Summary
Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text,
Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m2. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy.
INTRODUCTION
Glucagon-like peptide-1 receptor agonists (GLP-1RA) are approved for the treatment of type 2 diabetes mellitus and obesity by the Food and Drug Administration (FDA). Of the GLP-1RAs, semaglutide and liraglutide have the most significant effect on weight loss, with the seminal STEP 8 clinical trial reporting semaglutide at the maximal dose
of 2.4 mg had a statistically significant greater effect on reduction in body weight from baseline when compared to the maximal dose of liraglutide (3.0 mg). Tirzepatide is a dual GLP-1RA and glucose dependent insulinotropic polypeptide (GIP) co-agonist, otherwise known as GIP/GLP-1RA. GIPs have a similar method of action as GLP-1RAs and, when combined, create a synergistic effect resulting in increased weight loss similar in effect to those observed with semaglutide.
Roughly, 50% of persons with type 2 diabetes and 68% of those engaging in weight loss care who start a GLP-1RA are reported to discontinue treatment after 1 year. For many patients, the reason for stopping the medication is multifactorial. Along with the many potential side effects and injection fatigue, shortages and expenses of GLP-1RAs pose a threat to the continuation of treatments. In addition, GLP-1RA therapy can be costprohibitive10 as many insurance companies will not cover GLP-1RAs without an existing diagnosis of type 2 diabetes mellitus or cardiac risk factors.
Studies that have explored weight loss during GLP-1RA treatment have noted a clear need for research focused on the long-term efficacy of weight loss maintenance, as early follow-up studies on GLP-1 treatment have observed that patients regain weight upon discontinuation. Recently, pharmacokinetic/pharmacodynamic modeling, including data from three randomized controlled trials, predicted how much weight one would lose on GLP-1RA treatment and how much a patient would regain after discontinuation. However, there are limited definitive data available to quantify on how much weight a patient will potentially regain following discontinuation of GLP-1RA.
Upon careful review of the literature, there are no systematic reviews or meta-analyses evaluating weight loss maintenance following the discontinuation of GLP-1RAs to guide current practice. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation
of the drug.
DISCUSSION
Summary of key findings
The percentage of weight and BMI that is regained from what was originally lost predictably increased between the short-term and long term subgroups of liraglutide. In the short-term, after liraglutide discontinuation, participants regained between 25.3% and 29.6% of the weight that they lost on GLP-1 treatment, and in the long-term, between 60.0% and 163.0% of the weight was regained. Similarly, after semaglutide/tirzepatide discontinuation, participants regained between 52.6% and 63.5% of weight lost on treatment.
The percentage of BMI regained that was lost on GLP-1RA treatment was almost equal to corresponding weight regain in all but one study.23 As time passes after the cessation of GLP-1RA treatment, the mean weight and BMI regain also increase, regardless of the GLP-1RA used. The weight regain shown, in addition to lifestyle modifications being continued in six5,19–21,23,24 of the eight studies, shows that weight loss was not sustainable with long-term discontinuation of GLP-1RA therapy. All studies except Kelly et al (who had personalized nutrition counseling) employed the World Health Organization exercise and diet guidelines for lifestyle interventions and provided advice from a dietician or nutritionist; additionally, participants were encouraged to engage in 150 minutes of high-intensity exercise per week, and except for Wilding et al, to continue these after stopping GLP-1RA therapy. Thus, if participants continued lifestyle modifications as they were encouraged to do, they theoretically should have been able to keep the weight off. Yet, they still regained a significant portion of the weight lost. Meta-analysis shows calorie deficit is the primary weight loss driver, followed by macronutrient composition, and in these data, without the use of GLP-1RA, these dietary suggestions became challenging to adhere to.27
Overall, the proportion of waist circumference regained from the cessation of treatment to the end of the study was not similar to the proportion of weight and BMI regained. This was particularly true for GLP-1RA's liraglutide and semaglutide. After liraglutide discontinuation, between 16.1% and 18.4% of waist circumference was regained
in the short term, and 19.6% was regained in the long term. 32.7% of waist circumference was regained in the semaglutide study. These percentages are smaller when compared to the percentages of regain of weight and BMI. Tirzepatide did not have the same effect and participants regained 47.7% of the waist circumference that was originally lost which was proportional to the weight and BMI regain...
CONCLUSION
This systematic review and meta-analysis detail the result of body habitus outcomes post GLP-1RA treatment cessation, demonstrating that discontinuation of GLP-1RA treatment leads to increased body size outcomes, regardless of lifestyle interventions. As more time passes off the drug regimen, the larger the body habitus outcomes
increase; therefore, long-term studies are needed to quantify a trend in weight regain plateaus. Semaglutide or tirzepatide discontinuation causes a clinically meaningful weight regain, which was proportional to the original weight loss. GLP-1RA should be considered chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity and type 2 diabetes.