Does tirzepatide have the same cardiovascular evidence as semaglutide?

No. SELECT tested semaglutide. Outcome evidence belongs to the compound tested and does not transfer across a drug class.

Is the cardiovascular benefit just from weight loss?

Post-hoc analysis of SELECT suggested it was not fully explained by weight reduction, but that remains under investigation rather than established.

Are these indications approved in the UK?

Approvals differ by regulator, indication and product. Several submissions described here have been under review rather than authorised.

GLP-1 & Incretin Science

GLP-1 Drugs Beyond Weight Loss

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-234 cited sources

Incretin agonists have moved well beyond weight and glucose. SELECT demonstrated a 20% reduction in major adverse cardiovascular events with semaglutide in 17,604 participants. Further indications including heart failure with preserved ejection fraction, chronic kidney disease and peripheral artery disease have followed or are under regulatory review.

Key facts

SELECT: 17,604 participants, 20% MACE reduction
SELECT population: BMI ≥27, established CVD, no diabetes
HFpEF: Under FDA review for semaglutide
HFpEF signal: NYHA class improvement 32.6% vs 21.5%
Kidney disease: FLOW trial — renal events and mortality
Peripheral artery disease: Under review; walking distance endpoint
Retatrutide: CVD and kidney trials within TRIUMPH

Why cardiovascular outcomes changed the category

Weight reduction is a surrogate endpoint. It is assumed to predict benefit, but assumption is not demonstration, and obesity medicines have a long history of failing on hard outcomes. SELECT tested the real question directly in 17,604 people aged 45 or over with a BMI of 27 or above and established cardiovascular disease but no diabetes, across 41 countries, and found a 20% reduction in major adverse cardiovascular events. That converted the class from plausible to demonstrated.

The finding that complicated the story

Post-hoc analysis of SELECT suggested the cardiovascular benefit was not fully explained by the amount of weight lost. If correct, incretin agonism is doing something to cardiovascular risk beyond making people smaller — which would be a genuinely different claim about the mechanism, and one that remains under investigation rather than settled.

Heart failure with preserved ejection fraction

HFpEF has been an unusually difficult indication with few effective options. Semaglutide has been under FDA review for HFpEF with obesity, with a prespecified analysis reporting that 32.6% of treated participants improved by at least one NYHA functional class against 21.5% on placebo. Functional class is a patient-relevant measure rather than a laboratory surrogate, which is part of why it drew attention.

Kidney outcomes

The FLOW trial reported reductions in renal events, major adverse cardiovascular events and mortality in people with chronic kidney disease and type 2 diabetes. Kidney and cardiovascular risk are tightly linked, and a compound acting on both is more valuable than one acting on either alone. Retatrutide's programme includes both a cardiovascular outcomes study and a dedicated renal-function trial.

Peripheral artery disease

Semaglutide has been submitted for peripheral artery disease in type 2 diabetes, on trial data reporting improved walking distance and quality of life. Walking distance is a direct functional measure, and PAD is a condition where symptomatic improvement is what patients actually notice.

How to read this expansion sceptically

Each indication rests on its own trial and its own endpoints, and none transfers automatically to another compound in the class. Tirzepatide produces greater weight reduction than semaglutide but does not inherit SELECT's cardiovascular result — that evidence belongs to the molecule that was tested. Outcome data takes years and large populations to generate, which is why the newest and most effective compounds have the least of it.

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Does tirzepatide have the same cardiovascular evidence as semaglutide?: No. SELECT tested semaglutide. Outcome evidence belongs to the compound tested and does not transfer across a drug class.
Is the cardiovascular benefit just from weight loss?: Post-hoc analysis of SELECT suggested it was not fully explained by weight reduction, but that remains under investigation rather than established.
Are these indications approved in the UK?: Approvals differ by regulator, indication and product. Several submissions described here have been under review rather than authorised.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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