Does Intensive Behavioral Therapy increases weight loss in patients using semaglutide?

Intensive behavioral therapy was put to the test. 611 participants were enrolled. Each patient in this study received IBT: 30 brief sessions, 19 in the first 24 weeks, monthly thereafter provided by a registered dietitian. Participants had obesity and overweight, lived in 41 states in the US, had >1 related comorbidity, no diabetes. They all were put on a low-calorie diet for 8 weeks and were randomized to receive either semaglutide or placebo. 

Weight loss was accelerated by the low-calorie diet and IBT earlier in the study, but at the end there was only 1% difference between the two groups, 17.6% weight loss with IBT vs 16.9% weight loss without IBT. Further research is needed to determine the potential benefits of including a low-carb diet to semaglutide to increase long term weight loss. 

STEP 4: What happens to weight loss if we stop semaglutide?

The focal point of this study was sustained weight management. Patients were randomized to placebo or semaglutide after 20 weeks, but continued lifestyle modifications

Those who remained in semaglutide, continued to lose weight up to 18% (lost 8% additional weight). The placebo arm gained half of their weight back. If you stop the medication weight is likely to come back. 

Weight loss comparison: Contrave® (bupropion-naltrexone) and Saxenda (liraglutide) ~5% weight loss, Qysimia® (phentermine-topiromate ~9%), semaglutide (Wegovy®) is about 15%. The average weight loss with semaglutide is higher than other meds, including liraglutide, after 1 year of use. Medullary thyroid cancer: Not shown to be increased risk.

Newer medications that act on the GLP-1 receptors are showing increased rates of weight loss.

• IBT is less important in weight management if a highly effective medication is used to curb appetite

•Improved glucose control and CVD risk reduction is achieved when patients have ≥10% weight reduction

•Obesity is a complex chronic disease that requires long-term management

Credit: This summary was inspired by Dr Robert F. Kushner, Professor of Medicine, Northwestern University Feinber School of Medicine.

Conclusion: Now we conclude our episode number 61 “Semaglutide for Obesity”. After listening to this episode, we hope you understand the role of semaglutide in the treatment of obesity. Semaglutide has shown to cause weight loss in patient with and without diabetes, and the benefits go beyond weight reduction to include lower blood pressure and triglycerides, among other health markers. Semaglutide is not for everyone, but it can surely be the answer to many of your patients with obesity. Even without trying, every night you go to bed being a little wiser.

Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza and Claudia Carranza. Audio edition: Suraj Amrutia. See you next week! 

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References:

1. Kyle TK, Dhurandhar EJ, Allison DB. Regarding Obesity as a Disease: Evolving Policies and Their Implications. Endocrinol Metab Clin North Am. 2016;45(3):511-520. doi:10.1016/j.ecl.2016.04.004, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988332/

1. AMA House of Delegates Adopts Policy to Recognize Obesity as a Disease, Obesity Medicine Association, June 19, 2013, https://obesitymedicine.org/ama-adopts-policy-recognize-obesity-disease/

1. Wildings, John P.H. et al., Once-Weekly Semaglutide in Adults with Overweight or Obesity, N Engl J Med 2021; 384:989-1002, DOI: 10.1056/NEJMoa2032183. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183 (STEP1)

1. Davies, Melanie et. al, Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, The Lancet, March 02, 2021, DOI: https://doi.org/10.1016/S0140-6736(21)00213-0   (STEP 2)

1. Wadden TA, Bailey TS, Billings LK, Davies M, et. al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1403-1413. doi: 10.1001/jama.2021.1831. PMID: 33625476; PMCID: PMC7905697. https://jamanetwork.com/journals/jama/article-abstract/2777025 (STEP 3)

1. Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414–1425. doi:10.1001/jama.2021.3224. https://jamanetwork.com/journals/jama/article-abstract/2777886 (STEP 4)