GLP-1 Weight Loss Drugs: What the Trials Actually Show

These are the most effective weight-loss drugs ever brought to market, and the trial evidence behind them is unusually good. There is also a finding in that evidence that men in particular should know, and that almost nobody reports.

How much weight, actually

SURMOUNT-5 is the trial that matters most for this question, because it put the two drugs against each other rather than against placebo. It randomised 751 adults with obesity and no diabetes, mean age 45, to maximum tolerated doses of either drug for 72 weeks.

Tirzepatide won on every measure in that trial, including tolerability. It acts on two receptors — GLP-1 and GIP — rather than one, which is the usual explanation offered for the difference.

For context on how large these numbers are: the lifestyle intervention trials that represent the best non-drug results produce roughly 5 to 10% weight loss, and bariatric surgery produces 25 to 30%. These drugs sit between the two, closer to surgery than to dieting.

The number for men

This is the part worth slowing down for.

The SELECT trial followed 17,604 people on semaglutide for up to five years and published its weight data separately. Mean weight loss at 208 weeks was 10.2% against 1.5% on placebo — sustained, with no rebound over four years, and a waist reduction of 7.7 cm.

But broken down by sex, the treatment difference was 11.1% in women and 7.5% in men.

Men lost meaningfully less. That is not a reason not to take them — 7.5% sustained for four years is a large and clinically valuable result, and it is more than most men achieve by any other means. But if your expectations were set by before-and-after photographs, the trial average for a man is lower than the number in your head, and knowing that in advance is the difference between a drug that worked and a drug that disappointed you.

Worth noting too that the SELECT figure is lower than the SURMOUNT-5 and STEP figures for a reason: SELECT enrolled people with established cardiovascular disease, at a lower dose ceiling in some cases, and followed them far longer.

The finding that changed the argument

SELECT was not primarily a weight-loss trial. It enrolled people aged 45 and over with a BMI of 27 or above, established cardiovascular disease, and no diabetes — and asked whether semaglutide prevented heart attacks and strokes.

It did. Major adverse cardiac events — cardiovascular death, non-fatal heart attack, non-fatal stroke — fell by 20%, with all three components contributing.

That result reframes the whole category. Before it, this was a cosmetic drug with metabolic benefits and an unknown long-term profile. After it, semaglutide is a cardiovascular drug in people with heart disease and obesity, and the weight loss is one of several mechanisms by which it appears to work.

It matters more for men than the headline suggests, because the population SELECT studied — middle-aged, overweight, existing cardiovascular disease — is exactly the population in which erectile dysfunction shows up as an early vascular warning. The same arteries are involved.

Side effects and who stops

The side effects are overwhelmingly gastrointestinal, and they cluster during dose escalation: nausea, vomiting, diarrhoea, constipation. Most are mild to moderate and most settle.

The discontinuation figures from SURMOUNT-5 are the useful measure of how bad they get in practice: 5.6% stopped semaglutide because of them, 2.7% stopped tirzepatide. So roughly one man in twenty on semaglutide, and one in forty on tirzepatide, found them intolerable.

Rarer but more serious concerns that belong in the conversation with a prescriber: gallbladder disease (rapid weight loss of any kind raises gallstone risk), pancreatitis, and a boxed warning about thyroid C-cell tumours based on rodent data, which makes these drugs unsuitable for anyone with a personal or family history of medullary thyroid carcinoma or MEN2.

The muscle question — whether the weight coming off is fat or lean tissue — gets its own page, because the answer is more reassuring than the headlines and more actionable than most coverage admits. See what the body composition data actually show.

How long you are signing up for

Indefinitely, on current evidence, and this is the single most under-communicated fact in the category.

When semaglutide was withdrawn in the STEP 1 extension, participants regained about two-thirds of the lost weight within a year, and blood pressure returned to baseline. The full numbers are in what happens when you stop.

Obesity behaves like a chronic condition in this respect. Nobody expects blood pressure to stay down after stopping an antihypertensive, and the same logic applies here — but the marketing rarely frames it that way, and people budget for a course rather than for a prescription they keep.

Who these are actually for

The approved indication is a BMI of 30 or above, or 27 and above with a weight-related condition — high blood pressure, type 2 diabetes, sleep apnoea, dyslipidaemia. That is the population the trials studied and the population the results apply to.

Two things are worth adding for men specifically.

If your testosterone is low and you are carrying excess weight, the weight is a plausible cause. Fat tissue converts testosterone to oestradiol and suppresses the signal to produce more. Weight loss reverses it measurably — a low-calorie diet raised total testosterone by about 83 ng/dL on average, and bariatric surgery by about 250. The numbers are here. Nobody has yet published equivalent figures for GLP-1-driven weight loss at scale, so that specific claim is not yet evidenced — but the mechanism is the same one.

Do not buy these from a website that does not want to see you. The compounded market has its own set of problems, and they changed substantially when the shortage ended — covered here.

This article is for information only and is not medical advice. It cannot account for your individual circumstances. Talk to a doctor about your own situation, particularly before starting or stopping any prescription medication.