Beyond weight loss: GLP-1 organ outcomes

On 11 August 2026 the Journal of the American College of Cardiology published an editorial by Harlan M. Krumholz with a blunt title: Reframing GLP-1 Therapies as Cardiometabolic Health Drugs: Beyond the Race to Weight Loss^[1]. PubMed carries no abstract for it, and an editorial is an argument rather than new data, so this piece does the more useful thing. It tests the argument against the randomised outcome trials it rests on, and against what the approved labels for semaglutide already say.

Why the scale is the wrong scoreboard for some patients

For someone with a body mass index of 32 and no heart history, the sensible question about a GLP-1 drug really is how much weight it will shift. For someone who has already had a heart attack, it is not. The SELECT trial made that distinction concrete. It randomised 17,604 adults aged 45 and over who had established cardiovascular disease and a body mass index of at least 27, and who did not have diabetes, to weekly semaglutide 2.4 mg or to placebo^[2]. Over a mean follow-up of 39.8 months, cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% of the semaglutide group and 8.0% of the placebo group, a hazard ratio of 0.80 (95% confidence interval 0.72 to 0.90)^[2].

Those participants were not enrolled because of their weight alone, and the trial did not count kilograms as its primary endpoint; it counted events instead. That is the shift the editorial asks the field to make in how these medicines are described, prescribed and paid for.

The kidney trial that used the diabetes dose

The clearest sign that this class does something other than shrink people comes from FLOW, which was not a weight trial at all. FLOW randomised 3,533 people with type 2 diabetes and chronic kidney disease to weekly semaglutide at 1.0 mg, the diabetes dose rather than the higher weight-management dose, or to placebo, with a median follow-up of 3.4 years^[3].

The primary endpoint was major kidney disease events: onset of kidney failure through dialysis or transplantation, an eGFR below 15, at least a 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. It occurred 331 times on semaglutide against 410 on placebo, a hazard ratio of 0.76 (95% confidence interval 0.66 to 0.88)^[4]. Death from cardiovascular causes fell (hazard ratio 0.71), major cardiovascular events fell (0.82), and death from any cause fell (0.80)^[4]. Not one of those numbers is a weight-loss number.

A different formulation, the same direction

SOUL tested the tablet. It randomised 9,650 people aged 50 and over who had type 2 diabetes plus atherosclerotic cardiovascular disease, chronic kidney disease or both, to once-daily oral semaglutide at a maximum dose of 14 mg or to placebo, with a mean follow-up of 47.5 months^[5]. Major adverse cardiovascular events occurred in 12.0% of the oral semaglutide group against 13.8% on placebo, a hazard ratio of 0.86 (95% confidence interval 0.77 to 0.96)^[5]. The honest qualifier is that SOUL's confirmatory secondary outcomes, which included a kidney composite, did not differ significantly between the two groups^[5].

Three trials, three different populations, two routes of administration and three different doses. The direction of the cardiovascular effect held each time, including at a dose and in a population where large weight loss was not the point of the treatment.

The labels moved before the conversation did

Regulators have already accepted a good part of this reframing. The US prescribing information for Ozempic lists three indications, and only one of them is about blood sugar. Its other two are to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, and to reduce the risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease^[6]. The Wegovy label opens its indications with cardiovascular risk reduction in adults with established cardiovascular disease and obesity or overweight, listed ahead of weight reduction^[7].

So the organ-protection claim is not an optimistic reading of the data by enthusiasts, but wording printed on the approved label. The gap the editorial points at sits downstream of that: how these drugs get described in public, how prescribing thresholds get written, and whether a payer files a heart-outcome indication under cosmetic spending. A patient who stops treatment because the scale disappointed them is responding to the weight framing, not to the indication the drug was actually licensed against. Indications and reimbursement rules differ by country, which is why our regulation hub tracks them separately from the clinical evidence.

What we do not yet know

None of these trials was built to separate a benefit carried by weight loss from a benefit travelling some other route. GLP-1 receptors are present in vascular and cardiac tissue, blood pressure and inflammatory markers shift on treatment, and glucose control improves. Any of those could be doing the work. The trials show that events fall. They do not show why, and readers should be wary of anyone who states the mechanism with confidence. Our earlier write-up of the pooled cardiovascular meta-analysis covers how consistent the effect looks across trials, and is the better place for the outcomes numbers in aggregate.

Two other gaps are worth naming. SOUL's kidney secondary endpoints were null, so the kidney result is not uniform across the semaglutide programme^[5]. And the JACC editorial is indexed without an abstract, so the public record of its argument is the title, the keyword list and the full text behind the journal^[1]. We have anchored this piece on the trials rather than paraphrase an argument we cannot quote in full.

What this means if you are the one deciding

If you have established cardiovascular disease or chronic kidney disease, the question worth taking to an appointment is not how much weight will I lose. It is whether the outcome evidence applies to someone with your history, and what the licensed indication supports where you live. The semaglutide page sets out the drug and its regulatory position country by country, and the tirzepatide page covers the dual agonist, whose outcomes programme is at a different stage.

This article is educational and is not medical advice. It does not recommend any dose, product or supplier. Decisions about starting, continuing or stopping a GLP-1 medicine belong with a qualified healthcare provider who knows your history and your cardiovascular and kidney risk.