Variety of GLP-1 Drugs Help People Without Diabetes Lose Weight: Review

Glucagon-like peptide-1 (GLP-1) receptor agonists, including those targeting additional pathways, help otherwise healthy people without diabetes shed pounds, albeit at the cost of some side effects, a systematic review affirms.

The 12 agents examined, which included three with approved indications for chronic weight management in people with overweight or obesity and nine that have not yet been approved for that purpose, all provided significant reductions in body weight in randomized, placebo-controlled trials, lead author Areesha Moiz, BSc (Jewish General Hospital and McGill University, Montreal, Canada), and colleagues report.

The review, published online this week in Annals of Internal Medicine, also confirmed that adverse events occur in most patients, with GI side effects—such as nausea, vomiting, diarrhea, and constipation—being most common. Those were typically seen during dose escalation, of mild-to-moderate severity, and transient in nature.

“These drugs are efficacious and they’re relatively safe,” Moiz told TCTMD. “For a while, we didn’t have much in our toolbox to treat obesity—we had lifestyle interventions. Obviously, these are still the cornerstone of obesity treatment, but they have been shown to be insufficient for sustained weight loss in this patient population.”

Older drugs like phentermine and orlistat were less effective for weight loss and came with substantial safety concerns, she noted. “Now we have these drugs that work, that are safe, and that are continuing to be investigated in additional conditions as well.”

The GLP-1 drugs, originally developed to treat type 2 diabetes, have exponentially grown in popularity over the last few years due to their weight-loss effects, even as they continue to be studied in additional patient populations. Last year, Moiz and colleagues performed a systematic review and meta-analysis of RCTs involving semaglutide (Wegovy; Novo Nordisk) in patients with overweight or obesity who did not have diabetes, finding sustained weight loss along with increased GI side effects relative to placebo.

To follow up on that study, the investigators wanted to explore the weight-loss effects of the broader class of GLP-1 receptor agonists, including agents that targeted one or two additional pathways, in individuals without diabetes. The review included three medications that have been approved by the US Food and Drug Administration for chronic weight management—semaglutide, liraglutide (Saxenda; Novo Nordisk), and tirzepatide (Zepbound; Eli Lilly), which is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. Nine other medications without an indication for weight management, including dual or triple agonists influencing additional pathways involved in appetite regulation and metabolism, were included as well.

Of the 12 medications studied, seven are single agonists of GLP-1, four are dual agonists (including tirzepatide and three investigational agents that act on the GLP-1 and glucagon pathways), and one (retatrutide) is a triple agonist of the GLP-1, GIP, and glucagon pathways.

Moiz and colleagues identified 26 randomized, placebo-controlled trials in otherwise healthy individuals with overweight or obesity but not diabetes or other conditions like cardiovascular disease, polycystic ovary syndrome, or chronic obstructive pulmonary disease. There was a total of 15,491 participants (mean age 34 to 57 years; 72% women), who had a mean body mass index (BMI) at baseline of 41 kg/m².

Active treatment induced weight loss relative to placebo across all trials, with varying effects. Among the three FDA-approved medications, weight loss was greatest (up to 17.8% through 72 weeks) with tirzepatide 15 mg once weekly, followed by semaglutide 2.4 mg once weekly (up to 13.9% through 68 weeks) and liraglutide (up to 5.8% through 26 weeks).

Among the investigational agents, retatrutide 12 mg once weekly provided up to 22.1% weight loss after 48 weeks, although this was based on data from only 268 patients.

There were, the authors note, no head-to-head trials to compare the efficacy of the different medications.

Although the investigators didn’t examine the impact of weight loss on cardiovascular risk specifically, there were positive signals, with declines in BMI, waist circumference, and systolic and diastolic blood pressure across at least half of the trials.

In terms of safety, overall adverse events generally occurred at a higher rate with active treatment (80-97%) than with placebo (63-100%). Most of these were GI-related (47-84% vs 13-63%), but no bowel obstruction or gastroparesis was reported.

Moiz et al observed low rates of various serious adverse events of interest, including severe GI and biliary disorders (3.5% or less), pancreatitis (< 2%), and psychiatric disorders (15% or less)—that last category encompassed less serious events like insomnia and mood alterations.

There are some concerns around use of the GLP-1 agents, such as weight regain after stopping treatment, the potential for a loss of skeletal muscle mass, long-term adherence, and the limited evidence that exists for long-term safety, Moiz et al say.

But on the plus side, the GLP-1 receptor agonists have shown “important cardiorenal protective effects,” they add, citing evidence from trials like SELECT, STEP-HFpEF, and STEP-HFpEF DM. In addition, the FLOW trial showed that semaglutide reduced the progression of kidney disease and lessened kidney-related complications.

“This review highlights the potential clinical benefits of GLP-1 receptor agonists and co-agonists as tools in the management of obesity. Their demonstrated efficacy in promoting weight loss and improving cardiometabolic health underscores their potential role in addressing obesity as a chronic disease,” Moiz et al write, adding that patients should be monitored closely for side effects.

“The emergence of oral formulations and combination therapies may also enhance patient adherence and expand treatment options, highlighting the need for continued research to optimize the use of GLP-1 receptor agonists and co-agonists across diverse populations,” they say.