Evidence reference only. Not medical advice, not a dosing guide, and not a recommendation to use any drug.
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Heart and circulation

22 findings across 11 drug records. Domain pages are descriptive indexes, not advice.

The grade rates how strong the evidence is, not how good or safe the drug is. A low or very-low grade means the evidence is thin, not that an effect is harmful or ruled out.

Most represented records

Semaglutide (9)

Dulaglutide (2)

Retatrutide (2)

Tirzepatide (2)

Albiglutide (1)

Efpeglenatide (1)

Exenatide (1)

GLP-1 and glucagon dual-agonist class (1)

Evidence spread

High evidence 10 Moderate evidence 12 Low evidence 0 Very low evidence 0

Albiglutide WITHDRAWN
Heart and circulation Decrease
High evidence

In T2D with established CVD, albiglutide reduced MACE versus placebo, a superiority result driven notably by reduced myocardial infarction.

Hernandez AF et al., Lancet, 2018 Source
PopulationHARMONY Outcomes: N=9463; T2D with established CVD; double-blind placebo-controlled RCT; median 1.6 years (short).
Fundingindustry - GlaxoSmithKline
Comparatorsplacebo
GLP-1-based therapies, multi-agent STATUS UNKNOWN
Heart and circulation Decrease
Moderate evidence

Class-level meta-analysis of 8 GLP-1RA CVOTs in T2D: ~14% MACE reduction, with consistent reductions in each MACE component, all-cause mortality, HF hospitalisation...

Sattar N, Lee MMY, Kristensen SL et al., Lancet Diabetes Endocrinol, 2021 Source
Full findingClass-level meta-analysis of 8 GLP-1RA CVOTs in T2D: ~14% MACE reduction, with consistent reductions in each MACE component, all-cause mortality, HF hospitalisation and a kidney composite; no significant heterogeneity by structural homology or eight other subgroups.
PopulationSystematic review and random-effects meta-analysis of 8 placebo-controlled GLP-1RA CVOTs (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, REWIND, PIONEER-6, AMPLITUDE-O); PROSPERO CRD42021259711.
Fundingacademic/independent - no funding (Funding: None)
Comparatorsplacebo (pooled across constituent trials)
Dulaglutide MARKETED
Heart and circulation Decrease
High evidence

In T2D with a majority WITHOUT established CVD (primary-prevention-weighted), dulaglutide reduced MACE versus placebo, driven notably by reduced non-fatal stroke.

Gerstein HC et al. (REWIND), Lancet, 2019 Source
PopulationREWIND: N=9901; T2D, broad CV-risk (majority primary-prevention); double-blind placebo-controlled RCT; median 5.4 years (longest GLP-1 CVOT).
Fundingindustry - Eli Lilly
Comparatorsplacebo
Dulaglutide MARKETED
Heart and circulation Decrease
Moderate evidence

In a dedicated REWIND analysis, dulaglutide reduced total stroke, driven by ischaemic stroke, with no effect on haemorrhagic stroke and no change in post-stroke...

Gerstein HC, Hart R, Colhoun HM, et al. The effect of dulaglutide on stroke: an explorato... Source
Full findingIn a dedicated REWIND analysis, dulaglutide reduced total stroke, driven by ischaemic stroke, with no effect on haemorrhagic stroke and no change in post-stroke disability severity.
PopulationREWIND stroke analysis: N=9901 type 2 diabetes, broad CV risk; double-blind placebo-controlled randomised trial; median follow-up 5.4 years; NCT01394952.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Comparatorsplacebo
Efpeglenatide INVESTIGATIONAL
Heart and circulation Decrease
Moderate evidence

In T2D with CVD or kidney disease plus another risk factor, efpeglenatide reduced MACE versus placebo, with a dose-dependent trend, and reduced a kidney composite. An...

Gerstein HC et al., N Engl J Med, 2021 Source
Full findingIn T2D with CVD or kidney disease plus another risk factor, efpeglenatide reduced MACE versus placebo, with a dose-dependent trend, and reduced a kidney composite. An exendin-4-based agent showing hard CV benefit.
PopulationAMPLITUDE-O: N=4076; T2D with CVD or kidney disease; double-blind placebo-controlled RCT; median 1.8 years.
Fundingindustry - Sanofi (efpeglenatide, AMPLITUDE-O; disclosed)
Comparatorsplacebo
Exenatide MIXED STATUS
Heart and circulation No change
High evidence

In T2D (most with prior CVD), once-weekly exenatide was non-inferior to placebo for MACE; superiority was not met (HR favoured exenatide, CI crossed 1).

Holman RR et al., N Engl J Med, 2017 Source
PopulationEXSCEL: N=14,752; T2D, ~73% with prior CVD; double-blind placebo-controlled pragmatic RCT; median 3.2 years.
Fundingindustry-Amylin Pharmaceuticals (AstraZeneca subsidiary)
Comparatorsplacebo
GLP-1 and glucagon dual-agonist class STATUS UNKNOWN
Heart and circulation Not directional
Moderate evidence

ABSENCE OF EVIDENCE: as of the 2026-06-21 (non-exhaustive) sweep, no powered hard-endpoint CV outcome trial has REPORTED for any GLP-1/glucagon dual agonist; the class...

Absence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial recor... Source
Full findingABSENCE OF EVIDENCE: as of the 2026-06-21 (non-exhaustive) sweep, no powered hard-endpoint CV outcome trial has REPORTED for any GLP-1/glucagon dual agonist; the class sits in the phase-2/early-phase-3 era with weight, glycaemic, hepatic (MASH) and CV-risk-factor readouts only. This absence is NOT reassurance: the glucagon arm's CV-risk hypothesis has never been tested at hard-endpoint level in any agent, so the net effect is UNMEASURED, not measured-and-null. It is an evidence GAP, not a demonstration of CV neutrality or harm, and does not exclude ongoing/unreported trials.
PopulationClass-level absence statement (cotadutide, survodutide, mazdutide, pemvidutide, efinopegdutide); efficacy/surrogate data only; no dedicated CVOT reported.
Fundingacademic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)
Liraglutide MARKETED
Heart and circulation Decrease
High evidence

In T2D at high CV risk, liraglutide reduced MACE versus placebo; unlike SUSTAIN-6, CV death and all-cause death were also significantly reduced.

Marso SP et al. (LEADER), NEJM, 2016 Source
PopulationLEADER: N=9340; T2D high CV risk; double-blind placebo-controlled RCT; median 3.8 years.
Fundingindustry-Novo Nordisk + academic-NIH (co-funded)
Comparatorsplacebo
Lixisenatide WITHDRAWN
Heart and circulation No change
High evidence

In T2D after a recent acute coronary syndrome, lixisenatide was non-inferior but NOT superior to placebo for the CV composite: a fully NEUTRAL CV outcome.

Pfeffer MA et al. (ELIXA), NEJM, 2015 Source
PopulationELIXA: N=6068; T2D with ACS within 180 days; double-blind placebo-controlled RCT; median 25 months.
Fundingindustry - Sanofi (disclosed in publication)
Comparatorsplacebo
Retatrutide INVESTIGATIONAL
Heart and circulation Not directional
Moderate evidence

OPEN QUESTION: no outcome trial isolates a glucagon (GCGR) arm, so the net CV-OUTCOME consequence of glucagon agonism is unresolved. The concern, whether...

Absence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial recor... Source
Full findingOPEN QUESTION: no outcome trial isolates a glucagon (GCGR) arm, so the net CV-OUTCOME consequence of glucagon agonism is unresolved. The concern, whether glucagon-driven sustained heart-rate elevation or increased cardiac workload could ERODE the CV benefit established for GLP-1 (with the GIP-containing dual agonist shown CV-safe at whole-molecule level via SURPASS-CVOT, GIP not isolated), is recorded as a tension to be settled by retatrutide's outcome programme, not as a quantified finding.
PopulationNo isolating trial exists. The only dedicated triple-agonist CVOT is TRIUMPH-Outcomes (NCT06383390), hard endpoints ~2029.
Fundingacademic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)
Retatrutide INVESTIGATIONAL
Heart and circulation Not directional
Moderate evidence

The retatrutide phase-2 trial produced NO hard CV-outcome data; MACE and CV death were not endpoints. Its heart-rate rise is a CV-mechanism signal held in the...

Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526 Source
Full findingThe retatrutide phase-2 trial produced NO hard CV-outcome data; MACE and CV death were not endpoints. Its heart-rate rise is a CV-mechanism signal held in the heart-rate / CV-mechanism thread, deliberately not counted in the cv-outcomes domain to avoid double-counting.
PopulationJastreboff AM et al. phase-2 (NCT04881760): N=338 adults with obesity (entry BMI-based: >=30, or 27-30 with a weight-related condition); retatrutide vs placebo, 48 weeks; double-blind RCT.
Fundingindustry-Eli Lilly
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
High evidence

In adults aged >=45 with pre-existing CVD and overweight/obesity (BMI >=27) but WITHOUT diabetes, once-weekly s.c. semaglutide 2.4 mg reduced 3-point MACE (CV death,...

Lincoff AM et al. (SELECT), NEJM, 2023 Source
Full findingIn adults aged >=45 with pre-existing CVD and overweight/obesity (BMI >=27) but WITHOUT diabetes, once-weekly s.c. semaglutide 2.4 mg reduced 3-point MACE (CV death, non-fatal MI, non-fatal stroke) versus placebo.
PopulationSELECT: N=17,604; established CVD + overweight/obesity, no diabetes; multicentre double-blind placebo-controlled event-driven superiority RCT; mean follow-up 39.8 months.
Fundingindustry-Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
High evidence

In T2D at high CV risk, s.c. semaglutide reduced first MACE versus placebo, meeting non-inferiority then superiority; reduction driven mainly by non-fatal stroke and...

Marso SP et al. (SUSTAIN-6), NEJM, 2016 Source
Full findingIn T2D at high CV risk, s.c. semaglutide reduced first MACE versus placebo, meeting non-inferiority then superiority; reduction driven mainly by non-fatal stroke and MI, with CV death unchanged.
PopulationSUSTAIN-6: N=3297; T2D high CV risk; double-blind placebo-controlled pre-approval CV-safety RCT; median 2.1 years.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation No change
High evidence

In T2D at high CV risk, once-daily oral semaglutide was non-inferior to placebo for MACE but did NOT demonstrate superiority (CV-safety trial, underpowered for...

Husain M et al. (PIONEER 6), NEJM, 2019 Source
Full findingIn T2D at high CV risk, once-daily oral semaglutide was non-inferior to placebo for MACE but did NOT demonstrate superiority (CV-safety trial, underpowered for superiority).
PopulationPIONEER 6: N=3183; T2D high CV risk; double-blind placebo-controlled CV-safety RCT; median 15.9 months.
Fundingindustry-Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
High evidence

In T2D with established ASCVD, CKD, or both, oral semaglutide 14 mg reduced MACE versus placebo in a dedicated superiority CVOT; the kidney composite did not differ.

McGuire DK, Marx N, Buse JB et al., N Engl J Med, 2025 Source
PopulationSOUL: N=9650; T2D age >=50, HbA1c 6.5-10.0%, with ASCVD and/or CKD; double-blind placebo-controlled event-driven superiority RCT; mean follow-up 47.5 months.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
Moderate evidence

Prespecified SELECT analysis: semaglutide produced sustained weight loss across every baseline BMI category to 4 years (208 weeks). The trial's headline 20% MACE...

Ryan DH, Lingvay I, Deanfield J et al., Nat Med, 2024 Source
Full findingPrespecified SELECT analysis: semaglutide produced sustained weight loss across every baseline BMI category to 4 years (208 weeks). The trial's headline 20% MACE reduction is restated as context; this paper reports weight-by-BMI, not a per-subgroup MACE analysis.
PopulationSELECT prespecified weight/BMI secondary analysis (prespecified secondary of the N=17,604 double-blind RCT); up to 208 weeks.
Fundingindustry - Novo Nordisk (SELECT sponsor)
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
Moderate evidence

CROSS-DOMAIN (kidney trial with CV components): in T2D with CKD, s.c. semaglutide 1.0 mg reduced the major-kidney-disease composite (which includes CV death) and...

Perkovic V et al., N Engl J Med, 2024 Source
Full findingCROSS-DOMAIN (kidney trial with CV components): in T2D with CKD, s.c. semaglutide 1.0 mg reduced the major-kidney-disease composite (which includes CV death) and separately reduced CV death, MACE and all-cause death.
PopulationFLOW: N=3533; T2D with CKD (eGFR 25-75, raised UACR); double-blind placebo-controlled RCT; median 3.4 years (stopped early at interim).
Fundingindustry - Novo Nordisk (FLOW sponsor)
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation Decrease
Moderate evidence

In the prespecified SELECT mediation analysis, semaglutide's cardiovascular benefit was largely INDEPENDENT of baseline adiposity and of the amount of weight lost -...

Deanfield J, Lincoff AM, Kahn SE et al. Semaglutide and cardiovascular outcomes by baseli... Source
Full findingIn the prespecified SELECT mediation analysis, semaglutide's cardiovascular benefit was largely INDEPENDENT of baseline adiposity and of the amount of weight lost - roughly two-thirds of the MACE reduction was not explained by waist-circumference change - indicating mechanisms of CV benefit beyond adiposity reduction. CRITICAL: this is the evidence the popular 'works even without weight loss' claim rests on, and it is SEMAGLUTIDE-SPECIFIC; there is NO equivalent tirzepatide mediation analysis, so the weight-independent CV claim must NOT be transferred to tirzepatide (the SURMOUNT-MMO obesity CV trial is ongoing).
PopulationPrespecified analysis of SELECT (NCT03574597): n=17,604 adults >=45 y, BMI >=27, with established CVD and WITHOUT diabetes; semaglutide 2.4 mg weekly vs placebo; 41 countries; primary outcome time-to-first MACE (CV death, non-fatal MI, non-fatal stroke). Mediation via time-varying adjustment for waist/weight change + week-20 and week-104 landmarks.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation No change
Moderate evidence

In SELECT, semaglutide's cardiovascular-death component did not independently reach significance, despite a positive composite MACE and a significant...

Lincoff AM et al. (SELECT), NEJM, 2023 Source
Full findingIn SELECT, semaglutide's cardiovascular-death component did not independently reach significance, despite a positive composite MACE and a significant all-cause-mortality reduction - a component null, NOT evidence that semaglutide fails to reduce CV death.
PopulationPeer-reviewed RCT (measured null)
Fundingindustry-Novo Nordisk
Comparatorsplacebo
Semaglutide MARKETED
Heart and circulation No change
Moderate evidence

In PIONEER-6, oral semaglutide showed no significant effect on the individual non-fatal MI or stroke components; the MACE 'non-superiority' is a design feature of a...

Husain M et al. (PIONEER 6), NEJM, 2019 Source
Full findingIn PIONEER-6, oral semaglutide showed no significant effect on the individual non-fatal MI or stroke components; the MACE 'non-superiority' is a design feature of a non-inferiority safety trial, not a measured efficacy null.
PopulationPeer-reviewed RCT (measured null)
Fundingindustry-Novo Nordisk
Comparatorsplacebo
Tirzepatide MARKETED
Heart and circulation No change
High evidence

In T2D with established ASCVD, tirzepatide was NON-INFERIOR to dulaglutide for 3-point MACE but did NOT meet superiority. The comparator is a CV-proven GLP-1RA, so...

Nicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 ... Source
Full findingIn T2D with established ASCVD, tirzepatide was NON-INFERIOR to dulaglutide for 3-point MACE but did NOT meet superiority. The comparator is a CV-proven GLP-1RA, so this establishes that the GIP-containing dual-agonist MOLECULE is CV-safe at the whole-molecule level; it does NOT isolate the GIP receptor's own contribution, because tirzepatide's GLP-1 moiety differs from dulaglutide's (cross-ref thread 11), so the null delta cannot be read as 'GIP adds nothing' rather than as offsetting differences between the two GLP-1 components. Despite materially greater HbA1c and weight reduction, the second incretin arm bought no incremental hard MACE.
PopulationSURPASS-CVOT: N=13,299 randomised (NCT04255433); T2D + established ASCVD, age >=40, HbA1c 7.0-10.5%, BMI >=25; double-blind active-comparator; tirzepatide up to 15 mg vs dulaglutide 1.5 mg; median follow-up ~4.0 years.
Fundingindustry - Eli Lilly (trial sponsor)
Comparatorsdulaglutide
Tirzepatide MARKETED
Heart and circulation No change
Moderate evidence

Pre-specified pre-registration pooled CV meta-analysis of the SURPASS phase-3 programme found tirzepatide did NOT increase MACE versus controls; the point estimate was...

Sattar N, McGuire DK, Pavo I et al., Nat Med, 2022 Source
Full findingPre-specified pre-registration pooled CV meta-analysis of the SURPASS phase-3 programme found tirzepatide did NOT increase MACE versus controls; the point estimate was favourable but the CI crossed 1 (exploratory CV-safety evidence, not powered superiority).
PopulationPre-specified pooled meta-analysis of 7 RCTs (>=26 weeks) in the SURPASS T2D programme; 4,887 tirzepatide vs 2,328 control; controls = placebo and active comparators.
Fundingindustry - Eli Lilly and Company
Comparatorsplacebo; semaglutide; dulaglutide; insulin glargine; insulin degludec