Effective GLP-1 Agonists for Weight Loss in Non-Diabetic Obesity

Researchers examined the advantages and disadvantages of starting Glucagon-like Peptide-1 (GLP-1) receptor agonists (RAs) against a placebo intervention for weight loss in individuals who are obese or overweight but do not have diabetes in a recent study that was published in eClinical Medicine.

According to their results, the cumulative risks of GLP-1 RA therapy were surpassed by the 10% weight loss that could be achieved.

However, the overall benefit depended on each patient’s tolerance for possible side effects and their specific treatment objectives.

Background: GLP-1 RAs were first licensed to help diabetic patients with their metabolic management. Nevertheless, recent randomized control studies (RCTs) have demonstrated their effectiveness in helping persons without diabetes lose weight, which has resulted in the approval of medications like liraglutide and semaglutide for weight management.

The benefits of these medications outweigh the potential risks, despite the fact that they significantly reduce weight and may even eliminate weight-related comorbidities. This is especially true given worries about off-label use, the impact on the economy, and the sharp increase in prescriptions that these medications are causing due to social media, which could result in overuse and supply shortages.

Regarding the study

To aid in making well-informed decisions, this study attempted to continually assess and track the benefit-harm balance of GLP-1 RAs. GLP-1 RAs’ impact on weight loss in persons without diabetes was evaluated by researchers using benefit-harm balance modeling.

Adults who were at least 18 years old and had a BMI of ≥30 kg/m² or ≥27 kg/m² along with at least one weight-related comorbidity were eligible to participate.

In order to sustain a daily calorie deficit and participate in regular physical exercise, all trial participants received lifestyle counseling. The study tested the effects of liraglutide, semaglutide, and tirzepatide against a placebo.

Comprehensive literature searches were conducted to obtain data on weight reduction (≥5% and ≥10%) and side effects, which were then collected from systematic reviews and RCTs and updated on a regular basis.

Common side effects like gastrointestinal problems and more severe consequences like pancreatitis were among the harms taken into consideration.

The relative treatment effects were evaluated using a random-effects meta-analysis, and cumulative positive and negative outcomes over one and two years were forecasted using exponential models.

The benefit-harm balance was adjusted using preference weights, which represent the relative relevance of the various outcomes. Sensitivity analysis varied assumptions about harm rates and preferences in order to verify the robustness of the results.

The number of people who lost a considerable amount of weight without suffering any major consequences was used to generate the net benefit index, which shows if benefits outweigh drawbacks. The goal of this living review was to provide decision-makers with ongoing updates based on fresh data.

R software was used for statistical studies, which followed the guidelines for quantitative benefit-risk modeling. Since the study used publicly available data, ethical approval was not necessary.

Results
There were eight RCTs in the analysis, totaling 8,847 participants, the majority of whom were women (74.1%) and people who were obese (96.0%). The participants’ average age was 46.7 years.

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

Additionally, there were greater harm outcomes noted in the GLP-1 RA group. Abdominal pain (RR 1.78), constipation (2.31), diarrhea (1.85), nausea (2.72), and vomiting (4.16) were the most frequent side events.

GLP-1 RA users had greater rates of moderate harm events, such as cholelithiasis (RR 1.90) and alopecia (5.67), with tirzepatide being particularly linked to alopecia.

When comparing the GLP-1 RA group to the placebo group, treatment withdrawal due to side events was more than twice as high (RR 2.17).

The benefit-harm analysis indicated that using GLP-1 RAs to achieve ≥10% weight loss over a two-year period had a net benefit; semaglutide, in particular, showed a net benefit of 208 per 1000 persons.

A ≥5% weight loss did not, however, justify the risks. Sensitivity analyses revealed that the net benefit was influenced by the preference for weight loss, especially with semaglutide.

Benefits related to weight loss were notable, but the overall benefit was diminished by frequent and severe adverse effects.

In conclusion
The results of this study show that within the first two years of treatment, GLP-1 RAs significantly improve the net benefits of helping overweight and obese individuals lose 10% of their body weight.

However, the advantages of losing five percent of one’s body weight are less obvious and heavily reliant on personal preferences regarding possible risks.

The most frequent side effects becoming less frequent with time, which could indicate that the early risks were exaggerated. When compared to tirzepatide, semaglutide and liraglutide exhibit more favorable benefit-harm profiles.

Unfortunately, there is a lack of long-term data, thus changes to the benefits-harm analysis are required whenever new information becomes available.

Some of the limitations include the use of RCT data, which could not accurately reflect the general population, subjectivity in harm selection, and insufficient evidence for all possible problems.

To maximize the advantages and reduce the risks of GLP-1 RA therapy, future research should concentrate on long-term results, individual preferences, and customized treatment plans.

For more information: GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit–harm modeling study, eClinical Medicine, https://doi.org/10.1016/j.eclinm.2024.102661