Benefits of GLP-1s outweigh harms when patients achieve 10% weight loss

Key takeaways:

• Although achieving 10% weight loss outweighed the harms of GLP-1 receptor agonists, 5% weight loss did not.
• The net benefit of GLP-1s also depends on patients’ willingness to accept harms, researchers said.

The net benefit of GLP-1 receptor agonists in adults with overweight or obesity who do not have diabetes depends on their weight loss target and willingness to accept harms, according to researchers.

Although GLP-1 receptor agonists have demonstrated effectiveness in reducing weight loss and risks for other chronic diseases, questions remain over whether the benefits outweigh the harms of the drugs, “including their cost-effectiveness and economic impact,” Hannah Moll, a PhD candidate from the department of epidemiology at the University of Zurich in Switzerland, and colleagues, wrote in eClinicalMedicine. There is also uncertainty over the long-term effects of GLP-1 receptor agonists for weight management in those without diabetes.

“As evidence on the topic is accumulating rapidly, there is a need for continuous evaluation and monitoring of the benefit-harm balance to guide up-to-date decisions,” they wrote.

The researchers analyzed data from eight randomized controlled trials involving 8,847 participants, most of whom were women (74%) and had obesity (96%). They then compared beneficial outcomes — 10% or 5% weight loss — against frequent harm outcomes over 1 and 2 years of treatment.

Among 1,000 people who received GLP-1 receptor agonists for 2 years, 375 and 318 achieved 10% and 5% weight loss, respectively, vs. those who received placebo.

Compared with the placebo group, the GLP-1 group more often experienced:

• abdominal pain (RR = 1.78; 95% CI, 1.37-2.3);
• cholelithiasis (RR = 1.9; 95% CI, 1.12-3.22);
• constipation (RR = 2.31; 95% CI, 1.81-2.94);
• hypoglycemia (RR = 2.89; 95% CI, 1.28-6.52);
• diarrhea (RR = 1.85; 95% CI, 1.37-2.5);
• alopecia (RR = 5.67; 95% CI, 2.47-13); and
• vomiting (RR = 4.16; 95% CI, 3.47-4.98).

However, most of the harms “were mild and could decrease over the duration of treatment,” the researchers pointed out.

They found that achieving 10% weight loss outweighed the cumulative risks, with a net benefit probability of 0.97 at year 1 and 0.91 at year 2.

The absolute net benefit of attaining 10% weight loss “without experiencing worrisome harms” over 2 years was equivalent to 104 (95% CI, 100-112) per 1,000 people, Moll and colleagues reported.

At 2 years, the probabilities of a net benefit for 10% weight loss were:

• 0.96 for semaglutide;
• 0.72 for liraglutide; and
• 0.6 for tirzepatide.

Although 5% weight loss did not show a net benefit, Moll and colleagues noted that “it could be net beneficial for some individuals, depending on their willingness to accept the harm outcomes.”

“For example, one of the harm outcomes that highly influenced the unfavorable benefit-harm balance of tirzepatide was alopecia,” they explained. “This may not be a concern at all for individuals who no longer have hair.”

When the researchers accounted for discontinuation, the probability of achieving 10% weight loss with GLP-1 receptor agonists was 1.

The researchers noted that the long-term benefits and harms are still unclear, highlighting a need for continuous updates on the benefit-harm balance. In addition, they could not find sufficient evidence for all the harm outcomes.

Still, the findings suggest “the need for patient-tailored decisions to maximize the benefits and minimize harms and overuse of treatments,” they concluded.