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Deep Dive10 min read

GLP-1 Cardiovascular Outcomes: From SUSTAIN-6 to SELECT and the SURPASS-CVOT Pending

Trial-level walkthrough of GLP-1 cardiovascular outcome evidence. SUSTAIN-6 in T2DM, SELECT in obesity without diabetes, and the SURPASS-CVOT tirzepatide gap.

By TH Labs Research Desk · Research Editor · · Compliance reviewed by TH Labs Compliance Desk

The GLP-1 cardiovascular outcomes evidence base is one of the cleanest examples in recent metabolic medicine of an evidence base evolving across a coherent program of trials. It begins with SUSTAIN-6 in type-2 diabetes (semaglutide), expands to SELECT in obesity without diabetes, and currently extends to the pending SURPASS-CVOT in tirzepatide. This article walks through the trial-level evidence, the mechanism reasoning that connects GLP-1 agonism to cardiovascular outcomes, and the open questions the next wave of trials will close.

SUSTAIN-6: the foundational trial

Marso and colleagues (2016, NEJM) 1 reported SUSTAIN-6, the first large-scale GLP-1 cardiovascular outcomes trial for semaglutide. Design: 3,297 patients with type-2 diabetes at high cardiovascular risk randomised to weekly subcutaneous semaglutide (0.5 or 1.0 mg) or placebo, on top of standard care. Primary composite endpoint: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE). Median follow-up: 2.1 years.

Result: semaglutide reduced 3-point MACE by 26% (HR 0.74, 95% CI 0.58–0.95, p=0.02 for non-inferiority and p=0.02 for superiority). The signal was driven primarily by reduced non-fatal stroke. Cardiovascular death and non-fatal MI also trended in the same direction but did not individually reach statistical significance.

SUSTAIN-6 established two things. First, GLP-1 cardiovascular benefit in T2DM was not a fluke from earlier liraglutide (LEADER) data — it replicated in a chemically distinct GLP-1 with a different half-life profile. Second, the trial design template (composite MACE primary endpoint, dedicated cardiovascular event adjudication, standard-care background) became the model for subsequent GLP-1 CVOTs.

STEP-1 and SURMOUNT-1: the obesity-without-diabetes expansion

Before SELECT could ask the cardiovascular question in obesity, the field needed to establish what GLP-1 agonism did in obesity without diabetes at all. Two trials anchor this.

STEP-1 (Wilding 2021, NEJM) 3 randomised 1,961 adults with overweight or obesity (BMI ≥27) to semaglutide 2.4 mg weekly or placebo over 68 weeks. Mean weight loss: 14.9% with semaglutide vs 2.4% with placebo. The trial was not powered for cardiovascular outcomes — but the magnitude of weight, blood pressure, and lipid changes implied a cardiovascular benefit if a properly powered trial were run.

SURMOUNT-1 (Jastreboff 2022, NEJM) 4 did the equivalent for tirzepatide: 2,539 adults with obesity (BMI ≥30) without diabetes randomised to tirzepatide (5, 10, or 15 mg) or placebo over 72 weeks. Mean weight loss: 15.0%, 19.5%, and 20.9% across the three doses vs 3.1% with placebo. Larger weight-loss magnitudes than STEP-1, especially at the 15 mg dose.

These two trials set up the cardiovascular question that SELECT would answer.

SELECT: cardiovascular benefit beyond diabetes

Lincoff and colleagues (2023, NEJM) 2 reported SELECT: 17,604 adults with established cardiovascular disease and overweight or obesity but without diabetes randomised to weekly semaglutide 2.4 mg or placebo, on top of standard cardiovascular care. Mean follow-up: 39.8 months. Primary composite endpoint: 3-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke).

Result: semaglutide reduced 3-point MACE by 20% (HR 0.80, 95% CI 0.72–0.90, p<0.001). The benefit appeared early — Kaplan-Meier curves separated within the first year — and persisted across follow-up. Secondary endpoints (heart failure composite, all-cause mortality) also trended favourably.

SELECT was the field-defining result. It demonstrated that GLP-1 cardiovascular benefit is not contingent on the presence of diabetes. The benefit appears in a metabolic-risk population (overweight/obese with established CVD) where the baseline glycaemic state is non-diabetic. The implication for mechanism: GLP-1 receptor effects on cardiovascular outcomes are not purely glycaemic.

Why the cardiovascular benefit, mechanistically

Several proposed pathways contribute, and the relative weight of each is unsettled.

Glycaemic improvement. In T2DM (the SUSTAIN-6 population), reduced HbA1c reduces microvascular and macrovascular complications. This is the canonical pathway and remains a contributor in diabetic populations.

Weight loss. Semaglutide-induced weight loss reduces myocardial strain, lowers systolic and diastolic blood pressure, improves lipid profile (reduces triglycerides, modest LDL improvement), and reduces visceral adiposity. The cardiovascular effect of weight loss in obesity is independently established; semaglutide produces it more reliably than diet-and-exercise interventions at scale.

Direct vascular effects. GLP-1 receptors are expressed in vascular endothelium, smooth muscle, and myocardium. Preclinical and surrogate-endpoint data suggest direct anti-inflammatory and endothelium-protective effects. The SELECT result (benefit in obesity without diabetes) is most easily explained if direct vascular effects contribute substantially to the cardiovascular signal independent of glycaemic effects.

Reduced systemic inflammation. GLP-1 agonism reduces multiple inflammatory markers. Whether this is causal or correlative for cardiovascular outcomes is unsettled.

The cleanest summary: the cardiovascular benefit is real, replicates across two distinct trials in two distinct populations (T2DM and obesity-without-diabetes), and appears to be mediated by a combination of metabolic (weight, blood pressure, lipid) and direct vascular pathways with the relative weight depending on the population.

The tirzepatide gap: SURPASS-CVOT is the pending result

Tirzepatide has produced larger metabolic effects than semaglutide at the doses each is used clinically — both in head-to-head T2DM (SURPASS-2, Frías 2021) 5 and in obesity (SURMOUNT-1 vs STEP-1 implicitly). Mechanism reasoning predicts cardiovascular benefit should be at least as large as semaglutide's.

But the SURPASS-CVOT trial is still running at time of publication. Until that trial reads out, the cardiovascular evidence base for tirzepatide is built from surrogate endpoints (blood pressure, lipid panel, weight, glycaemic control changes from SURPASS and SURMOUNT trials) — not direct MACE adjudication.

This creates a meaningful asymmetry in the current evidence base. Semaglutide has dedicated CVOT evidence in two populations. Tirzepatide does not yet. Researchers designing protocols with a cardiovascular endpoint should account for this asymmetry in their choice between the two compounds.

What's settled vs. exploratory

Settled:

  • Semaglutide reduces 3-point MACE in T2DM at high cardiovascular risk (SUSTAIN-6, 26% relative reduction)
  • Semaglutide reduces 3-point MACE in established CVD with obesity but without diabetes (SELECT, 20% relative reduction)
  • The cardiovascular benefit appears early (within first year on Kaplan-Meier) and persists
  • The mechanism is mixed glycaemic + weight-loss + direct vascular, with weights varying by population

Exploratory:

  • Tirzepatide's cardiovascular outcomes (SURPASS-CVOT pending)
  • Retatrutide's cardiovascular outcomes (no dedicated CVOT yet — earlier stage in the program)
  • Long-term cardiovascular benefit beyond the 3-4 year trial windows
  • Primary prevention in lower-cardiovascular-risk populations
  • Combinatorial cardiovascular effects with SGLT2 inhibitors (the other class with robust independent CVOT evidence)

For research protocol selection

If the research question is cardiovascular risk reduction, semaglutide currently has the cleanest evidence base. For T2DM populations the canonical reference is SUSTAIN-6; for obesity-without-diabetes the reference is SELECT. For trials in tirzepatide or retatrutide cardiovascular endpoints, the evidence base is currently surrogate-endpoint and pending dedicated CVOT readouts.

For the head-to-head metabolic comparison between semaglutide and tirzepatide, see the Semaglutide vs Tirzepatide trials article. For the broader GLP-1 program overview, see the GLP-1 research overview. For the triple-agonist next-generation pipeline, see the Retatrutide deep-dive.

Frequently asked

Why does GLP-1 cardiovascular evidence matter for non-diabetes research?
Because the SELECT trial (Lincoff 2023, NEJM) extended cardiovascular benefit to people with established cardiovascular disease and obesity without diabetes — a 20% reduction in major adverse cardiovascular events (MACE) over a mean 39.8-month follow-up. Before SELECT, GLP-1 cardiovascular benefit was framed as a T2DM-specific finding (SUSTAIN-6, LEADER). SELECT reframed the indication landscape: the benefit appears in metabolic risk populations broadly, not only in patients with established diabetes. This matters for research protocols that aim to study cardiovascular risk reduction independent of glycaemic control.
What did SUSTAIN-6 actually find?
Marso 2016 (NEJM) randomised 3,297 patients with type-2 diabetes at high cardiovascular risk to weekly semaglutide (0.5 or 1.0 mg) or placebo over a median 2.1 years. The primary composite endpoint (cardiovascular death, non-fatal MI, non-fatal stroke) was reduced by 26% with semaglutide. The signal was driven primarily by reduced non-fatal stroke. SUSTAIN-6 was the first large-scale GLP-1 trial to show cardiovascular benefit and established the framework that subsequent GLP-1 CVOTs followed.
Does tirzepatide have the same cardiovascular evidence?
Not yet. The dedicated tirzepatide cardiovascular outcomes trial (SURPASS-CVOT) is ongoing at time of publication. Short-term surrogate endpoints (blood pressure, lipids, weight, glycaemic control) suggest cardiovascular benefit is mechanistically likely, and the SURPASS-2 head-to-head versus semaglutide showed greater metabolic effect at tirzepatide doses. But the definitive composite-MACE evidence equivalent to SUSTAIN-6 or SELECT has not yet been published for tirzepatide. Until SURPASS-CVOT reads out, semaglutide retains the stronger cardiovascular evidence base.
What's the mechanism connecting GLP-1 agonism to cardiovascular outcomes?
Multiple proposed pathways, none individually sufficient to explain the effect size. (1) Glycaemic improvement reduces microvascular and macrovascular damage. (2) Weight loss reduces myocardial strain, lowers blood pressure, and improves lipid profile. (3) Direct GLP-1 receptor effects in vascular endothelium and myocardium may exist independently of weight and glycaemic effects. (4) Reduced systemic inflammation. The relative contribution of each is an active research area; the cardiovascular benefit in SELECT (obesity without diabetes) suggests the mechanism is not purely glycaemic, since the baseline glycaemia in SELECT enrolment was non-diabetic.
Are the weight loss effects in SELECT comparable to STEP-1 and SURMOUNT-1?
SELECT was a cardiovascular outcomes trial — weight loss was a secondary measure. Mean weight loss in SELECT was approximately 9.4% at week 104, substantial but lower than STEP-1's 14.9% at week 68 (Wilding 2021) or SURMOUNT-1's 20.9% at 15 mg tirzepatide at week 72 (Jastreboff 2022). The trial designs differed substantially: SELECT used established CVD patients on standard cardiovascular medication, vs the otherwise healthy obesity populations in STEP-1 and SURMOUNT-1. The lower weight-loss magnitude in SELECT reflects both the population and the secondary-endpoint focus, not a different drug effect.
What does this evidence base mean for selecting between semaglutide and tirzepatide in a research protocol with a cardiovascular research question?
Semaglutide has the direct cardiovascular evidence (SUSTAIN-6 in T2DM, SELECT in obesity without diabetes) and is the appropriate choice when cardiovascular risk reduction is the primary research endpoint. Tirzepatide may produce larger metabolic effects but lacks the dedicated CVOT data — researchers using tirzepatide for a cardiovascular question are extrapolating from surrogate endpoints. Once SURPASS-CVOT reads out, this calculus changes.
How fast did the cardiovascular signal appear in SELECT?
Lincoff 2023 reported that the MACE-reduction effect appeared early and persisted across the follow-up. Kaplan-Meier curves separated within the first year. This is consistent with mechanism reasoning: blood pressure, lipid, and inflammatory changes appear within months of semaglutide initiation and would be expected to reduce acute thrombotic events relatively quickly, rather than requiring years of cumulative effect.

References

  1. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6). N Engl J Med. 2016. PMID: 27633186
  2. Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023. PMID: 37952131
  3. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021. PMID: 33567185
  4. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022. PMID: 35658024
  5. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). N Engl J Med. 2021. PMID: 34170647

All references verified against PubMed via NCBI E-utilities.

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