Tirzepatide versus Dulaglutide in Type 2 Diabetes Mellitus: Cardiovascular Insights from SURPASS-CVOT and Relevance to South Asian Populations

Dear Editor, The cardiovascular safety of newer incretin-based therapies is of particular relevance in regions such as South Asia, where patients with type 2 diabetes mellitus (T2DM) develop atherosclerotic cardiovascular disease (ASCVD) at a younger age and at lower body mass index (BMI) thresholds than Western populations. In this context, the SURPASS-CVOT trial provides important evidence regarding the cardiovascular profile of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, evaluated against an established GLP-1 receptor agonist.[1] SURPASS-CVOT was a double-blind, randomized, active-comparator cardiovascular outcomes trial (CVOT) that enrolled 13,299 patients aged ≥40 years with T2DM and established ASCVD. Participants were randomized to once-weekly tirzepatide, titrated up to 15 mg, or dulaglutide 1.5 mg. Over a median follow-up of approximately 4.0 years, the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 12.2% of patients treated with tirzepatide and 13.1% of those treated with dulaglutide, yielding a hazard ratio (HR) of 0.92 (95.3% confidence interval [CI]: 0.83–1.01). The trial met its prespecified criterion for non-inferiority (P = 0.003) but did not demonstrate superiority (P = 0.09).[1] A notable finding of SURPASS-CVOT is the apparent dissociation between tirzepatide’s substantial metabolic efficacy and the absence of a statistically significant incremental reduction in major adverse cardiovascular events compared with dulaglutide. Tirzepatide produced markedly greater reductions in glycated hemoglobin (HbA1c) and body weight, along with favorable effects on triglycerides, blood pressure, and renal parameters (HbA1c: −1.66% vs. −0.88%, P < 0.001; body weight: −11.6% vs. −4.8%, P < 0.001).[1] However, these metabolic advantages did not translate into superior cardiovascular outcomes over the observed follow-up. This observation is biologically plausible given the use of an active comparator with established cardiovascular benefit and the widespread background use of cardioprotective therapies, including statins, antihypertensive agents, and sodium-glucose cotransporter-2 inhibitors. These findings reinforce the principle that improvements in surrogate metabolic markers do not necessarily yield proportional reductions in cardiovascular endpoints within a finite time horizon.[2] The choice of dulaglutide as the comparator is both clinically and methodologically important, distinguishing SURPASS-CVOT from earlier placebo-controlled GLP-1 receptor agonist CVOTs. In the REWIND trial, dulaglutide demonstrated cardiovascular superiority over placebo in a broad population of 9901 participants, followed for a median of 5.4 years, with 68.5% lacking prior cardiovascular disease at baseline. The primary composite outcome occurred at rates of 2.4 per 100 person-years with dulaglutide and 2.7 per 100 person-years with placebo, corresponding to an HR of 0.88 (95% CI: 0.79–0.99). Cardiovascular benefit was consistent across key subgroups, including those without established ASCVD.[3] Against this background, SURPASS-CVOT evaluated tirzepatide not versus placebo but against a GLP-1 receptor agonist already proven to reduce cardiovascular events, thereby setting a high threshold for demonstrating superiority. Within this framework, the results of SURPASS-CVOT are best interpreted as evidence of cardiovascular equivalence to a benchmark therapy rather than an absence of cardiovascular benefit. Secondary analyses suggesting lower all-cause and noncardiovascular mortality with tirzepatide lay outside the prespecified hierarchical testing strategy and were not adjusted for multiplicity, and therefore remain exploratory.[1] An additional consideration relevant to Asian populations is the ethnic composition of SURPASS-CVOT. More than 80% of participants were White, limiting the direct extrapolation of the findings to South Asian populations. Asians, particularly South Asians, develop cardiometabolic complications at lower-BMI thresholds and exhibit a characteristic “thin-fat” phenotype driven by disproportionate visceral adiposity, features that were underrepresented in SURPASS-CVOT.[4] In this context, evidence from Asian obesity trials involving GLP-1 receptor agonists and dual incretin therapies offers complementary insights into the metabolic responsiveness of Asian populations.[5] In SURMOUNT-CN, conducted exclusively in Chinese adults with obesity using BMI inclusion criteria as low as ≥24 kg/m2, tirzepatide achieved approximately 13%–16% weight loss with the 10 mg and 15 mg doses.[6] These findings demonstrate clinically relevant metabolic efficacy in Asian populations at BMI levels relevant to the South Asian phenotype. However, SURMOUNT-CN was an obesity-focused trial without cardiovascular endpoints, and cardiovascular safety or benefit observed in SURPASS-CVOT cannot be assumed to extend to lower-BMI Asian populations. Dedicated cardiovascular outcome trials enrolling South Asian participants are, therefore, needed to define tirzepatide’s cardiovascular profile in this high-risk group characterized by early-onset ASCVD. From a clinical perspective, SURPASS-CVOT provides reassurance regarding the cardiovascular safety of tirzepatide when compared with dulaglutide in patients with T2DM and established ASCVD. When cardiovascular risk reduction is the primary therapeutic objective, agents with proven placebo-controlled cardiovascular benefits, such as dulaglutide, liraglutide, and semaglutide, also represent suitable therapeutic options [Table 1]. In patients in whom substantial weight reduction and greater glycemic improvement are prioritized, tirzepatide may be preferred. Finally, considerations of affordability, accessibility, and long-term adherence are particularly important in low- and middle-income settings and should be integral to individualized clinical decision-making.Table 1: Cardiovascular outcomes trials of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus (T2DM)Acknowledgment None. Author contributions The author solely contributed to the conception, drafting, and revision of the manuscript and approved the final version. Data availability statement No new data were generated or analyzed for this article. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.