The research team, led by Lara Haidar and Sherif Eltonsy of the University of Manitoba together with Heidi Crane and colleagues at the University of Washington, drew on an unusually rich data source: the Centers for AIDS Research Network of Integrated Clinical Systems, or CNICS. This network pools standardized electronic health record data from nine sites across the United States, capturing longitudinal clinical information on people engaged in HIV care. The investigators identified 1,572 people with HIV who initiated one of four antidiabetic drug classes between 2013 and 2023: glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas. Because the study spanned a decade, it captured the full arc of the modern obesity-pharmacotherapy era, from the early GLP-1 agonists through the arrival of high-dose semaglutide.

Methodologically, the study was designed to avoid the classic pitfalls of observational drug comparisons. The investigators used a new-user, active-comparator cohort design, meaning that every participant was starting one of the four drug classes for the first time, and each drug class was compared directly against the others rather than against no treatment. This design minimizes confounding by indication and by prior drug exposure. The primary outcome was percent bodyweight change at one year, modeled with covariate-adjusted linear mixed models under an on-treatment approach, which counts weight trajectories only while patients remain on their assigned therapy. Secondary analyses examined absolute weight change in kilograms and the time needed to reach clinically meaningful thresholds of at least 5 percent and at least 10 percent bodyweight loss, using adjusted Cox proportional hazards models. Weight trajectories were followed for up to three years.

The headline result was striking in its magnitude. At one year, people with HIV taking GLP-1 receptor agonists lost an average of 4.44 percent of their bodyweight (95 percent confidence interval, −5.51 to −3.36 percent), a reduction that crosses the 5 percent threshold often cited as the minimum for clinically meaningful benefit. SGLT2 inhibitors produced a far more modest average loss of 1.00 percent, with a confidence interval (−2.25 to 0.24 percent) that brushed against zero. DPP-4 inhibitors and sulfonylureas were associated with essentially no weight change at all, and sulfonylureas, an older class that stimulates insulin secretion, are well known to promote weight gain in other populations. When the researchers compared each drug class against sulfonylureas as the reference, both GLP-1RAs and SGLT2 inhibitors were associated with a significantly higher likelihood of achieving at least 5 percent and at least 10 percent weight loss.

Subgroup analyses added nuance that matters for clinical decision-making. The weight-loss effect of GLP-1 receptor agonists was larger among people with HIV who did not have diabetes than among those who did, a pattern consistent with the broader obesity-medicine literature, where glycemic status can blunt the magnitude of GLP-1-mediated weight reduction. The effect was also greater among patients with higher baseline body mass index, meaning that the patients with the most weight to lose tended to benefit the most. Within the GLP-1RA class, semaglutide was associated with the largest reductions, an expected finding given its higher receptor-binding potency and its approval specifically for chronic weight management at higher doses. These gradients suggest that the drugs are behaving in people with HIV much as they do in the general population, which is reassuring given longstanding concerns that HIV infection, antiretroviral therapy, or chronic immune activation might alter drug response.

The temporal shape of the weight loss also carried information. The investigators found that GLP-1RA-associated weight reduction was nonlinear, with the steepest declines occurring early in treatment and the trajectory flattening over time. This pattern mirrors the pharmacology of incretin-based therapies: appetite suppression and slowed gastric emptying are most pronounced in the initial months, dose escalation takes time, and physiological compensatory mechanisms gradually temper the energy deficit. For clinicians, the practical implication is that early response in the first months of therapy may be a useful signal, while patients and providers should anticipate a plateau rather than indefinite loss. The three-year trajectory data, though limited by the realities of real-world adherence and treatment switching, offer a rare long-window view of how these drugs perform outside the controlled confines of a randomized trial.

Why does this evidence gap exist in the first place? People with HIV were historically excluded from major cardiometabolic trials because of concerns about drug interactions with antiretroviral therapy, immune dysfunction, and overlapping comorbidities. Yet the exclusion created a self-reinforcing problem: without trial data, clinicians hesitated to prescribe; without prescribing, no real-world data accumulated. Studies like this one break that cycle by exploiting routine clinical care as a natural laboratory. The CNICS infrastructure is particularly well suited to the task because it harmonizes laboratory values, medication records, and visit data across sites, allowing researchers to adjust for antiretroviral regimen, kidney function, baseline weight, and other covariates that could otherwise distort the comparison. The authors note that integrase strand transfer inhibitors and tenofovir alafenamide, two antiretroviral components associated with weight gain, are common in modern regimens, making effective weight-management options especially relevant for today’s patients.

The clinical stakes extend well beyond the bathroom scale. Excess adiposity in people with HIV amplifies an already elevated burden of insulin resistance, dyslipidemia, hypertension, and nonalcoholic fatty liver disease, and it compounds the cardiovascular risk conferred by both HIV itself and some antiretroviral agents. A drug class that delivers roughly 4 to 5 percent average weight loss, with a substantial fraction of users achieving 5 percent or more, could shift cardiometabolic trajectories across an entire population of aging patients. The finding that GLP-1RAs outperformed not only older agents like sulfonylureas but also the popular SGLT2 inhibitors is important, because SGLT2 inhibitors have often been the default choice for patients with diabetes and kidney or heart disease. The results suggest that when weight is a treatment priority, class selection should weigh GLP-1RA therapy more heavily, even accounting for their higher cost, injectable formulation, and gastrointestinal side-effect profile.

As with any observational study, caveats apply. The on-treatment analysis captures the experience of patients who persist with therapy, which may not reflect the substantial fraction of real-world patients who discontinue GLP-1RAs within a year, often because of cost or intolerance. Confounding by indication cannot be fully eliminated, and prescribers may have preferentially chosen GLP-1RAs for patients motivated to lose weight. The authors also published the work as an early-release, peer-reviewed accepted article subject to further editorial edits. Still, the consistency of the findings with randomized evidence from the general population, the rigorous new-user design, and the sheer granularity of the CNICS data make this the strongest available evidence that GLP-1 receptor agonists deliver clinically meaningful weight loss in people with HIV. For a population that helped bear the brunt of one epidemic and now faces another of metabolic disease, that is a result worth paying attention to.

Subject of Research: Comparative weight-change effects of antidiabetic drug classes in people with HIV

Article Title: Comparative effectiveness of GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and sulfonylureas on weight change among people with HIV: a real-world longitudinal cohort study

Article References: Haidar, L., Crane, H. M., Nance, R. M., Whitney, B. M., Kyle, R. P., Ruderman, S. A., Heath, S., Hwang, Y. J., Yendewa, G., Karris, M., Alba, D. L., Drumright, L. N., Fredericksen, R. J., Hahn, A., Mayer, K., Napravnik, S., Pettit, A., Rodriguez, A., Aboulatta, L., … Eltonsy, S. (2026). Comparative effectiveness of GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and sulfonylureas on weight change among people with HIV: a real-world longitudinal cohort study. BMC Medicine. https://doi.org/10.1186/s12916-026-05219-7

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05219-7

Keywords: HIV, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, sulfonylureas, obesity, weight loss, diabetes, semaglutide, CNICS cohort, cardiometabolic risk, antidiabetic medications