Most weight-loss drugs don’t provide cardiovascular benefits or meaningfully improve quality of life, a new study suggested. But some experts urged caution in interpreting the findings.

A meta-analysis of 262 randomized trials, involving nearly 100,000 participants, found that several newer and emerging drugs produce substantial weight loss. However, that loss was accompanied by higher rates of adverse events, including stomach and bowel symptoms, fatigue, and loss of lean muscle mass.

And despite substantial weight loss, no drug led to clinically important improvements in quality of life.

Furthermore, the drugs’ benefits weren’t sustained after discontinuation, “indicating a clear benefit-harm trade-off,” wrote Kailei Nong of Sichuan University in Chengdu, China, and colleagues.

The study was published online in The BMJ.

‘Treatments Should Be Individualized’

The network meta-analysis included 262 randomized controlled trials comparing one or more drugs with lifestyle changes, placebo, or another drug, for a total of 99,791 participants. Studies evaluated 19 drugs approved by regulatory agencies or pending approval, with follow-up from 12 to 172 weeks. The analysis provided data on 24 clinical outcomes, including weight changes, risk for cardiovascular events, kidney disease progression, lean mass changes, quality of life, adverse events, and all-cause mortality.

At 1 year, compared with lifestyle modification alone, moderate- to high-certainty evidence showed substantial weight loss with tirzepatide (mean difference, -14.9%), cagrilintide-semaglutide (CagriSema, -14.8%), oral semaglutide (-10.9%), orforglipron (-9.9%), subcutaneous semaglutide (-9.8%), and phentermine-topiramate (-8.1%).

Very low-/low-certainty evidence suggested that emerging drugs such as ecnoglutide, mazdutide, and retatrutide may produce similar or greater reductions (13.1%-14.6%).

Discontinuation because of adverse events was highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratio [RR], 1.9-4.2).

Gastrointestinal events were most common with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (incidence RR, 3.1-4.2).

The risk for fatigue increased, most notably with naltrexone-bupropion (RR, 8.9), orforglipron (RR, 3.4), and CagriSema (RR, 3.2).

Tirzepatide reduced the most fat mass (by 25.7%) but also the most lean mass (by 8.3%).

Subcutaneous semaglutide was the only drug associated with lower all-cause mortality (RR, 0.81) and myocardial infarction (RR, 0.72). These estimates were informed mainly by cardiovascular outcome trials in high-risk populations.

Heart failure risk was reduced with subcutaneous semaglutide (RR, 0.43) and tirzepatide (RR, 0.49).

No drug convincingly reduced kidney failure or showed clinically important improvements in quality of life.

The authors acknowledged limitations, including relatively short follow-up for most included trials, limiting conclusions about long-term safety, quality of life, and effects on cardiovascular and kidney outcomes. In addition, evidence for several newer drugs was sparse and of low certainty, and the lack of individual participant data precluded a more robust exploration of treatment effects across key subgroups, including age, sex, and comorbidity burden.

Taken together, the findings imply that “treatment decisions for obesity should be individualized, balancing expected benefits, harms, treatment burden, costs, availability, and patient preferences,” the authors wrote.

‘Careful Interpretation’ Needed

Several experts commented on the study. Authors of a linked editorial wrote, “This study represents an important step in providing comparative information to inform patient-clinician discussions about obesity drugs in this rapidly evolving landscape of treatment options.”

Marie Spreckley, a weight management researcher, University of Cambridge, Cambridge, England, urged caution in interpreting the data. “The findings do not show that obesity medications have no wider health benefits. Rather, they highlight that while the evidence for weight loss is strong, evidence for some longer-term outcomes is still developing and differs considerably between individual medications.

“This is particularly important for cardiovascular outcomes. Many weight-loss trials were not primarily designed or sufficiently long to assess outcomes such as heart attacks, heart failure, or mortality. The absence of demonstrated benefit for all medications should therefore not be interpreted as evidence that these benefits do not exist…. Quality of life is complex and varies between individuals. While standardized measures provide valuable information, they may not capture all aspects of treatment experience that matter to people living with obesity.”

John Wilding, a professor in the Department of Cardiovascular and Metabolic Medicine at the University of Liverpool in Liverpool, England, said, “Trying to analyze all these drugs (some are not approved for obesity and unlikely to ever be approved for that indication), alongside older and newer approved treatments and others that are in various stages of clinical development in one article, is a tall order and in my view creates a lot of inconsistencies and problems with interpretation.

“Some of them (metformin, SGLT2i, exenatide, and dulaglutide) have never been approved for obesity treatment (they are treatments for diabetes), so it is not even clear why they have been included. Exenatide is no longer in use.”

Some of the included drugs are not approved in many countries, and new drugs like CagriSema are not yet approved anywhere, he said. “This distorts overall interpretation. What the article shows is lack of data for most of the included treatments, which is not the same as lack of effect…. The fact that effects are not sustained after stopping treatment is hardly surprising. We don’t expect other drugs used to treat chronic diseases like hypertension, dyslipidemia, diabetes, asthma, etc. to continue to work if people stop taking them.”

Some of the conclusions drawn by the authors “appear premature and insufficiently supported by the totality of the available evidence,” said Naveed Sattar, professor of cardiometabolic medicine/honorary consultant at the University of Glasgow in Glasgow, Scotland. “There is already considerable evidence that many individuals experience meaningful improvements in well-being that are not adequately captured by traditional patient-reported outcome measures. This may help explain why millions of people worldwide are willing to pay for these medications out of pocket, whereas comparatively few would do so for treatments such as statins or antihypertensive drugs.

“It is also worth noting the limitations acknowledged by the authors themselves. As stated in the paper, ‘Most trials had relatively short follow-up, with only a small number extending beyond 2 years, limiting conclusions about long-term safety, quality of life, and effects on cardiovascular and kidney outcomes.’ Given this admission, strong conclusions regarding the absence of benefit in these domains seem difficult to justify.”

The study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project; Chengdu Science and Technology Bureau Key R&D Support Plan; National Natural Science Foundation of China; and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University. 

The study authors declared receiving fees from various pharmaceutical companies and other commercial interests. Their interests are available in the study. 

The editorialists declared no relevant conflicts of interest. Spreckley declared no personal financial interests, consultancy roles, advisory roles, speaker fees, stock ownership, or honoraria from companies manufacturing incretin-based therapies. 

Wilding reported consultancy advisory board work for the pharmaceutical industry contracted via the University of Liverpool in the past 36 months (no personal payment) for Alnylam, Amgen, AstraZeneca, Boehringer Ingelheim, Cytoki, Kailera, Lilly, Menarini, Napp, Novo Nordisk, Pfizer, Prosciento, Response Pharmaceuticals, Rhythm Pharmaceuticals, Saniona, and Shionogi; funding for clinical trials from Amgen, AstraZeneca, and Novo Nordisk; and personal honoraria/lecture fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Medscape, Novo Nordisk, and Menarini. He is past president of the World Obesity Federation, a member of the Association for the Study of Obesity, Diabetes UK, European Association for the Study of Diabetes, American Diabetes Association, Society for Endocrinology, and the Rank Prize Funds Nutrition Committee. From 2009 to 2024, he was national lead for the Metabolic and Endocrine Specialty Group of the UK NIHR Clinical Research Network. 

Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gan & Lee, GlaxoSmithKline, Hanmi Pharmaceuticals, Janssen, Kailera, Mass Medicines, Menarini Ricerche, Merck Sharp & Dohme, Metsera, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche, Sanofi, UCB Pharma, and Verdiva Bio. He has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche. He holds no shares in any medical areas. 

Marilynn Larkin, MA, is an award-winning medical writer and editor based in New York City whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.