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

The research team analyzed medical records from 240 adults with documented type 2 diabetes who had undergone comprehensive audiological evaluation, alongside 105 normoglycemic control individuals drawn from the same clinical archive. Strict exclusion criteria were applied to sharpen diagnostic specificity: patients with type 1 diabetes, occupational noise exposure, acoustic trauma, conductive middle ear pathology, previous otological surgery, or current use of ototoxic medications were systematically removed from the analysis. Severe renal impairment, hereditary hearing loss, and syndromic deafness were also grounds for exclusion, minimizing confounding from uremia-induced auditory dysfunction and genetic forms of impairment. All participants provided written informed consent in accordance with Declaration of Helsinki principles.

Hearing function was assessed using standardized pure-tone audiometry performed with a clinical audiometer in a soundproof room. Micro-otoscopy ruled out middle ear pathology and active infection, while tympanometry confirmed stable middle ear mechanics. The primary outcome was the pure-tone average at speech frequencies, known as PTA-mean, calculated as the arithmetic mean of air-conduction thresholds at 0.5, 1, 2, and 4 kilohertz, the frequencies most critical for speech intelligibility. Lower PTA-mean values indicate better-preserved hearing, while higher values reflect greater impairment. For participants with asymmetric loss, thresholds from each ear were averaged to provide a representative global estimate, reducing ear-specific variability.

When the researchers compared diabetic and non-diabetic participants using analysis of covariance, adjusting for age, biological sex, body mass index, and smoking status, the presence of type 2 diabetes emerged as a statistically significant predictor of worse hearing thresholds. On average, diabetic patients showed PTA-mean values approximately 8 decibels higher than controls, a difference the authors describe as clinically meaningful, since a 10 decibel rise in auditory threshold is perceptually equivalent to halving perceived loudness. Notably, none of the demographic covariates, including age, reached statistical significance in the adjusted model, a result the authors attribute to the fact that the entire cohort consisted of individuals already diagnosed with sensorineural hearing loss, which compressed the natural variation in auditory function across ages.

The most provocative portion of the study examined whether specific antidiabetic treatments were associated with different auditory outcomes within the diabetic subgroup. Using multivariable linear regression adjusted for age and BMI, the team found that several agents stood out. Semaglutide and dulaglutide, two widely prescribed GLP-1 receptor agonists, were associated with substantially lower PTA-mean values, with large regression coefficients reflecting more favorable hearing thresholds. Metformin, the first-line biguanide used by 55 percent of the cohort, was also linked to better thresholds, and pioglitazone, a thiazolidinedione, showed a similar individual-level association. The remaining drug classes, including sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, and glinides, showed no statistically significant connections to hearing outcomes.

When medications were grouped into pharmacological classes, GLP-1RAs again showed the strongest association, with roughly a 9.95 decibel reduction in PTA-mean compared with the reference category, and biguanides were associated with a smaller but significant reduction of about 4.05 decibels. Glinides showed a quantitatively relevant trend that narrowly missed statistical significance, while thiazolidinediones did not reach significance at the class level, likely because only 11 patients in the cohort were taking them. The overall drug-class model explained just over 5 percent of the variance in hearing thresholds, a modest figure consistent with the multifactorial nature of hearing loss, but the medication-related associations persisted even after adjustment for age and BMI, neither of which remained a significant predictor once drug class entered the model.

Why might GLP-1 receptor agonists and metformin be linked to healthier cochleae? The authors point to a convergence of plausible biological mechanisms. Diabetes-related hearing loss is thought to arise from cochlear microangiopathy that compromises blood flow to the stria vascularis, the metabolically demanding tissue that maintains the ionic gradients needed for sound transduction. Chronic hyperglycemia also floods the cochlea with reactive oxygen species, damaging the vulnerable outer hair cells, while advanced glycation end products, mitochondrial dysfunction, low-grade inflammation, and disruption of potassium and calcium homeostasis further erode cochlear and neural function. GLP-1RAs, in this framework, are appealing candidates for auditory protection because they enhance mitochondrial function, suppress inflammasome activation and pro-inflammatory cytokine production, reduce oxidative stress, and improve endothelial function, all of which may preserve the delicate microvascular perfusion the cochlea depends upon.

Metformin’s potential benefit rests on a different but complementary foundation. The drug is a pleiotropic agent that activates AMP-activated protein kinase, a cellular metabolic sensor governing mitochondrial biogenesis, oxidative stress defenses, and inflammatory responses. Through AMPK signaling, metformin may counteract the oxidative damage and microvascular dysfunction that characterize diabetic cochlear pathology, and its systemic metabolic and cardiovascular benefits could secondarily nourish ischemia-sensitive auditory tissue. Intriguingly, the authors note that metformin’s association with better hearing persisted after statistical adjustment, hinting that its potential auditory effects may not be mediated by glycemic control alone. The same logic applies across the medication spectrum: because every drug class studied effectively lowers blood glucose, the differential associations observed suggest that auditory preservation, if real, may stem from antioxidant, anti-inflammatory, and microvascular mechanisms rather than glucose lowering per se. Sulfonylureas, which stimulate insulin secretion without meaningful anti-inflammatory or antioxidant effects, fit neatly into this interpretation by showing no auditory association.

The authors are careful to frame these results as hypothesis-generating rather than practice-changing. The retrospective, non-interventional design precludes causal conclusions, and residual confounding from unmeasured variables, including diabetes duration, HbA1c levels, hypertension, renal function, cumulative drug exposure, treatment duration, and adherence, cannot be excluded. Because longitudinal audiometric follow-up was unavailable, hearing preservation was defined operationally as lower thresholds at a single assessment rather than demonstrated slowing of decline. Some treatment subgroups were small, making the large coefficients for individual agents particularly sensitive to sparse-data effects, outliers, and unmeasured clinical differences. The study also relied on pure-tone audiometry, which does not capture retrocochlear or central auditory processing, and included only hearing-impaired patients, which may explain why age failed to predict thresholds. The authors explicitly caution that the evidence is insufficient to support any change in antidiabetic prescribing based on hearing outcomes.

Even with these caveats, the implications are substantial. Diabetes already affects an estimated 589 million adults worldwide, and hearing loss, a historically underappreciated complication that erodes communication, social integration, and psychological well-being, may deserve a firmer place in routine diabetes care. The study’s authors suggest that audiological monitoring could become a useful adjunctive screening component of comprehensive diabetes management, particularly for older patients with long-standing disease or additional microvascular risk factors. If prospective studies confirm that GLP-1RAs and metformin are genuinely associated with slower auditory decline, hearing outcomes could eventually join cardiovascular and renal endpoints as extra-glycemic measures of treatment success, a notable prospect given the enormous clinical attention these drug classes already command. The mechanistic pathways outlined, from oxidative stress and microvascular inflammation to endothelial dysfunction, now await testing in experimental and translational studies that examine cochlear tissue directly, potentially yielding insights relevant to both diabetes-related and age-related hearing loss.

Subject of Research: Associations between antidiabetic pharmacotherapy and hearing thresholds in adults with type 2 diabetes and sensorineural hearing loss

Article Title: Associations Between Antidiabetic Pharmacotherapy and Hearing Thresholds in Adult Hearing‐Impaired Patients With Type 2 Diabetes

Article References: Martines, F., Salvago, P., Vaccaro, F., Vaccaro, D., Malta, G., Plescia, F., Cascioferro, S., Lavanco, G., & Plescia, F. (2026). Associations Between Antidiabetic Pharmacotherapy and Hearing Thresholds in Adult Hearing‐Impaired Patients With Type 2 Diabetes. Pharmacology Research & Perspectives, 14(5), Article e70316. https://doi.org/10.1002/prp2.70316

Image Credits: AI Generated

DOI: 10.1002/prp2.70316

Keywords: type 2 diabetes, hearing loss, GLP-1 receptor agonists, metformin, pure-tone audiometry, sensorineural hearing impairment, cochlear microangiopathy, oxidative stress, semaglutide, pioglitazone, diabetes complications, audiology