GLP-1 Receptor Agonists at CROI 2026: Revolution, Hype — or the Beginning of a New Era?

At CROI 2026, a conference traditionally focused on antiretroviral therapy, viral persistence and immune activation, one plenary session shifted the spotlight to a different kind of molecule — yet one that may reshape far more than diabetes care. In his lecture, “GLP-1 Receptor Agonists: Are They a Cure for Everything?”, Professor Todd T. Brown of Johns Hopkins University addressed a question that increasingly extends beyond endocrinology:

Are we witnessing a genuine therapeutic revolution — or a moment of medical “irrational exuberance”?

Beyond Blood Sugar: A Cardiometabolic Shift

GLP-1 receptor agonists (GLP-1 RAs) were developed to treat type 2 diabetes. Their biological mechanism is well understood: they enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying and act centrally to reduce appetite. In clinical trials, drugs such as semaglutide and tirzepatide lower HbA1c by as much as 2–2.3 percentage points — an impressive metabolic effect.

But glucose control is no longer the main story.

The turning point came with cardiovascular outcome trials. In the SELECT trial, semaglutide reduced major adverse cardiovascular events — heart attack, stroke or cardiovascular death — by 20% in people with established cardiovascular disease. Importantly, only about one third of that benefit could be explained by changes in waist circumference. The implication is striking: these drugs do more than induce weight loss. They appear to modify cardiovascular biology itself.

For decades, diabetes treatment focused primarily on glycemic control. GLP-1 receptor agonists altered that paradigm. For the first time, clinicians could prescribe a glucose-lowering medication that also demonstrably reduces cardiovascular risk.

The metabolic effects extend even further. In obesity trials, semaglutide produces roughly 16% body-weight reduction, while tirzepatide reaches close to 18% — translating into average losses approaching 20 kilograms in some studies. These outcomes begin to rival bariatric surgery. Clinical data now show improvements in heart failure with preserved ejection fraction, slowing of chronic kidney disease progression, resolution of metabolic dysfunction-associated steatohepatitis (MASH), and dramatic reductions — up to 64% — in sleep apnea severity.

And yet an important scientific question remains unresolved: how much of these benefits are mediated by weight loss itself, and how much reflect direct cellular and tissue-specific effects of GLP-1 signaling? If the mechanism extends beyond adiposity, we may be looking at a new class of systemic modulators rather than sophisticated appetite suppressants.

Inflammation, the Brain — and Unexpected Horizons

One of the most compelling discussions at CROI centered on inflammation. GLP-1 receptor agonists consistently reduce inflammatory markers such as C-reactive protein by 40–60% in clinical studies. Only part of this reduction can be explained by changes in body weight or glucose, suggesting intrinsic immunometabolic effects.

For populations living with chronic immune activation — including people with treated HIV — this observation is particularly intriguing. In a randomized study of semaglutide in individuals with HIV-associated lipohypertrophy, participants experienced a 19% reduction in total body fat and a 31% decrease in visceral adipose tissue. More strikingly, C-reactive protein fell by nearly 50%, alongside reductions in interleukin-6 and sCD163. Some of these changes appeared partly independent of fat loss.

Inflammation is a common thread linking cardiovascular disease, aging, neurodegeneration and metabolic dysfunction. If GLP-1 RAs influence inflammatory pathways directly, their relevance could extend well beyond obesity management.

The neurological dimension adds another layer. GLP-1 receptors are expressed in brain reward centers, and preclinical studies show reduced alcohol, nicotine and opioid seeking in animal models. Early human data are emerging. In a randomized study in alcohol use disorder, weekly semaglutide reduced laboratory alcohol consumption and craving, and even decreased cigarette use among smokers. More than twenty randomized trials are underway.

If confirmed, GLP-1 agonists may represent a new biological approach to compulsive reward behavior — a development that would fundamentally broaden their clinical scope.

The Reality Check: Durability, Aging and Access

Amid enthusiasm, the conference also presented sobering realities. In a real-world cohort of over 125,000 adults initiating GLP-1 therapy, one-year discontinuation rates were 46% among people with diabetes and 65% among those without diabetes. After stopping treatment, weight regain was rapid. A recent meta-analysis projected return to baseline weight within approximately 1.4 years after discontinuation of newer incretin therapies, with parallel loss of cardiometabolic improvements.

These data underline a critical truth: GLP-1 receptor agonists behave like chronic disease treatments. Short-term use followed by discontinuation is biologically inconsistent with the pathophysiology of obesity. Yet long-term maintenance strategies remain undefined.

Life-course considerations add further complexity. Older adults — particularly those over 75 — are underrepresented in major trials. Lean mass reduction, including around 9% decline in psoas muscle volume in some analyses, raises questions about frailty and sarcopenia. Bone density and fracture risk require additional data. At the same time, observational analyses suggest up to a 45% reduction in incident dementia among GLP-1 users, although recent Alzheimer’s trials have produced mixed results. The interaction between GLP-1 signaling and biological aging remains an open field of investigation.

Globally, the implications are immense. Roughly 27% of the world’s population could meet eligibility criteria for GLP-1 therapy. Yet current production capacity would cover only a fraction of those in need. Patent expirations beginning in 2026 in several countries, new oral formulations, and more than sixty GLP-1-based compounds in development may expand access — but without coordinated policy, inequities may widen.

A Transformation — But Not a Panacea

So, are GLP-1 receptor agonists a cure for everything?

The message from CROI 2026 was neither naïve nor dismissive. These agents have transformed diabetes and obesity care and introduced a new cardiometabolic paradigm. They show credible promise in inflammatory modulation, addiction medicine and possibly neurodegeneration. But they are not universal solutions, and their long-term safety, sustainability and accessibility remain unresolved.

Perhaps the most accurate conclusion is this: we are not at the peak of GLP-1 therapy — we are at the beginning of understanding its systemic implications.

The enthusiasm appears rational. The responsibility now is to ensure that it remains guided by evidence rather than driven by hype.