Is weight loss sustained after discontinuation of glucagon-like peptide 1 receptor agonists for obesity?
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Introduction
Obesity, a complex and multifactorial chronic disease that can be influenced by a combination of genetic, behavioral, and environmental factors, occurs when an individual’s weight is higher than what is considered healthy for their height.1 The body mass index (BMI), albeit controversial, remains a common and simple to use screening tool to estimate body fat based on height, and determine whether an individual is considered underweight, overweight, or obese. A BMI is calculated by dividing a person’s weight in kilograms by their height in meters squared. A BMI of 30 kg/m2 or higher is considered within the “obese” range, whereas a BMI of 25 to 29.9 kg/m2 is considered within the “overweight” range. The Centers for Disease Control and Prevention (CDC) report that obesity prevalence in the United States was 41.9% in 2017, with ethnic minorities and individuals with lower education levels being disproportionately affected by the condition.2 Obesity is associated with a number of health risks, including cardiovascular disease, diabetes, cancer, and musculoskeletal disorders.1
Conventional therapies to promote weight loss include lifestyle changes such as increased physical activity, a healthy diet, and behavioral therapy.3,4 Medications or surgery may also be necessary to reduce weight if lifestyle interventions alone are insufficient. Amongst the available pharmacologic therapies for weight loss, the glucagon-like peptide 1 receptor agonists (GLP1 RAs) have recently gained popularity due to their impressive efficacy and relatively good safety profile. While this class of drugs is more commonly known for its role in stimulating glucose-dependent insulin release from the pancreatic islets in patients with diabetes, the GLP1 RAs also delay gastric emptying by binding to the GLP1 receptor.4 The later action cause food to move more slowly through the digestive system, increasing feelings of fullness and decreasing appetite. Additional weight-loss promoting actions of GLP1 RAs include reduced food intake through influence on appetite-regulating hormones in the hypothalamus, and increased secretion of leptin, a hormone that signals the brain to reduce food intake and increase energy expenditure. Importantly, the GLP1 RAs have been shown to cause weight loss irrespective of comorbid diabetes, most likely through a combination of the aforementioned mechanisms.
Currently, 2 GLP1 RAs have been approved for the treatment of obesity under different brand names than those approved for diabetes. SaxendaÒ (liraglutide) and WegovyÒ (semaglutide) are approved for chronic weight management in adults who are either obese with a BMI of 30 kg/m2 or greater or those who are overweight (BMI at least 27 kg/m2) with at least 1 weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.5,6 Both agents are also approved for use in pediatric patients 12 to 17 years of age with a BMI that corresponds to a range of BMI of 30 kg/m2 or greater in adults (ie, 95th percentile or greater for age and sex) and a body weight above 60 kg. Both agents are administered subcutaneously (SC) once daily.
This review will explore whether weight loss is sustained after discontinuation of glucagon-like peptide 1 receptor agonists used for the treatment of obesity.
Guideline recommendations
In 2022, the American Gastroenterological Association (AGA) published an update to their guideline on pharmacological interventions for adults with obesity.3 The primary recommended interventions remain lifestyle modifications, which include changes to diet, physical activity, and behavior. In addition to lifestyle modifications, the guideline recommends consideration of pharmacotherapy for adults who have not achieved weight loss goals with lifestyle interventions alone and have a BMI at least 30 kg/m² or at least 27 kg/m² with comorbidities. Semaglutide 2.4 mg SC is generally recommended over other available anti-obesity medications for long-term treatment of obesity in most adults due to its superior efficacy and safety profile. Liraglutide is also recommended amongst other anti-obesity treatments, but the guideline does not specifically suggest prioritizing liraglutide over other anti-obesity medications like it does for semaglutide. The 2023 American Diabetes Association (ADA) statement on obesity and weight management in type 2 diabetes (T2DM) provides similar recommendations for adults with comorbid obesity and diabetes to those provided by the AGA.8 However, neither guideline addresses whether or not weight loss is sustained after discontinuation of GLP1 RAs.
Literature review
Three randomized, double-blind, placebo-controlled trials evaluated weight loss maintenance following discontinuation of GLP1 RA therapy in adults with BMI at least 30 kg/m2 or BMI at least 27 kg/m2 with other comorbidities (see Table 1).7,8,9 Semaglutide 2.4 mg SC once weekly (plus lifestyle interventions) was studied in patients without diabetes (STEP 1 extension and Step 4), and liraglutide was studied in patients with pre-diabetes.
The STEP 1 trial demonstrated clinically relevant weight loss with semaglutide over a 68-week treatment period.7 In the STEP 1 extension trial, the effects of discontinuing semaglutide treatment were investigated during the study’s 1-year off-treatment follow-up period (ie, week 68 to 120; N=327). This analysis demonstrated that participants regained two-thirds of their prior weight loss within 1 year after discontinuing semaglutide. At week 120, the group previously randomized to semaglutide regained 11.6% of body weight relative to baseline weight and 14.8% of body weight relative to week 68 weight, whereas the placebo group regained only 1.9% and 2.1% of weight, respectively. Additionally, from week 68 to 120, weight regain and BMI increases were numerically greater in the group previously randomized to semaglutide as compared to placebo. Nonetheless, from week 0 to 120, those in the semaglutide group experienced a net mean body weight loss of 5.6%, whereas those in the placebo group experienced only a 0.1% net mean body weight loss.
The STEP 4 withdrawal trial examined the efficacy of semaglutide in maintaining weight loss in overweight or obese adults who completed a 20-week run-in phase of semaglutide treatment and who reached a maintenance dose of 2.4 mg SC weekly (N=803).8 Following the run-in phase, patients were randomized to continued semaglutide or placebo and followed for an additional 48 weeks. The estimated mean change in weight from week 20 to week 68 was -7.9% with continued semaglutide compared to +6.9% with placebo (difference, -14.8; 95% CI, -16.0 to -13.5, p<0.001). The group that continued semaglutide from week 20 to 68 likewise had significantly greater reductions in waist circumference, body weight, and BMI.
Lastly, le Roux et al. (2017) investigated the efficacy of liraglutide in reducing the risk of type 2 diabetes and managing weight in individuals with prediabetes over a 3-year period (N=2254).9 At week 160, liraglutide yielded more weight loss than placebo and likewise resulted in significant improvements in other weight-related endpoints such as decreases in BMI and waist circumference. After stopping treatment at week 160, some weight was regained in the liraglutide group compared to the placebo group, but the treatment difference remained significant at week 172 in favor of the group that was treated with liraglutide as compared to placebo (difference, -3.5 kg; 95% CI, -4.7 to -2.4, p<0.0001); a similar trend was seen for waist circumference.
Limitations
Further research is needed to gain a better understanding of weight loss maintenance after discontinuing GLP1 RAs in patients using these agents for weight loss. While the available evidence indicates that some weight regain occurs after treatment cessation, the off-treatment follow-up periods in the studies ranged from 3 months to 1 year, which may not be sufficient to fully identify the long-term effects of GLP1 RA therapy on weight loss maintenance and other obesity-related outcomes. The majority of participants in the 3 trials discussed were White females, so it remains uncertain whether males and individuals from other racial or ethnic groups would experience similar outcomes. Furthermore, only one trial has reported on maintenance of weight loss for liraglutide following treatment withdrawal.
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| Table 1. Randomized, double-blind trials examining sustained weight loss with GLP1 RAs.7,8,9 | |||
|---|---|---|---|
| Study | le Roux et al. (2017)9 | Wilding et al. (2022)7 STEP 1 extension | Rubino et al. (2021)8 STEP 4 |
| Population | BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with other comorbidities |
||
| N | N=2254 (liraglutide group: n=1505; placebo group: n=749) | N=327 (semaglutide group: n=228; placebo group: n=99) | Run in phase: N=903 Randomized, withdrawal phase: N=803 (semaglutide group: n=535; placebo group: n=268) |
| Treatment | Liraglutide 3.0 mg SC once daily Placebo Duration: 0 to 160 weeks (treatment phase) and 160 to 172 weeks (withdrawal phase) | Semaglutide 2.4 mg SC once weekly plus lifestyle interventions Placebo plus lifestyle interventions Duration: 0 to 68 weeks (STEP 1 [treatment phase]) and 68 to 120 weeks (STEP 1 extension [ie, withdrawal phase]) | Semaglutide 2.4 mg SC once weekly plus lifestyle interventions Placebo plus lifestyle interventions Duration: 0 to 20 weeks (run-in phase) and 20 to 68 weeks (randomized, withdrawal phase) |
| Key results for weight loss endpoints | Mean (±SD) change in body weight from baseline for liraglutide vs placebo groups · Baseline to week 160: -6.5 kg (8.1) vs -2.0 kg (7.3) (estimated treatment difference, -4.6 kg, 95% CI, -5.3 to -3.9) · Baseline to week 172: -5.6 kg (9.2) vs -2.2 kg (8.4) (estimated treatment difference, -3.5 kg, 95% CI, -4.7 to -2.4) | Weight changes (mean [±SD]) during the withdrawal phase in the group previously treated with semaglutide as compared to placebo: · % change baseline to week 120: +11.6 (7.7) vs +1.9 (4.8) · % change week 68 to week 120: +14.8 (10.7) vs +2.1 (4.9) · Body weight (kg): +12 (8.4) vs +2 (4.8) · BMI (kg/m2): +4.3 (2.9) vs + 0.7 (1.7) | Changes during the randomized, withdrawal phase with continued semaglutide as compared to switching to placebo: · Body weight (% change): -7.9 vs +6.9 (difference, -14.8; 95% CI, -16 to -13.5) · Waist circumference (cm): -6.4 vs +3.3 (difference, -9.7; 95% CI, -10.9 to -8.5) · Body weight (kg): -7.1 vs +6.1 (difference, -13.2 95% CI, -14.3 to -12.0) · BMI (kg/m2): -2.6 vs +2.2 (difference, -4.7; 95% CI, -5.2 to -4.3) |
| Abbreviations: BMI: body mass index; CI: confidence interval; SC: subcutaneous; SD: standard deviation. | |||
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Conclusion
Individuals are likely to regain weight after discontinuing GLP1 RA therapy. The off-treatment follow-up periods in 3 randomized trials ranged from 3 months to 1 year, which may be insufficient to fully deduce the long-term effects of GLP1 RA therapy on obesity outcomes.
References
- About Overweight & Obesity. Centers for Disease Control and Prevention. Updated May 17, 2023. Accessed April 4, 2023. https://www.cdc.gov/obesity/about-obesity/index.html
- Adult Obesity Facts. Centers for Disease Control and Prevention. Updated May 17, 2023. Accessed April 4, 2023. https://www.cdc.gov/obesity/data/adult.html
- Grunvald E, Shah R, Hernaez R, et al. AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity. Gastroenterology. 2022;163(5):1198-1225. doi:10.1053/j.gastro.2022.08.045
- ElSayed NA, Aleppo G, Aroda VR, et al. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S128-S139. doi:10.2337/dc23-S008
https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014 - Wegovy(semaglutide) [prescribing information]. Novo Nordisk Inc; December 2022.
- Saxenda (liraglutide) [prescribing information]. Novo Nordisk Inc; June 2022.
- Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725
- 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
- le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389(10077):1399-1409. doi:10.1016/S0140-6736(17)30069-7
Prepared by:
Michael Wong
PharmD Candidate Class of 2023
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
May 2023
The information presented is current as April 1, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.