GLP-1RAs reduce weight in overweight/obese individuals without diabetes

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) results in significant weight loss in patients with obesity or overweight without diabetes, a study has shown. In addition, the best GLP-1RA agent appears to be semaglutide, showing superior efficacy and low-to-moderate risk of side effects.

A team of investigators conducted a systematic review with meta-analysis and trial sequential analysis using the databases of PubMed, Embase, and Cochrane Central Register of Controlled Trials, searched from inception to 1 January 2022. They identified studies reporting on outcomes such as body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), or total body fat (TBF).

Finally, random-effects models were used to summarize mean differences (MDs) as well as standardized MDs (SMDs).

Forty-one trials including a total of 15,135 participants met the eligibility criteria. Use of GLP-1RAs contributed to significant decreases in BW (MD, ‒5.319 kg, 95 percent CI, ‒6.465 to ‒4.174), BMI (MD, ‒2.373 kg/m², 95 percent CI, ‒2.821 to ‒1.924), WC (MD, ‒4.302, 95 percent CI, ‒5.185 to ‒3.419), WHR (MD, ‒0.011, 95 percent CI, ‒0.015 to ‒0.007), but not TBF (MD, ‒0.320, 95 percent CI, ‒1.420 to ‒0.780). [Am J Clin Nutr 2023;118:614-626]

The beneficial effects of GLP-1RAs on BW, BMI, and WC for weight loss were confirmed in trial sequential analysis. Additionally, GLP-1RAs showed a nonlinear dose-response relationship with weight loss.

These findings were further confirmed in sensitivity analyses, but the GRADE certainty of the evidence ranged from high to very low. Notably, high to moderate GRADE certainty of evidence indicated that semaglutide was the most effective GLP-1RA agent, as seen in its robust efficacy and low-to-moderate risk of adverse events.

“Considering the weight-loss effects and adverse effects together, we can conclude that semaglutide is likely to be the most effective agent due to the superior weight-loss effects and moderate risk of adverse events,” the investigators said.

“The greatest effectiveness in weight reduction was obtained at the maximum dose of semaglutide (0.4 mg/d),” they added.

Mechanisms

Previous studies reported the link between GLP-1RAs and appetite. While the mechanisms remained uncertain, evidence showed that GLP-1 could prevent gastric emptying, act on the central nervous system to suppress appetite, and support the balance between total energy intake and consumption. [Mol Metab 2019;30:72-130; Diabetes 2014;63:4186-4196; Diabetologia 2016;59:954-965]

“After appetite suppression, feelings of hunger decrease, and satiety will be stimulated to increase, leading to reduced food intake and body weight,” the investigators said. [Diabetes 2014;63:4186-4196]

In a 2001 meta-analysis, GLP-1 resulted in a reduction in ad libitum energy intake in a dose-dependent manner and an increase in sense of satiety. [J Clin Endocrinol Metab 2001;86:438-439]

“[T]hese mechanistic studies support our findings,” the investigators said.

The current findings, however, were limited by the relatively short duration (<60 weeks) of the trials included in this meta-analysis. Thus, ongoing trials must be followed-up, and further research on the longevity of the effect of GLP-1RAs is warranted.

“It is necessary to explore further what is the optimal procedure of GLP-1RA treatment, including dosing, frequency, and duration, for patients with obesity/overweight without diabetes,” the investigators said. “Although we have conducted some exploratory analyses … additional well-designed trials are still necessary.”