# Tirzepatide and Major Adverse Cardiovascular Events in Type 2 Diabetes: A Comprehensive Synthesis of Dedicated Cardiovascular Outcome Trial Data Versus Exploratory Endpoints from Glycemic Efficacy Trials

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### Background and Context

The intersection of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) represents one of the most consequential clinical challenges in modern medicine. Cardiovascular diseases — principally coronary artery disease, heart failure, and stroke — constitute the leading cause of death and disability in patients with T2DM, with CVD accounting for the majority of premature mortality in this population (PMC6761728). The global prevalence of T2DM continues to escalate, with an estimated 536.6 million individuals affected in 2021 and projections reaching 783.2 million by 2045 (PMC12277171). More than 30% of patients with T2DM are diagnosed with CVD, a comorbidity that substantially amplifies the risk of cardiovascular death and non-fatal atherothrombotic events (PMC9351217). The economic burden is correspondingly enormous, with cardiovascular complications accounting for 5–11% of total healthcare spending in European countries and direct costs of complicated diabetes estimated at approximately EUR 8,409 per person per year (PMC11434261).

Against this backdrop, the regulatory landscape for antihyperglycemic drug development underwent a fundamental transformation in 2008, when the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued guidance mandating formal cardiovascular safety evaluation for all new T2DM therapies through dedicated cardiovascular outcome trials (CVOTs) (PMC9351217, PMC9400320). These trials were required to demonstrate a hazard ratio (HR) for major adverse cardiovascular events (MACE) with an upper bound of the 95% confidence interval (CI) below 1.8 at initial application and 1.3 for final approval. What began as a safety mandate rapidly evolved into a scientific revolution: several CVOTs not only demonstrated cardiovascular safety but revealed statistically significant cardioprotective benefits, fundamentally reshaping treatment guidelines and clinical practice. The EMPA-REG OUTCOME trial with empagliflozin (2015), the LEADER trial with liraglutide (2016), and subsequent trials with semaglutide, dulaglutide, and canagliflozin established that certain glucose-lowering agents could meaningfully reduce MACE, cardiovascular mortality, and hospitalization for heart failure — benefits that appear to operate through mechanisms beyond glycemic control alone (PMC9351217, PMC12277171).

Tirzepatide (LY3298176), a novel dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, represents the first approved agent in a new pharmacological class — the "twincretins" or dual incretin receptor agonists (PMC9606350, PMC11434261). Approved by the FDA in May 2022 for T2DM and subsequently for obesity, tirzepatide has demonstrated superior glycemic control and weight loss compared to semaglutide 1 mg, insulin degludec, and insulin glargine across the SURPASS phase III clinical trial program (PMC9606350, PMC9774036). However, the critical question for clinicians and guideline developers is whether tirzepatide's impressive metabolic efficacy translates into statistically significant reductions in hard cardiovascular endpoints — specifically 3-point MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) — in a dedicated, adequately powered cardiovascular outcome trial. This question is not merely academic: the presence or absence of a labeled cardiovascular indication determines whether tirzepatide can be recommended preferentially over established GLP-1 receptor agonists with proven MACE reduction in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD). The current evidence base, as synthesized in this review, reveals a nuanced picture: tirzepatide's cardiovascular safety has been established through pre-specified meta-analyses of the SURPASS program, and the dedicated SURPASS-CVOT trial has now reported results demonstrating non-inferiority to dulaglutide, while real-world observational data suggest potentially superior outcomes compared to GLP-1 receptor agonists — but the evidentiary hierarchy, methodological limitations, and regulatory implications of each data source require careful delineation.

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### Molecular and Mechanistic Pathways

#### Dual Incretin Receptor Agonism: The Pharmacological Rationale for Tirzepatide

Tirzepatide is a synthetic 39-amino-acid peptide based on the native GIP sequence, incorporating dual agonism of both the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), with a C20 fatty diacid moiety attached via a linker at Lys20 to enable albumin binding, extend half-life, and permit once-weekly subcutaneous administration (PMC9606350). The pharmacodynamic profile of tirzepatide is distinctive: it binds the GIP receptor with high affinity (Ki = 0.135, comparable to native GIP) and the GLP-1 receptor with approximately 5-fold lower affinity than native GLP-1 (Ki = 4.23), yet demonstrates potent activation of both receptors in vivo (PMC9606350). Critically, tirzepatide shows a preference for cyclic adenosine monophosphate (cAMP) signaling at the GLP-1 receptor relative to native GLP-1, a pharmacodynamic distinction that may underlie its outsized efficacy relative to selective GLP-1 receptor agonists (PMC9774036).

The mechanistic rationale for dual incretin agonism in cardiovascular risk reduction is multifaceted. GLP-1 receptor activation promotes glucose-dependent insulin secretion, inhibits glucagon release, delays gastric emptying, suppresses appetite, and exerts direct cardiovascular effects including anti-atherosclerotic, anti-inflammatory, and endothelial-protective actions (PMC6292070). GIP receptor activation enhances glucose-stimulated insulin secretion, promotes beta-cell proliferation, and inhibits apoptosis. Preclinical and mechanistic data further suggest that nutrition-independent regulation of the GIP pathway through inflammatory stimuli may stabilize atherosclerotic plaques by inhibiting monocyte and macrophage activation and suppressing cardiomyocyte enlargement, apoptosis, and interstitial fibrosis (PMC11320168). In animal models, GIP analogs have been shown to significantly reduce atherosclerosis and improve vascular function in ApoE-deficient mice (PMC11387164). The synergistic activation of both GLP-1 and GIP signaling pathways by tirzepatide is hypothesized to produce cardiovascular benefits that exceed those achievable through GLP-1 receptor agonism alone — a hypothesis that the SURPASS-CVOT trial was designed to test.

The precise molecular mechanisms by which tirzepatide may confer cardiovascular protection remain an active area of investigation. Available evidence from the SURPASS program and mechanistic studies suggests that tirzepatide improves glycemic control, thereby reducing vascular damage mediated by advanced glycation end-products (AGEs), oxidative stress, and protein kinase C activation; promotes substantial weight loss that reduces systemic inflammation, blood pressure, and atherogenic dyslipidemia; and favorably modifies lipid metabolism, including reductions in LDL cholesterol, VLDL cholesterol, and triglycerides (PMC11387164). Additionally, GIP receptor signaling on epicardial and peri-renal adipose tissue may exert anti-inflammatory effects, and preclinical data suggest potential direct cardioprotective effects on cardiomyocytes. However, the review authors of PMC11387164 explicitly note that research on tirzepatide's cardiovascular mechanisms remains preliminary, with most mechanistic evidence extrapolated from GLP-1 receptor agonist class data or animal models, and that definitive conclusions about the specific contributions of each pathway cannot yet be drawn.

#### GLP-1 Receptor-Mediated Cardiovascular Mechanisms

The cardiovascular mechanisms of GLP-1 receptor agonism have been extensively characterized in the context of established GLP-1 receptor agonists and are presumed to apply, at least in part, to tirzepatide's GLP-1 receptor component. Accumulating evidence in animals and humans shows that GLP-1 receptor stimulation has beneficial effects on the cardiovascular system, including enhanced nitric oxide production, increased glucose uptake, and improved coronary flow in isolated rodent hearts (PMC6292070). In vascular smooth muscle and endothelial cells, GLP-1 receptor activation reduces macrophage adhesion to the endothelium, inhibits atherosclerotic plaque formation, and suppresses platelet activity, contributing to cardiovascular protection (PMC12277171, PMC6292070). Liraglutide has been shown to inhibit progression of early-onset atherosclerosis in ApoE-deficient mouse models, and clinical studies have demonstrated improvements in carotid intima-media thickness with liraglutide treatment in T2DM patients with metabolic syndrome (PMC6292070).

The anti-atherosclerotic effects of GLP-1 receptor agonists appear to operate through multiple mechanisms: reduction in postprandial dyslipidemia (including chylomicron overproduction and postprandial triglyceridemia), improvement in endothelial function through increased endothelial nitric oxide synthase expression, attenuation of platelet aggregation through cyclic AMP-mediated pathways, and reduction in systemic blood pressure compared to placebo (PMC6292070). Kaplan-Meier curves in GLP-1 receptor agonist CVOTs (LEADER, SUSTAIN-6, HARMONY) showed divergence at 12–18 months from randomization, suggesting anti-atherosclerotic rather than purely hemodynamic mechanisms, since hemodynamic benefits would be expected to manifest more rapidly (PMC6761728, PMC6292070). This temporal pattern is relevant to tirzepatide: if its cardiovascular benefits are mediated through similar anti-atherosclerotic pathways, adequate trial duration is essential for event accrual.

#### GIP Receptor-Mediated Cardiovascular Mechanisms and Competing Hypotheses

The cardiovascular role of GIP receptor agonism is more complex and, in some respects, contested. Historically, GIP was considered to promote obesity and was not viewed as a therapeutic target for cardiovascular risk reduction (PMC9606350). However, the remarkable metabolic efficacy of tirzepatide — which exceeds that of selective GLP-1 receptor agonists despite tirzepatide's weaker GLP-1 receptor affinity — has prompted intensive investigation of GIP receptor-mediated cardiovascular mechanisms. Preclinical data suggest that GIP receptor agonism may stabilize atherosclerotic plaques by inhibiting monocyte and macrophage activation, suppress cardiomyocyte enlargement and interstitial fibrosis, and attenuate local adipose tissue inflammation through reduction of proinflammatory cytokine levels (PMC11320168). In vitro studies on cardiac cell lines have demonstrated that tirzepatide reduces cardiomyocyte injury and fibrosis under high-glucose conditions (PMC12090002).

A competing hypothesis, however, suggests that GIP receptor agonism may have neutral or even adverse cardiovascular effects in some contexts. A prospective study found that higher fasting levels of GIP were associated with increased cardiovascular mortality, suggesting a complex and incompletely understood role of GIP in cardiovascular health (PMC12090002). Furthermore, some observational and pharmacovigilance studies have raised questions about whether GIP receptor agonism provides additive cardiovascular benefit beyond GLP-1 receptor agonism, or whether the superior metabolic outcomes with tirzepatide (greater weight loss, greater HbA1c reduction, more favorable lipid profiles) are the primary drivers of any cardiovascular advantage (PMC11320168). The mechanistic distinction between GIP-specific cardiovascular effects and those attributable to superior metabolic control remains unresolved and represents a critical gap in the current evidence base.

A third mechanistic hypothesis focuses on the unique receptor internalization dynamics of tirzepatide. Structural alterations in GIP/GLP-1 dual agonists may alter agonist-induced receptor internalization in ways that differ markedly from selective agonists, potentially explaining why a GIP receptor agonist can produce weight loss (typically associated with GIP receptor antagonism in animal models) while simultaneously activating the receptor (PMC9606350). This "biased agonism" hypothesis — wherein tirzepatide preferentially activates certain downstream signaling cascades over others at both the GIP and GLP-1 receptors — remains an active area of mechanistic investigation and may ultimately explain tirzepatide's distinctive pharmacological profile.

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### Dose-Response and Pharmacokinetics

Tirzepatide is administered as a once-weekly subcutaneous injection, initiated at 2.5 mg and uptitrated by 2.5 mg every 4 weeks to maintenance doses of 5 mg, 10 mg, or 15 mg, with a half-life of approximately 5 days, approximately 80% bioavailability, and approximately 99% albumin binding. The pharmacokinetic profile is characterized by dose-proportional exposure following subcutaneous injection, a time to maximum plasma concentration (tmax) of 8–72 hours. Steady-state plasma concentrations are achieved after four once-weekly injections. Metabolic clearance occurs through proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis, with metabolites excreted via urine and feces. Importantly, the pharmacokinetics of tirzepatide are not significantly altered by age, sex, race, ethnicity, body weight, or renal or hepatic function — a clinically important characteristic given the frequent comorbidity of chronic kidney disease in T2DM patients (PMC9606350, PMC11387164).

A clear dose-response relationship has been demonstrated for both efficacy and certain adverse events. In the SURPASS-1 trial (n=478), HbA1c reductions at 40 weeks were −1.87%, −1.89%, and −2.07% for the 5 mg, 10 mg, and 15 mg doses, respectively, versus +0.04% with placebo (p<0.0001 for all comparisons) (PMC9606350). Body weight reductions were −7.0, −7.8, and −9.5 kg for the 5, 10, and 15 mg doses versus −0.7 kg with placebo (p<0.0001 for all). The meta-analysis by Wang et al. (PMC9774036) confirmed a statistically significant dose-response for HbA1c reduction (p<0.00001), body weight loss (p<0.00001), nausea (p=0.004), and vomiting (p=0.03) across doses of 1 mg, 5 mg, 10 mg, and 15 mg, but not for hypoglycemia, diarrhea, pancreatitis, or cholelithiasis. In the real-world observational study by Chuang et al. (PMC11320168), tirzepatide doses of 10 mg or greater were associated with lower hazards of all-cause mortality, MACE, and major adverse kidney events compared to doses of 7.5 mg or less, providing preliminary real-world evidence for a dose-response relationship in hard clinical outcomes.

The distinction between therapeutic doses (5–15 mg once weekly, as used in clinical trials) and suprapharmacological doses is clinically relevant. All SURPASS trials used the approved dose range of 5–15 mg, initiated at 2.5 mg with stepwise uptitration. The cardiovascular safety meta-analysis by Sattar et al. (referenced in PMC9606350 and PMC9774036) was conducted using data from trials employing these therapeutic doses. Extrapolation of cardiovascular findings from in vitro or animal studies using non-physiological concentrations to clinical practice should be approached with caution, as the mechanistic literature on tirzepatide's cardiovascular effects remains largely preclinical.

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### Clinical Evidence and Implications

#### The SURPASS Phase III Glycemic Efficacy Trials: Cardiovascular Endpoints as Exploratory or Secondary Outcomes

The SURPASS clinical trial program comprised nine global and regional phase III trials evaluating tirzepatide across a spectrum of T2DM treatment backgrounds and comparators. These trials were designed and powered primarily to assess glycemic efficacy (change in HbA1c from baseline) and were not individually powered to detect statistically significant differences in MACE. Cardiovascular endpoints in the SURPASS trials were therefore exploratory or secondary outcomes, and any cardiovascular findings from individual trials must be interpreted with this fundamental limitation in mind.

The SURPASS-4 trial is the most informative of the SURPASS trials for cardiovascular outcomes, as it specifically enrolled patients with T2DM and high cardiovascular risk and compared tirzepatide (5 mg, 10 mg, 15 mg) with insulin glargine over 52 weeks (PMC9606350). In this study, 2,002 patients were randomized. Adjudicated 4-point MACE events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina) occurred in 109 participants across all study arms, with the hazard ratio for MACE-4 directionally favorable for tirzepatide but not achieving statistical significance — a finding entirely expected given that the trial was not powered for this endpoint (PMC9606350). Importantly, SURPASS-4 demonstrated that tirzepatide was not associated with excess cardiovascular risk compared to insulin glargine, providing initial cardiovascular safety reassurance.

The SURPASS-2 trial (n=1,879) compared tirzepatide (5 mg, 10 mg, 15 mg) with semaglutide 1 mg over 40 weeks in patients on background metformin (PMC9606350). This trial demonstrated superior HbA1c reduction with all tirzepatide doses versus semaglutide 1 mg (−2.01%, −2.24%, −2.30% vs. −1.86%; p<0.02 for all comparisons) and superior weight loss (treatment differences of −1.9, −3.6, and −5.5 kg; p<0.001 for all) (PMC9606350). Cardiovascular events were not a pre-specified primary or key secondary endpoint in SURPASS-2, and the trial was not designed or powered to detect cardiovascular differences.

The SURPASS-3 study enrolled 1,437 patients and compared tirzepatide with insulin degludec over 52 weeks in patients on metformin with or without SGLT-2 inhibitors (PMC9606350). The least-squares mean change in HbA1c from baseline at week 52 was −1.93%, −2.20%, and −2.37% with tirzepatide 5, 10, and 15 mg, respectively, versus −1.34% with insulin degludec (p<0.02 for all tirzepatide arms versus insulin degludec). The least-squares mean change in body weight from baseline at week 52 was −7.5, −10.7, and −12.9 kg with tirzepatide 5, 10, and 15 mg, respectively, versus +2.3 kg with insulin degludec (p<0.0001 for all) (PMC9606350). Again, cardiovascular outcomes were not primary endpoints.

#### Pre-Specified Meta-Analysis of SURPASS Trials: Establishing Cardiovascular Safety

Recognizing that individual SURPASS trials were not powered for cardiovascular outcomes, a pre-specified meta-analysis of cardiovascular safety data from the SURPASS program was conducted by Sattar and colleagues (referenced in PMC9606350 and PMC9774036). This analysis pooled data from seven double-blind randomized controlled trials with tirzepatide lasting at least 26 weeks, encompassing 7,215 study participants (4,887 in tirzepatide arms, 2,328 in control groups). The primary cardiovascular safety endpoint was time to first occurrence of MACE-4 (cardiovascular death, myocardial infarction, stroke, hospitalized unstable angina).

A pre-specified meta-analysis indicated that tirzepatide did not increase the risk of major cardiovascular events in T2D participants compared with the control group (PMC9774036). The pooled results showed directionally favorable point estimates for all cardiovascular endpoints, with the confidence intervals crossing unity, meaning that cardiovascular superiority could not be claimed on the basis of this meta-analysis (PMC9606350). A cardiovascular meta-analysis of seven RCTs (n=7,215) found an HR of 0.80 (95% CI, 0.57–1.11) for MACE-4 with tirzepatide versus standard therapy, supporting cardiovascular safety without demonstrated superiority (PMC9606350). These results established that tirzepatide did not increase the risk of major cardiovascular events compared to standard therapy — satisfying the regulatory requirement for cardiovascular safety. The authors noted a trend toward stronger effects in subjects with T2DM and higher cardiovascular risk, consistent with the pattern observed across GLP-1 receptor agonist CVOTs where patients with established ASCVD derive greater absolute benefit (PMC9606350).

A subsequent meta-analysis by Patoulias and collaborators (referenced in PMC11434261) analyzed eight trials and reported that tirzepatide was associated with a significantly reduced risk of MACE by 48% (RR 0.52, 95% CI 0.38–0.72), cardiovascular death by 49% (RR 0.51, 95% CI 0.29–0.89), and all-cause death by 49% (RR 0.51, 95% CI 0.34–0.77) compared to the control group. This more favorable meta-analytic result contrasts with the Sattar et al. analysis and likely reflects differences in included studies, comparators (which included placebo, insulin, and GLP-1 receptor agonists), and statistical methodology. The substantial heterogeneity in comparators across included trials — ranging from placebo to active antidiabetic agents with established cardiovascular benefits — represents a critical limitation of both meta-analyses and precludes definitive conclusions about tirzepatide's cardiovascular efficacy versus placebo.

#### The SURPASS-CVOT: The Dedicated Cardiovascular Outcome Trial

The SURPASS-CVOT is the pivotal dedicated cardiovascular outcome trial for tirzepatide, designed specifically to evaluate cardiovascular safety and efficacy in patients with T2DM and established atherosclerotic cardiovascular disease. This large-scale, randomized, double-blind, multinational phase III trial compared tirzepatide against dulaglutide 1.5 mg — a GLP-1 receptor agonist with a product-labeled cardiovascular indication based on the REWIND trial — with a primary endpoint of time to first occurrence of 3-point MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) (PMC11387164, PMC9400320). Notably, a substantial proportion of enrolled participants had peripheral artery disease, making this trial also informative for the PAD subpopulation (PMC11434261).

The SURPASS-CVOT represents a methodological innovation in CVOT design: rather than comparing tirzepatide to placebo (which would be ethically problematic given the established cardiovascular benefits of GLP-1 receptor agonists), it employed an active comparator design with a pre-specified non-inferiority margin derived from a Bayesian hierarchical meta-analysis of six placebo-controlled GLP-1 receptor agonist CVOTs restricted to patients with established ASCVD. This analysis established a median HR of 0.85 and a 97.5th percentile of 0.95 for GLP-1 receptor agonists versus placebo, yielding a pre-specified M1 non-inferiority margin of 1/0.95 = 1.05 (PMC9400320). The trial was designed to accrue 1,600 primary outcome events comprising the time to first event of cardiovascular death, MI, or stroke, providing approximately 90% power to establish superiority to a putative placebo, assuming a 10% lower MACE risk for tirzepatide compared to dulaglutide (PMC9400320).

According to the narrative review by Tirzepatide vs. semaglutide (PMC13143735), the SURPASS-CVOT demonstrated that tirzepatide was non-inferior to dulaglutide for 3-point MACE (HR approximately 0.90–0.95), with directionally favorable but non-superior results. The trial achieved greater improvements in key cardiometabolic risk factors with tirzepatide compared to dulaglutide, including glycemic control, body weight, blood pressure, and lipid parameters. The non-inferiority finding is clinically significant: by demonstrating non-inferiority to dulaglutide (which itself demonstrated superiority to placebo in REWIND), the SURPASS-CVOT methodology allows for the inference that tirzepatide is superior to a putative placebo — a novel regulatory approach that, if accepted by regulatory agencies, would support a cardiovascular indication for tirzepatide (PMC9400320). However, it is critical to note that tirzepatide did not demonstrate direct superiority over dulaglutide for the primary MACE endpoint in SURPASS-CVOT, meaning that the cardiovascular evidence for tirzepatide remains contextually dependent on the imputed placebo methodology rather than a direct head-to-head superiority demonstration.

The SUMMIT trial represents a complementary cardiovascular outcomes study for tirzepatide, focused specifically on adults with heart failure with preserved ejection fraction (HFpEF) and obesity — a population with high unmet need and limited therapeutic options. As described in PMC11387164, the SUMMIT trial enrolled 731 participants and was designed to compare the long-term effects of tirzepatide versus placebo on major adverse cardiovascular events, weight, and metabolic indicators, with primary outcome measures including change in KCCQ Clinical Summary Score and incidence of cardiovascular death or heart failure events over time. Real-world evidence from the TriNetX platform (PMC12090002) demonstrates that tirzepatide was associated with significantly lower risks of acute heart failure exacerbation, MACE, stroke, and CKD progression in patients with heart failure without diabetes over a four-year follow-up period, providing complementary observational support for tirzepatide's potential benefit in HFpEF populations. This finding is consistent with the STEP-HFpEF trial of semaglutide in HFpEF, which demonstrated improved symptoms, function, and inflammation, and collectively suggests that dual incretin receptor agonism may have particular utility in the HFpEF population where weight loss and anti-inflammatory effects are mechanistically relevant.

#### Comparison with Established GLP-1 Receptor Agonist CVOTs

To contextualize tirzepatide's cardiovascular evidence, it is essential to compare it with the established CVOT evidence base for GLP-1 receptor agonists. The LEADER trial (n=9,340) demonstrated that liraglutide reduced 3-point MACE by 13% (HR 0.87; 95% CI 0.78–0.97; p=0.01), cardiovascular death by 22% (HR 0.78; 95% CI 0.66–0.93; p=0.007), and all-cause mortality by 15% (HR 0.85; 95% CI 0.74–0.97; p=0.02) versus placebo over a median follow-up of 3.8 years (PMC12277171, PMC6292070). In the SUSTAIN-6 trial (n=3,297), semaglutide reduced 3-point MACE by 26% (HR 0.74; 95% CI 0.58–0.95; p=0.02) versus placebo (PMC9351217, PMC6761728). Across the individual MACE components in SUSTAIN-6, nonfatal stroke was significantly reduced (HR 0.61; 95% CI 0.38–0.99), while nonfatal MI (HR 0.74; 95% CI 0.51–1.08) and CV death (HR 0.98; 95% CI 0.65–1.48) did not reach statistical significance individually — a pattern consistent with the composite endpoint being driven primarily by stroke reduction in this trial (PMC9351217, PMC6761728). The REWIND trial demonstrated that dulaglutide reduced 3-point MACE (HR 0.88; 95% CI 0.79–0.99; p=0.026), with the unique feature of including a substantial proportion of participants without established CVD (PMC9351217, PMC6761728). The HARMONY OUTCOMES trial (n=9,463) demonstrated that albiglutide reduced 3-point MACE by 22% (HR 0.78; 95% CI 0.68–0.90; p=0.0006) (PMC9351217, PMC6292070).

A meta-analysis of eight GLP-1 receptor agonist CVOTs demonstrated reductions in 3-point/4-point MACE and cardiovascular death of 14% and 13%, respectively, across the class compared to placebo (PMC9351217). More recently, the SOUL trial (n=9,650; median follow-up 49.5 months) demonstrated that oral semaglutide reduced MACE by 14% (HR 0.86; 95% CI 0.77–0.96; p=0.006) (PMC12277171). These trials collectively establish a robust evidence base for GLP-1 receptor agonist-mediated MACE reduction, with statistically significant superiority to placebo demonstrated in multiple large, adequately powered, dedicated CVOTs.

By contrast, tirzepatide's cardiovascular evidence — while promising — currently rests on: (1) a pre-specified meta-analysis of glycemic efficacy trials showing cardiovascular safety but not superiority; (2) the SURPASS-CVOT demonstrating non-inferiority to dulaglutide (HR approximately 0.90–0.95) with the imputed placebo methodology supporting superiority to a putative placebo; and (3) real-world observational evidence in HFpEF and other populations. The absence of a placebo-controlled CVOT demonstrating direct superiority for tirzepatide — analogous to LEADER, SUSTAIN-6, or REWIND — means that tirzepatide's cardiovascular evidence, while supportive, is structurally different from and arguably less direct than the evidence for established GLP-1 receptor agonists with labeled cardiovascular indications.

#### Real-World Observational Evidence: Tirzepatide vs. GLP-1 Receptor Agonists

In the absence of completed head-to-head cardiovascular outcome trials comparing tirzepatide directly to semaglutide or other GLP-1 receptor agonists, several large real-world observational studies using electronic health record databases have attempted to fill this gap. These studies consistently report favorable cardiovascular outcomes with tirzepatide compared to GLP-1 receptor agonists, but must be interpreted with appropriate caution given the inherent limitations of observational designs.

The retrospective cohort study by Chuang et al. (PMC11320168) used the TriNetX US Collaborative Network to compare 14,832 tirzepatide users with 14,832 propensity score-matched GLP-1 receptor agonist users in patients with T2DM, followed for a median of 10.5 months (IQR 5.2–15.7 months). Tirzepatide was associated with significantly lower hazards of all-cause mortality (95 vs. 166 events; AHR 0.58; 95% CI 0.45–0.75; p<0.001), MACE (472 vs. 589 events; AHR 0.80; 95% CI 0.71–0.91; p<0.001), kidney events (53 vs. 102 events; AHR 0.52; 95% CI 0.37–0.73; p<0.001), major adverse kidney events (129 vs. 241 events; AHR 0.54; 95% CI 0.44–0.67; p<0.001), and acute kidney injury (506 vs. 652 events; AHR 0.78; 95% CI 0.70–0.88; p<0.001). E-value analyses indicated that unmeasured confounders would need to be associated with both treatment and outcome by risk ratios of at least 2.82-fold (mortality) and 3.24-fold (kidney events) to fully explain away the observed associations. Tirzepatide was also associated with greater reductions in HbA1c (treatment difference −0.34 percentage points; 95% CI −0.44 to −0.24) and body weight (−2.9 kg; 95% CI −4.8 to −1.1) over 20 months.

The observational study by Dani et al. (PMC12235410) used the TriNetX Global Research Network to compare 751 tirzepatide users with 751 propensity score-matched GLP-1 receptor agonist users (semaglutide, liraglutide, dulaglutide, lixisenatide) in adults with T2DM, age ≥40 years, ischemic heart disease, and BMI ≥25 kg/m², followed for 12 months. Tirzepatide was associated with a 40% relative risk reduction in the primary composite outcome of acute myocardial infarction, ischemic stroke, and all-cause mortality (HR 0.60; 95% CI 0.42–0.84; p=0.003). Individual components showed significant reductions in acute myocardial infarction (HR 0.59; 95% CI 0.38–0.91; p=0.016) and all-cause mortality (HR 0.35; 95% CI 0.14–0.89; p=0.021), while ischemic stroke reduction did not reach significance (HR 0.81; 95% CI 0.45–1.43; p=0.468). Significant secondary benefits included heart failure exacerbation (HR 0.60; p=0.04), new systolic heart failure (HR 0.73; p=0.045), new-onset atrial fibrillation/flutter (HR 0.23; p=0.004), and new-onset acute kidney injury (HR 0.67; p=0.028). Tirzepatide was also associated with greater likelihood of achieving HbA1c ≤7% (HR 1.50; p<0.001), LDL ≤70 mg/dL (HR 1.32; p=0.002), and triglycerides ≤150 mg/dL (HR 1.26; p=0.006).

The international retrospective cohort study by Alam et al. (PMC11377141) used the TriNetX Global Collaborative Network to compare tirzepatide with semaglutide in two populations: adults with obesity but without T2DM (n=6,923 per group after PSM) and adults with existing T2DM (n=4,223 per group after PSM). In the T2DM cohort, tirzepatide was associated with a 46% reduction in the composite MACE outcome (HR 0.54; 95% CI 0.38–0.76; p<0.001; E-value=2.43), a 67% reduction in all-cause mortality (HR 0.33; 95% CI 0.15–0.73; p=0.004; E-value=3.69), and a 55% reduction in cerebral infarction (HR 0.45; 95% CI 0.24–0.84; p=0.010). In the non-T2DM obesity cohort, tirzepatide was associated with a 27% lower rate of incident T2D compared to semaglutide (HR 0.73; 95% CI 0.58–0.92; p<0.001; E-value=1.79), with greater weight loss (−7.7 kg vs. −4.8 kg) and greater HbA1c reduction (−0.24% vs. −0.10%).

The real-world study by Chuang et al. (PMC12090002) examined tirzepatide in patients with heart failure without T2DM (n=897 per group after PSM), finding that non-treated patients were at significantly higher risk of acute heart failure (HR 3.12; 95% CI 2.24–4.35; p<0.001), MACE (HR 3.57; 95% CI 2.32–5.48; p<0.001), stroke (HR 2.80; 95% CI 1.35–5.78; p<0.01), and CKD progression (HR 1.48; 95% CI 1.08–2.03; p=0.015) compared to tirzepatide-treated patients over four years.

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### Safety Profile and Adverse Events

#### Gastrointestinal Adverse Events

The most common adverse events associated with tirzepatide are gastrointestinal in nature, consistent with the GLP-1 receptor agonist class effect. Pooled data from SURPASS-1 through SURPASS-5 demonstrated gastrointestinal adverse events in 37.1%–43.6% of tirzepatide-treated patients versus 20.4% in placebo/comparator groups, with discontinuation due to GI adverse events in 3.0%–6.6% of tirzepatide-treated patients versus 0.4% in placebo groups (PMC9606350). Specific rates from SURPASS-1 included nausea (12%–18% vs. 6% with placebo), diarrhea (12%–14% vs. 8%), and vomiting (2%–6% vs. 2%). The meta-analysis by Wang et al. (PMC9774036) confirmed that tirzepatide significantly increased the risk of nausea, diarrhea, dyspepsia, decreased appetite, and vomiting compared to control, primarily in the add-on therapy setting, while monotherapy was associated with fewer gastrointestinal events. Importantly, gastrointestinal adverse events were predominantly mild to moderate in severity, occurred primarily during the dose-escalation phase, and attenuated over time with continued treatment (PMC11387164). Discontinuation rates due to adverse events in the SURMOUNT-1 obesity trial were 4.3%, 7.1%, and 6.2% for the 5 mg, 10 mg, and 15 mg tirzepatide groups, respectively, versus 2.6% for placebo (PMC11387164).

In the head-to-head comparison with semaglutide 1 mg in SURPASS-2, gastrointestinal adverse event rates were similar between tirzepatide and semaglutide (nausea 17%–22% vs. 18%; diarrhea 13%–16% vs. 12%; vomiting 6%–10% vs. 8%) (PMC9606350). The meta-analysis by Wang et al. (PMC9774036) found no significant differences in nausea, dyspepsia, decreased appetite, vomiting, or cholelithiasis between tirzepatide and GLP-1 receptor agonists, but did find a significantly higher rate of diarrhea with tirzepatide. The observational study by Dani et al. (PMC12235410) reported lower rates of GI symptoms with tirzepatide compared to GLP-1 receptor agonists over 12 months, a finding that may reflect differences in patient selection, dose titration practices, or the GIP receptor component's ability to block nausea and emesis from GLP-1 agonism without affecting satiety or energy intake reduction, thereby improving overall treatment tolerability (PMC11320168). However, this observational finding contrasts with the broadly similar GI event rates observed in the randomized SURPASS-2 head-to-head comparison, and the discrepancy likely reflects residual confounding in the real-world setting rather than a true pharmacological difference.

#### Hypoglycemia

Tirzepatide does not have intrinsic hypoglycemic risk, as its insulin-stimulating effects are glucose-dependent. Tirzepatide did not significantly increase events of blood glucose <70 mg/dL (RR 1.48; 95% CI 0.80–2.74), <54 mg/dL (RR 0.54; 95% CI 0.24–1.22), or severe hypoglycemia (RR 0.52; 95% CI 0.21–1.32) compared to control. However, in SURPASS-4, rates of blood glucose <70 mg/dL and <54 mg/dL were 34.77% and 7.64%, respectively, reflecting background sulfonylurea use, and in SURPASS-5, rates were 61.13% and 16.34%, reflecting background insulin glargine use (PMC9774036). In the real-world observational study by Alam et al. (PMC11377141), no significant difference in clinically significant hypoglycemia was observed between tirzepatide and semaglutide (HR 1.07; 95% CI 0.62–1.86; p=0.804).

#### Cardiovascular Safety Signals and Other Adverse Events

The pre-specified cardiovascular safety meta-analysis of the SURPASS program (Sattar et al., referenced in PMC9606350) demonstrated no excess cardiovascular risk with tirzepatide, establishing cardiovascular safety as required by regulatory guidance. Tirzepatide is associated with sinus tachycardia with concomitant heart rate increase ≥15 beats per minute (4.6%–10.0% vs. 4.3% with placebo), hypersensitivity reactions including severe reactions (3.2% vs. 1.7%), injection site reactions (3.2% vs. 0.4%), and acute gallbladder disease (0.6% vs. 0%), and carries a black box warning for thyroid C-cell tumors with contraindication in individuals with personal or family history of medullary thyroid carcinoma or MEN2 (PMC9606350). Pancreatitis was not significantly increased in the meta-analysis by Wang et al. (PMC9774036) (no significant difference between tirzepatide and control or GLP-1 receptor agonists). In the real-world study by Dani et al. (PMC12235410), gallbladder and pancreatic disorders were comparable between tirzepatide and GLP-1 receptor agonist groups (HR 0.81; 95% CI 0.35–1.85; p=0.620).

A potentially important safety signal from the real-world study by Alam et al. (PMC11377141) was a modest but statistically significant increase in incident diabetic neuropathy with tirzepatide compared to semaglutide in the T2DM cohort (HR 1.14; 95% CI 1.02–1.29; p=0.024; E-value=1.53). The authors attributed this to treatment-induced neuropathy from rapid glycemic improvement — a recognized phenomenon associated with rapid HbA1c reduction — rather than a direct adverse effect of tirzepatide. Diabetic retinopathy and nephropathy were not significantly different between groups (HR 1.12; p=0.225 and HR 1.18; p=0.151, respectively). No significant difference in suicidal ideation or attempt was observed between tirzepatide and semaglutide (HR 0.55; 95% CI 0.22–1.37; p=0.192), providing reassurance regarding a safety concern that has been raised for GLP-1 receptor agonists (PMC11377141).

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### Unresolved Controversies and Disagreements

#### The Magnitude of Cardiovascular Benefit: Meta-Analytic Discordance

A fundamental controversy in the tirzepatide cardiovascular literature concerns the magnitude of cardiovascular benefit suggested by different meta-analyses. The pre-specified Sattar et al. meta-analysis of SURPASS trials (referenced in PMC9606350 and PMC9774036) showed directionally favorable point estimates for MACE-4, with confidence intervals crossing unity — supporting cardiovascular safety but not superiority. By contrast, the meta-analysis by Patoulias et al. (referenced in PMC11434261) reported a 48% reduction in MACE (RR 0.52; 95% CI 0.38–0.72) and a 49% reduction in cardiovascular death (RR 0.51; 95% CI 0.29–0.89). This striking discordance — between a neutral meta-analysis and one suggesting nearly 50% MACE reduction — reflects fundamental differences in included studies, comparators, and statistical methodology. The Patoulias meta-analysis included trials with heterogeneous comparators (placebo, insulin, and GLP-1 receptor agonists), which inflates the apparent treatment effect when active comparators with established cardiovascular benefits are included in the control arm. The Sattar meta-analysis, by contrast, was pre-specified and used a more conservative approach. The Wang et al. meta-analysis (PMC9774036) found no significant difference in MACE-4 between tirzepatide and control (RR 0.76; 95% CI 0.53–1.09), consistent with the Sattar analysis. Clinicians and guideline developers should be aware that the more favorable meta-analytic estimates likely reflect comparator heterogeneity rather than a true 48–50% MACE reduction attributable to tirzepatide.

#### Real-World Effect Sizes: Plausibility and Confounding

The real-world observational studies consistently report cardiovascular effect sizes for tirzepatide that are substantially larger than those observed in randomized controlled trials of GLP-1 receptor agonists. The Dani et al. study (PMC12235410) reported a 65% reduction in all-cause mortality (HR 0.35; 95% CI 0.14–0.89) and a 40% reduction in the primary composite outcome (HR 0.60; 95% CI 0.42–0.84) with tirzepatide versus GLP-1 receptor agonists. The Alam et al. study (PMC11377141) reported a 67% reduction in all-cause mortality (HR 0.33; 95% CI 0.15–0.73) and a 46% reduction in composite MACE (HR 0.54; 95% CI 0.38–0.76). The Chuang et al. study (PMC11320168) reported a 42% reduction in all-cause mortality (AHR 0.58; 95% CI 0.45–0.75). These effect sizes substantially exceed those observed in the largest GLP-1 receptor agonist CVOTs (13–26% MACE reduction) and are implausibly large for a drug that has not yet demonstrated superiority over an active comparator in a dedicated CVOT.

The authors of the Dani et al. study (PMC12235410) themselves acknowledge that the observed all-cause mortality benefits appear larger than those typically found in randomized controlled trials and explicitly caution against overinterpretation. Multiple sources of bias could explain these inflated effect sizes: (1) healthy user bias — tirzepatide users may be systematically healthier, more adherent to medications, and more engaged with healthcare than GLP-1 receptor agonist users; (2) channeling bias — tirzepatide may have been preferentially prescribed to patients with better metabolic control or lower cardiovascular risk; (3) immortal time bias — the period between drug initiation and outcome ascertainment may not be handled consistently; (4) residual confounding from unmeasured variables including socioeconomic status, education, insurance status, and lifestyle factors; and (5) the relatively short follow-up periods (median 10.5 months in Chuang et al., 12 months in Dani et al.) that may not capture the full cardiovascular risk profile of both groups. The E-value analyses in these studies, while providing some reassurance, cannot fully exclude confounding from unmeasured variables.

#### The Active Comparator Design of SURPASS-CVOT: Regulatory Novelty and Limitations

The SURPASS-CVOT's use of an active comparator (dulaglutide) with an imputed placebo methodology represents a novel regulatory approach that has not previously been used to support a cardiovascular indication for a diabetes medication (PMC9400320). This design raises important questions about the validity of the imputed placebo comparison. The SURPASS-CVOT methodology paper (PMC9400320) explicitly acknowledges that an important assumption is that the efficacy of dulaglutide versus placebo demonstrated in the REWIND trial remains unchanged despite changing background care, noting that the "best standard of care" is evolving with time as numerous cardioprotective drug classes have been introduced to clinical practice. The authors argue that a meaningful interaction between background cardioprotective therapies and GLP-1 receptor agonist efficacy is unlikely given differing mechanisms of action — but this assumption cannot be fully verified and represents a source of uncertainty in the imputed placebo comparison.

Furthermore, the non-inferiority of tirzepatide to dulaglutide in SURPASS-CVOT does not establish that tirzepatide is superior to dulaglutide for cardiovascular outcomes — a distinction that is clinically important when choosing between agents in patients with established ASCVD. The SURPASS-CVOT was not powered to demonstrate superiority of tirzepatide over dulaglutide, and the observed HR of approximately 0.90–0.95 for tirzepatide versus dulaglutide, while directionally favorable, does not reach statistical significance for superiority. This means that clinicians cannot currently conclude that tirzepatide provides greater cardiovascular protection than dulaglutide or other GLP-1 receptor agonists with established cardiovascular indications.

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### Limitations of the Evidence Base

The current evidence base for tirzepatide's cardiovascular effects is characterized by several important methodological limitations that must be explicitly acknowledged.

**Trial design and power limitations in the SURPASS program.** The SURPASS phase III glycemic efficacy trials were designed and powered to assess HbA1c reduction as the primary endpoint, not cardiovascular outcomes. Individual SURPASS trials enrolled between 475 and 2,002 participants and followed patients for 40–52 weeks — sample sizes and durations that are fundamentally inadequate to detect statistically significant differences in MACE, which are relatively rare events requiring thousands of patients followed for years. The pre-specified cardiovascular safety meta-analysis pooled 7,215 participants across seven trials (PMC9606350, PMC9774036).

**The absence of a placebo-controlled CVOT demonstrating direct superiority.** Unlike liraglutide (LEADER), semaglutide (SUSTAIN-6, PIONEER-6, SOUL), dulaglutide (REWIND), and albiglutide (HARMONY), tirzepatide has not been evaluated in a placebo-controlled CVOT demonstrating statistically significant superiority for MACE reduction. The SURPASS-CVOT's active comparator design, while methodologically innovative and ethically appropriate, provides a structurally different and arguably less direct form of cardiovascular efficacy evidence than placebo-controlled superiority trials (PMC9400320).

**Short follow-up and database limitations in real-world observational studies.** The real-world observational studies comparing tirzepatide to GLP-1 receptor agonists have follow-up periods of only 10.5–12 months (PMC11320168, PMC12235410, PMC11377141), substantially shorter than the 1.6–5.4-year follow-up periods of landmark GLP-1 receptor agonist CVOTs. Cardiovascular outcome trials in T2DM typically require years of follow-up to accrue sufficient events and to capture the full cardiovascular risk trajectory. The short follow-up in observational studies may not adequately capture long-term cardiovascular outcomes and may be particularly susceptible to immortal time bias and healthy user bias in the early post-initiation period (PMC11320168). Furthermore, these studies rely on electronic health record databases that may not accurately capture all health conditions or outcomes occurring outside the contributing institutions (PMC12235410).

**Residual confounding in observational studies.** Despite propensity score matching on extensive covariate sets (48 variables in Chuang et al., PMC11320168), observational studies cannot fully account for unmeasured confounders. Tirzepatide was approved in May 2022 and was initially prescribed predominantly to patients with better metabolic control, higher socioeconomic status, and greater healthcare engagement — characteristics that are independently associated with better cardiovascular outcomes. The Chuang et al. study (PMC11320168) noted that most patients in their cohort had eGFR ≥45 mL/min/1.73 m² and few had established cardiovascular disease or advanced kidney disease, limiting generalizability to higher-risk patients. By contrast, the Dani et al. study (PMC12235410) specifically enrolled patients with ischemic heart disease, representing a higher-risk population; these two studies therefore reflect different patient populations, and their findings should not be assumed to be directly comparable.

**Heterogeneity of comparators in meta-analyses.** The meta-analyses of tirzepatide cardiovascular outcomes have included trials with highly heterogeneous comparators — ranging from placebo to insulin glargine to semaglutide — making it impossible to isolate the cardiovascular effect of tirzepatide versus a consistent reference standard. The inclusion of active comparators with established cardiovascular benefits (such as semaglutide in SURPASS-2) in the control arm of meta-analyses inflates the apparent cardiovascular benefit of tirzepatide (PMC9774036).

**Tirzepatide's recent market entry limits long-term safety data.** Tirzepatide received FDA approval in May 2022, meaning that real-world experience is limited to approximately 2–3 years at the time of this review. Long-term cardiovascular safety data beyond the SURPASS-CVOT follow-up period are not yet available, and rare adverse events may not yet be fully characterized (PMC11387164).

**Dosage information unavailable in observational studies.** Real-world observational studies using administrative databases cannot ascertain drug dosage, dose escalation patterns, or treatment adherence — factors that are likely to influence both metabolic and cardiovascular outcomes. The dose-response relationship observed in clinical trials (PMC11320168) suggests that patients receiving higher tirzepatide doses may derive greater cardiovascular benefit, but this cannot be assessed in current observational data.

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### Comparative Effectiveness

#### Tirzepatide vs. Semaglutide: Head-to-Head Metabolic Efficacy

The SURPASS-2 trial (n=1,879) provides the only completed randomized head-to-head comparison of tirzepatide and semaglutide (at the 1 mg dose approved for T2DM) (PMC9606350, PMC13143735). Tirzepatide was superior to semaglutide 1 mg for HbA1c reduction at all doses (−2.01%, −2.24%, −2.30% vs. −1.86%; p<0.02 for all) and for weight loss (treatment differences of −1.9, −3.6, and −5.5 kg; p<0.001 for all) (PMC9606350). The SURMOUNT-5 trial demonstrated that tirzepatide achieved −20.2% body weight reduction versus −13.7% for semaglutide 2.4 mg in adults with obesity or overweight, with 50% of tirzepatide-treated patients achieving ≥20% weight loss versus 27% on semaglutide, and 33% versus 16% achieving ≥25% weight loss (PMC13143735). Gastrointestinal adverse event rates were similar between tirzepatide and semaglutide in head-to-head trials (~17–22% vs. ~18%), and hypoglycemia rates were low in both groups (0.2–1.7% vs. 0.4%) (PMC13143735).

For cardiovascular outcomes specifically, no completed randomized head-to-head trial comparing tirzepatide and semaglutide on MACE endpoints exists. The SURPASS-CVOT compared tirzepatide to dulaglutide, not semaglutide. Comparative cardiovascular effectiveness data therefore rely entirely on observational studies, which consistently favor tirzepatide but are subject to the confounding limitations described above. The narrative review by Tirzepatide vs. semaglutide (PMC13143735) explicitly concludes that "semaglutide currently retains the most mature and robust evidence for cardiovascular risk reduction" while tirzepatide has "contextual cardiovascular outcome data" from SURPASS-CVOT demonstrating non-inferiority to dulaglutide.

#### Tirzepatide vs. Established GLP-1 Receptor Agonists: Guideline Implications

Current international guidelines — including those from the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), American College of Cardiology (ACC), and European Society of Cardiology (ESC) — recommend GLP-1 receptor agonists with proven cardiovascular benefit (specifically liraglutide, semaglutide, and dulaglutide) as preferred agents for patients with T2DM and established ASCVD or high cardiovascular risk (PMC9351217, PMC6761728). These recommendations are based on statistically significant MACE reduction demonstrated in dedicated, placebo-controlled CVOTs. Tirzepatide is not yet included in these guideline recommendations with a cardiovascular indication, reflecting the current state of evidence: cardiovascular safety established, non-inferiority to dulaglutide demonstrated in SURPASS-CVOT, but direct placebo-controlled superiority not yet demonstrated in a dedicated CVOT.

The systematic review of cardiovascular effectiveness in T2DM and PAD (PMC11434261) notes that a substantial proportion of SURPASS-CVOT participants had PAD, making this trial informative for the PAD subpopulation — a group with particularly high cardiovascular risk and limited therapeutic options. The review concludes that tirzepatide's promising cardiometabolic effects warrant its consideration in PAD patients once CVOT data are fully analyzed.

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### Special Populations

#### Heart Failure with Preserved Ejection Fraction

The SUMMIT trial provides the most direct evidence for tirzepatide in a specific cardiovascular subpopulation: adults with HFpEF and obesity. As described in PMC11387164, the SUMMIT trial enrolled 731 participants in a randomized, double-blind, placebo-controlled phase 3 design, with primary outcome measures including change in KCCQ Clinical Summary Score and incidence of cardiovascular death or heart failure events over time. Real-world observational data from the TriNetX platform (PMC12090002) demonstrate that tirzepatide was associated with significantly lower risks of acute heart failure exacerbation, MACE, stroke, and CKD progression in patients with heart failure without diabetes over a four-year follow-up period, providing complementary observational support for tirzepatide's potential benefit in HFpEF populations. This finding is clinically significant because HFpEF represents a condition with limited evidence-based pharmacotherapy, and the combination of obesity and HFpEF is particularly prevalent and difficult to treat. The SUMMIT results complement the STEP-HFpEF trial of semaglutide in HFpEF, collectively suggesting that incretin-based therapies — particularly those with substantial weight loss effects — may have particular utility in this population.

#### Patients with Peripheral Artery Disease

The systematic review by Coppola et al. (PMC11434261) specifically addresses the cardiovascular effectiveness of antidiabetic drugs in T2DM patients with PAD. For tirzepatide, the review notes that a substantial proportion of SURPASS-CVOT participants had PAD, providing a meaningful subgroup for future analysis. The review concludes that GLP-1 receptor agonists (particularly liraglutide and semaglutide) are currently the preferred agents for T2DM patients with PAD and high limb-complication risk, based on established CVOT data showing MACE reduction in PAD subgroups and reduced amputation risk. Tirzepatide's role in PAD management awaits subgroup analysis from SURPASS-CVOT.

#### Patients with Chronic Kidney Disease

Post-hoc analyses of SURPASS-4 demonstrated that tirzepatide was associated with a slower decline in eGFR (ameliorating annual eGFR decline by 2.2 mL/min/1.73 m²), reduced urine albumin-to-creatinine ratio (by 31.9%), and fewer composite kidney endpoints compared to insulin glargine (PMC11320168). Pharmacokinetic studies have confirmed that tirzepatide exposure is not significantly affected by kidney function impairment, making it a viable therapy for patients with stage 4 and 5 CKD — a population for whom few options exist (PMC11320168). The real-world study by Chuang et al. (PMC11320168) demonstrated significantly lower hazards of kidney events (AHR 0.52; 95% CI 0.37–0.73) and acute kidney injury (AHR 0.78; 95% CI 0.70–0.88) with tirzepatide versus GLP-1 receptor agonists, though these findings require confirmation in dedicated renal outcome trials.

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### Conclusions and Future Directions

#### What the Evidence Supports

The current evidence base supports the following conclusions regarding tirzepatide and cardiovascular outcomes in adults with T2DM:

**Cardiovascular safety is established.** The pre-specified meta-analysis of SURPASS trials and the SURPASS-CVOT (demonstrating non-inferiority to dulaglutide) collectively establish that tirzepatide does not increase cardiovascular risk compared to standard therapy or an active comparator with proven cardiovascular efficacy. This satisfies the regulatory requirement for cardiovascular safety and is consistent with the cardiovascular safety profiles of other GLP-1 receptor agonists (PMC9606350, PMC9400320).

**Non-inferiority to dulaglutide in a dedicated CVOT has been demonstrated.** The SURPASS-CVOT demonstrated that tirzepatide is non-inferior to dulaglutide for 3-point MACE in patients with T2DM and established ASCVD. Using the pre-specified imputed placebo methodology — based on a Bayesian meta-analysis establishing a 97.5th percentile HR of 0.95 for GLP-1 receptor agonists versus placebo in ASCVD patients — the SURPASS-CVOT results support the inference that tirzepatide is superior to a putative placebo for MACE reduction (PMC9400320). This represents a novel and important form of cardiovascular efficacy evidence, though it is structurally different from the direct placebo-controlled superiority demonstrated by LEADER, SUSTAIN-6, REWIND, and HARMONY.

**Tirzepatide demonstrates superior metabolic efficacy compared to semaglutide and other GLP-1 receptor agonists.** Across the SURPASS program and SURMOUNT-5, tirzepatide consistently achieved greater HbA1c reductions (by 0.15–0.45 percentage points) and greater weight loss (by 1.9–5.5 kg in T2DM; by 6.5 percentage points in obesity) compared to semaglutide, with favorable effects on blood pressure, lipid profiles, and inflammatory markers (PMC9606350, PMC13143735, PMC11320168). These metabolic advantages are biologically plausible mediators of cardiovascular benefit.

**Real-world observational data consistently favor tirzepatide over GLP-1 receptor agonists for cardiovascular outcomes.** Multiple large propensity score-matched observational studies using the TriNetX platform report significantly lower hazards of MACE, all-cause mortality, heart failure, and kidney events with tirzepatide compared to GLP-1 receptor agonists (PMC11320168, PMC12235410, PMC11377141). However, the magnitude of these effects (40–67% reductions) substantially exceeds what has been observed in randomized trials and is likely inflated by residual confounding, healthy user bias, channeling bias, and the short follow-up periods of 10.5–12 months in these observational datasets (PMC11320168, PMC12235410).

**Tirzepatide demonstrates potential benefit in HFpEF.** The SUMMIT trial was designed to evaluate tirzepatide versus placebo on cardiovascular death and heart failure events in patients with HFpEF and obesity, and real-world observational data demonstrate significantly lower risks of acute heart failure exacerbation and MACE with tirzepatide in patients with heart failure — a population with high unmet need (PMC12090002, PMC11387164).

#### What the Evidence Does NOT Support

**Tirzepatide has not demonstrated statistically significant superiority over placebo for MACE in a direct, placebo-controlled CVOT.** Unlike liraglutide, semaglutide, dulaglutide, and albiglutide — each of which demonstrated statistically significant MACE reduction versus placebo in dedicated CVOTs — tirzepatide's cardiovascular efficacy evidence rests on an active comparator design with an imputed placebo comparison. This is a meaningful distinction for guideline development and clinical decision-making (PMC9400320, PMC13143735).

**Tirzepatide has not demonstrated superiority over semaglutide or other GLP-1 receptor agonists for cardiovascular outcomes in a randomized trial.** The SURPASS-CVOT compared tirzepatide to dulaglutide, not semaglutide, and demonstrated non-inferiority rather than superiority. No completed randomized trial has demonstrated that tirzepatide reduces MACE more than any established GLP-1 receptor agonist (PMC13143735).

**The large cardiovascular effect sizes reported in real-world observational studies should not be taken at face value.** Effect sizes of 40–67% MACE reduction in observational studies are implausibly large given the 12–26% reductions observed in randomized GLP-1 receptor agonist CVOTs and the 10–20% lower MACE risk assumed for tirzepatide versus dulaglutide in SURPASS-CVOT power calculations. These observational findings are hypothesis-generating and require confirmation in randomized trials (PMC11320168, PMC12235410, PMC11377141).

**Current cardiovascular evidence does not support preferential use of tirzepatide over established GLP-1 receptor agonists with labeled cardiovascular indications in patients with T2DM and established ASCVD.** Until a direct head-to-head randomized trial demonstrates cardiovascular superiority of tirzepatide over semaglutide or liraglutide, or until regulatory agencies grant tirzepatide a labeled cardiovascular indication based on SURPASS-CVOT data, clinical guidelines appropriately continue to recommend GLP-1 receptor agonists with established cardiovascular indications as the preferred agents for this population (PMC13143735, PMC9351217).

#### Future Research Priorities

Six concrete future research priorities emerge from the gaps identified in this review:

**1. Head-to-head randomized cardiovascular outcome trial: tirzepatide versus semaglutide.** The most critical unmet need in the tirzepatide cardiovascular evidence base is a randomized, double-blind, adequately powered trial comparing tirzepatide directly to semaglutide (at the 1.0 mg T2DM dose or the 2.4 mg obesity dose) on 3-point MACE in patients with T2DM and established ASCVD. Such a trial would definitively resolve whether tirzepatide's superior metabolic efficacy translates into superior cardiovascular protection compared to the best-established GLP-1 receptor agonist (PMC13143735).

**2. Subgroup analyses from SURPASS-CVOT.** Detailed subgroup analyses from SURPASS-CVOT — including analyses by PAD status, heart failure status, renal function, and degree of weight loss — are needed to identify which patient subgroups derive the greatest cardiovascular benefit from tirzepatide and to inform individualized treatment decisions (PMC11434261).

**3. Dedicated renal outcome trial for tirzepatide.** Given the promising renal data from SURPASS-4 post-hoc analyses and real-world observational studies, a dedicated renal outcome trial for tirzepatide — analogous to CREDENCE (canagliflozin) or DAPA-CKD (dapagliflozin) — is needed to establish whether tirzepatide reduces the risk of kidney disease progression, end-stage kidney disease, and renal death in patients with T2DM and chronic kidney disease (PMC11320168).

**4. Mechanistic studies to disentangle GIP-specific from GLP-1-specific cardiovascular effects.** The relative contributions of GIP receptor agonism and GLP-1 receptor agonism to tirzepatide's cardiovascular effects remain poorly understood. Mechanistic studies using selective GIP receptor agonists, GIP receptor antagonists, and tirzepatide in head-to-head comparisons — in both animal models and human clinical studies — are needed to clarify whether GIP receptor agonism provides additive cardiovascular benefit beyond GLP-1 receptor agonism (PMC12090002, PMC11320168).

**5. Long-term real-world cardiovascular outcome studies with extended follow-up.** Current real-world observational studies have follow-up periods of only 10.5–12 months. Longer-term real-world studies with follow-up of 3–5 years, using rigorous active comparator new-user designs and comprehensive covariate adjustment, are needed to provide more reliable estimates of tirzepatide's real-world cardiovascular effectiveness (PMC11320168, PMC11377141).

**6. Cardiovascular outcome trials in primary prevention populations.** The SURPASS-CVOT enrolled patients with established ASCVD. Given that a substantial proportion of T2DM patients do not have established CVD but are at elevated cardiovascular risk, future trials should evaluate whether tirzepatide's cardiovascular benefits extend to primary prevention populations — analogous to the REWIND trial of dulaglutide, which enrolled a substantial proportion of participants without established CVD (PMC9351217, PMC9400320).

In summary, tirzepatide represents a pharmacological advance with compelling metabolic efficacy and a promising cardiovascular profile. The SURPASS-CVOT has established non-inferiority to dulaglutide and, through the imputed placebo methodology, supports the inference of superiority to a putative placebo — a meaningful regulatory milestone. However, the current evidence base for tirzepatide's cardiovascular effects is structurally different from, and less direct than, the placebo-controlled superiority evidence that underpins the cardiovascular indications of established GLP-1 receptor agonists. Clinicians should recognize that tirzepatide's cardiovascular evidence is primarily derived from exploratory endpoints in glycemic efficacy trials, a pre-specified safety meta-analysis, an active comparator CVOT with an imputed placebo comparison, and observational studies subject to substantial confounding — rather than from a dedicated placebo-controlled CVOT demonstrating direct MACE superiority. The field awaits regulatory decisions on tirzepatide's cardiovascular indication based on SURPASS-CVOT data, and the research community must prioritize the head-to-head randomized trials needed to definitively establish tirzepatide's place in the cardiovascular risk reduction armamentarium for T2DM.

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