A systematic review has confirmed that glucagon-like peptide-1 (GLP-1) receptor agonists, including those targeting additional metabolic pathways, help individuals without diabetes achieve significant weight loss. While these drugs offer promising results, they are not without side effects.
The review, led by Areesha Moiz, BSc from the Jewish General Hospital and McGill University in Montreal, evaluated 12 GLP-1 medications—three of which are FDA-approved for chronic weight management, and nine that are still in development. All the drugs demonstrated notable reductions in body weight in randomized, placebo-controlled trials.
Published this week in the Annals of Internal Medicine, the study also highlighted gastrointestinal (GI) side effects, including nausea, vomiting, diarrhea, and constipation, which were most frequently experienced during dose escalation phases. However, these side effects were generally mild to moderate and temporary, the review noted.
“These drugs are effective and largely safe,” Moiz said in an interview with TCTMD. “For a long time, our only approach to obesity treatment was lifestyle changes, which, while essential, have proven insufficient for sustained weight loss in many patients. These new medications provide additional tools.”
Older drugs, like phentermine and orlistat, were less effective for weight loss and raised significant safety concerns. Now, with the introduction of GLP-1 agonists, Moiz noted that both efficacy and safety have improved, with further investigations underway for additional uses in other health conditions.
Initially developed for treating type 2 diabetes, GLP-1 drugs have gained widespread popularity due to their impact on weight loss. Last year, Moiz’s team published a study reviewing the weight loss effects of semaglutide (Wegovy; Novo Nordisk) in individuals without diabetes, finding sustained weight reduction but increased GI side effects compared to placebo. This new review sought to expand on those findings by evaluating a broader range of GLP-1 receptor agonists and other related treatments in non-diabetic individuals.
The review focused on three FDA-approved medications for weight management: semaglutide, liraglutide (Saxenda; Novo Nordisk), and tirzepatide (Zepbound; Eli Lilly). Tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated the greatest weight loss, with up to 17.8% of body weight shed after 72 weeks. Semaglutide and liraglutide also showed strong results, with weight reductions of up to 13.9% and 5.8%, respectively.
Among the experimental treatments, retatrutide, a triple agonist targeting GLP-1, GIP, and glucagon pathways, showed the most significant weight loss in the review, achieving a reduction of up to 22.1% after 48 weeks, although this data came from a small sample of just 268 patients.
While no direct comparisons were made between the different drugs, the study’s findings suggest that GLP-1-based therapies could provide substantial benefits in the treatment of obesity.
Although the review did not focus on the cardiovascular impacts of weight loss, there were indications of positive outcomes, including reductions in body mass index (BMI), waist circumference, and both systolic and diastolic blood pressure across various trials.
In terms of safety, active treatments led to higher rates of adverse events compared to placebo, with GI-related issues being the most common. However, serious complications like bowel obstruction, pancreatitis, or severe psychiatric disorders were rare, and most adverse events were transient.
Some concerns remain about the long-term use of GLP-1 drugs, such as potential weight regain after discontinuation, the impact on skeletal muscle mass, and the limited data on their long-term safety. Nonetheless, the review notes that GLP-1 receptor agonists have shown potential cardiorenal benefits, including improvements in kidney function and reductions in kidney disease progression, as demonstrated by trials like SELECT, STEP-HFpEF, and FLOW.
“The findings underscore the growing role of GLP-1 receptor agonists in managing obesity as a chronic condition,” Moiz and colleagues wrote. “Their effectiveness in promoting weight loss and enhancing cardiometabolic health highlights their potential to address the obesity epidemic. However, careful monitoring of side effects is essential.”
Looking ahead, the development of oral formulations and combination therapies may improve patient adherence, expanding the therapeutic options available and ensuring more effective long-term management of obesity, the researchers concluded.
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