GLP-1 receptor agonists effective for weight loss in obesity without diabetes

In a recent study published in eClinical Medicine, researchers investigated the benefit-harm balance of initiating Glucagon-like Peptide-1 (GLP-1) receptor agonists (RAs) versus a placebo intervention for weight loss among people living with obesity and overweight without diabetes.

Their findings indicate that achieving a 10% weight loss with GLP-1 RA therapy outweighed the cumulative harms.

Still, the net benefit was dependent on individual treatment goals and tolerance for potential adverse effects.

​​​​​​​​​​​​​​Study: GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit–harm modelling study. Image Credit: KK Stock/Shutterstock.com

Background

GLP-1 RAs were initially approved to improve metabolic control in diabetes patients. Still, recent randomized control trials (RCTs) have shown their efficacy in weight reduction for non-diabetic adults, leading to approvals of drugs like semaglutide and liraglutide for weight management.

While these drugs demonstrate significant weight loss and potential reduction in weight-related comorbidities, the balance of their benefits against potential harms remains unclear, especially with concerns about off-label use, economic impact, and the rapid rise in prescriptions fueled by social media, leading to supply shortages and potential overuse.

About the study

This study aimed to continuously evaluate and monitor the benefit-harm balance of GLP-1 RAs to guide informed decision-making. Researchers employed benefit-harm balance modeling to assess the effects of GLP-1 RAs on weight loss in adults without diabetes.

Participants were adults aged 18 or older with a BMI of ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity.

The study compared liraglutide, semaglutide, and tirzepatide against a placebo, with all participants receiving lifestyle counseling to maintain a daily calorie deficit and engage in regular physical activity.

Data on weight loss (≥5% and ≥10%) and adverse effects were gathered from systematic reviews and RCTs, sourced through comprehensive literature searches and updated continuously.

Harms considered included common adverse effects like gastrointestinal issues and more serious outcomes like pancreatitis.

A random-effects meta-analysis estimated the relative treatment effects, and exponential models predicted cumulative negative and positive outcomes over one and two years.

Preference weights were applied to adjust the benefit-harm balance, reflecting the relative importance of outcomes. Sensitivity analyses tested the robustness of results by varying assumptions about harm rates and preferences.

The net benefit index, indicating whether benefits outweighed harms, was calculated and interpreted as the number of people achieving significant weight loss without serious harm. This living evaluation aimed to guide decision-makers by continuously updating with new evidence.

Statistical analyses were conducted using R software, adhering to quantitative benefit-risk modeling standards. The study did not require ethical approval as it used published data.

Findings

The study included eight RCTs with 8,847 participants, mostly women (74.1%) and individuals with obesity (96.0%). The average age of the participants was 46.7 years.

GLP-1 RAs significantly increased the likelihood of achieving ≥5% and ≥10% weight loss compared to placebo, with relative risks (RR) of 2.51 and 4.11, respectively. Semaglutide had the highest efficacy for ≥10% weight loss (RR 5.42), followed by tirzepatide (4.29) and liraglutide (2.91).

Harm outcomes were also observed more frequently in the GLP-1 RA group. The most common adverse effects included abdominal pain (RR 1.78), constipation (2.31), diarrhea (1.85), nausea (2.72), and vomiting (4.16).

Moderate harm events like cholelithiasis (RR 1.90) and alopecia (5.67) were higher among GLP-1 RA users, with tirzepatide specifically associated with alopecia.

Treatment discontinuation due to adverse effects was more than twice as high in the GLP-1 RA group compared to placebo (RR 2.17).

The benefit-harm analysis showed a net benefit for achieving ≥10% weight loss over two years with GLP-1 RAs, particularly for semaglutide, which had a net benefit of 208 per 1000 people.

However, a ≥5% weight loss did not outweigh the harms. Sensitivity analyses indicated that preference for weight loss influenced the net benefit, particularly for semaglutide.

Weight loss benefits were prominent, but frequent and severe side effects reduced the net benefit.

Conclusions

This study finds that GLP-1 RAs provide significant net benefits in achieving a 10% weight loss in people who are overweight and obese during the first two years of treatment.

Still, the benefits of a 5% weight loss are less clear and highly dependent on individual preferences regarding potential harm.

The most common adverse effects decrease over time, suggesting early harms may be overestimated. Semaglutide and liraglutide show more favorable benefit-harm profiles compared to tirzepatide.

However, long-term data is limited, necessitating ongoing benefits-harm analysis updates as more evidence becomes available.

Limitations include insufficient evidence for all potential harms, subjectivity in harm selection, and reliance on RCT data, which may not fully represent the general population.

Future research should focus on long-term outcomes, individual preferences, and personalized treatment strategies to optimize the benefits and minimize the harms of GLP-1 RA therapy.