Cardiovascular disease remains the leading cause of mortality among individuals with type 2 diabetes 1. Over the past decade, the management of type 2 diabetes has undergone a major shift with the advent of glucagon-like peptide-1 (GLP-1) receptor agonists, which mimic the actions of the endogenous incretin hormone GLP-1. By activating GLP-1 receptors (GLP-1R), these agents enhance glucose-dependent insulin secretion and slow gastric emptying, leading to improved glycemic control and weight loss 2. Importantly, multiple cardiovascular outcome trials have demonstrated the cardioprotective effects of GLP-1 receptor agonists (GLP-1RA) 3-5. Agents such as liraglutide, dulaglutide, and semaglutide have been shown to reduce the risk of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke 3-5. Recently, Nicholls et al. reported the results of a large randomized clinical trial, SURPASS-CVOT, demonstrating the potential cardiovascular benefits of tirzepatide—another member of the glucagon-like peptide-1 receptor agonist family 6. This landmark study is the first randomized clinical study to provide evidence that tirzepatide confers a cardiovascular benefit comparable to that of dulaglutide, a GLP-1RA with established cardiovascular benefit. In the trial, the primary composite outcome of cardiovascular death, myocardial infarction, or stroke occurred in 12.2% of participants receiving tirzepatide and 13.1% of those receiving dulaglutide (hazard ratio HR, 0.92; 95.3% confidence interval CI, 0.83–1.01; p = 0.003 for noninferiority), demonstrating that tirzepatide was noninferior to dulaglutide. In addition to cardiovascular outcomes, tirzepatide demonstrated significantly greater improvements in several metabolic risk factors compared with dulaglutide, including reductions in glycated hemoglobin, body weight, triglyceride levels, and systolic blood pressure. Interestingly, these favorable metabolic effects did not translate into a statistically significant reduction in the incidence of primary cardiovascular events compared with dulaglutide. This observation raises questions as to whether the cardiovascular protection mechanisms extend beyond these metabolic risk factors or whether the use of a comparator with established cardiovascular benefit attenuated detectable differences between the treatment groups. Another explanation may lie in the unique pharmacologic mechanism of tirzepatide compared with traditional GLP-1 receptor agonists, as discussed below. Tirzepatide is unique among incretin-based therapies in that it is a dual agonist of both the GLP-1R and the glucose-dependent insulinotropic polypeptide (GIP) receptor, with higher affinity for the GIP receptor (GIPR) than GLP-1R 7. This dual receptor activation is thought to underlie its superior glycemic control and weight loss compared with conventional GLP-1RAs, including semaglutide 8-11. However, the pathophysiological role of GIP in diabetes and obesity remains incompletely understood (Figure 1). In the pancreas, GIP is thought to act on β-cells to potentiate insulin secretion while simultaneously stimulating glucagon release from α-cells. This dual action on both α- and β-cells enables GIP to coordinate islet cell communication and ensure optimal postprandial hormone secretion, resulting in smoother glucose regulation 12. Multiorgan effects of tirzepatide mediated through GLP-1 receptor and context-dependent GIP receptor signaling. The role of GIP in lipid metabolism remains controversial, primarily because its actions are highly context dependent. GIP has been reported to exert both pro- and anti-adipogenic effects, with outcomes influenced by insulin availability, metabolic state (lean vs. obese; fasting vs. nonfasting; glucose levels), and sex. In vitro studies demonstrate that GIP increases lipoprotein lipase (LPL) activity in adipocytes, promoting exogenous triglyceride uptake and storage; however, this effect is strictly insulin dependent 13. Consistent with this conditional effect, human studies show that GIP infusion enhances LPL activity and stimulates free fatty acid re-esterification in abdominal subcutaneous white adipose tissue (WAT) only under hyperinsulinemic–hyperglycemic conditions, leading to increased triglyceride storage. In contrast, GIP infusion does not significantly influence WAT metabolism in the fasted state 14. Sex further modifies GIP's metabolic actions: early studies reported that GIP lowers LDL cholesterol levels independent of insulin in both men and women; however, elevated circulating GIP levels have been associated with increased visceral abdominal fat specifically in men 15. Paradoxically, pharmacologic GIPR agonism demonstrates consistent metabolic benefits when combined with GLP-1R activation 9, 10, underscoring the complexity and context-dependent nature of GIP signaling. Of note, LDL cholesterol was the only major metabolic risk factor that failed to improve with tirzepatide compared with dulaglutide in SURPASS-CVOT. This finding contrasts with findings from SURPASS J-mono, conducted in Japan, where tirzepatide significantly reduced LDL cholesterol compared with dulaglutide 16. Although differences in follow-up duration and dulaglutide dosing may partially explain the discrepancy, participants in SURPASS J-mono also had substantially lower BMI (28 vs. 32), a much shorter duration of diabetes (4.8 vs. 14.8 years), and a significantly different ethnic composition than those enrolled in SURPASS-CVOT. Long-standing diabetes and obesity may reshape tissue-specific expression of GLP-1R and GIPR, local insulin concentrations, and adipocyte gene expression profiles, thereby altering metabolic responses to tirzepatide and dulaglutide. The context-dependent nature of GIP signaling, together with the discrepancy in LDL cholesterol levels between SURPASS-CVOT and SURPASS J-mono, raises the question of whether diabetes subtyping could better predict the effects of tirzepatide on lipid metabolism and cardiovascular outcomes. Recent studies have made progress in classifying diabetes into distinct clusters based on BMI, age, insulin resistance, glycemic control, and related parameters 17. These clusters are associated with different insulin sensitivities and lipid profiles, including LDL cholesterol levels and hepatic lipid content, as well as divergent long-term complication risks, such as liver fibrosis 18. Further refinement of clustering approaches using more precise parameters such as demographic variables and disease stage, coupled with analyses of cardiovascular risk, represents an essential next step to improve prediction of cardiovascular outcomes. Defining how diabetes clusters modify the response to tirzepatide may illuminate key determinants of GIP signaling in cardiovascular disease and refine the mechanistic understanding of treatment heterogeneity. GIPR is also expressed in tissues beyond the pancreas, including adipose tissue, the heart, and the vasculature, where it may exert tissue-specific effects relevant to cardiometabolic disease 19. Recently it was found that specific GIPR induction in adipocytes results in increased lipid oxidation and energy expenditure exclusively in white fat depots through futile calcium cycling 20. However, no comprehensive studies have systematically characterized tissue-specific changes in GIPR expression across stages of obesity or across different stages and clusters of diabetes in human subjects. Although GIPR is highly expressed in certain adipocyte subsets, adipocyte composition varies widely across fat compartments and cardiometabolic disease contexts and undergoes dynamic remodeling during disease progression. Because the proportion of subcutaneous and visceral fat differs between men and women, depot-specific differences in GIPR expression may also contribute to sex-specific responses to tirzepatide. Systematic longitudinal profiling of tissue-specific GIPR expression across cardiometabolic disease stages in both sexes would help clarify the mechanisms of tirzepatide and identify populations with the greatest therapeutic benefit. Heart failure represents another critical cardiovascular outcome in type 2 diabetes, with heart failure with preserved ejection fraction (HFpEF) being the predominant phenotype 21. In SURPASS-CVOT, tirzepatide was associated with a numerically lower, though not statistically significant, incidence of the composite outcome of cardiovascular death, or hospitalization, for urgent visits for heart failure compared with dulaglutide (7.8% vs. 8.5%; HR, 0.91; 95% CI, 0.81–1.03). A novel adipokine hypothesis proposes that all coexisting disorders of HFpEF arise from a single cause—excessive visceral fat—which secretes adipokines that drive insulin resistance, systemic inflammation, and cardiac remodeling 22. The superior reductions in body weight and fat mass observed with tirzepatide in SURPASS-CVOT and SURMOUNT-5 may therefore contribute to a favorable trend toward HFpEF risk reduction. Whether tirzepatide also reduces the risk of heart failure with reduced ejection fraction (HFrEF) by improving cardiomyocyte dysfunction and apoptosis, potentially through attenuation of lipotoxicity and mitochondrial reactive oxygen species, remains an open question. Interpretation is limited by the absence of heart failure phenotype classification in SURPASS-CVOT. Detailed characterization of visceral adipose tissue distribution across different anatomical sites, with stratification of subjects treated with tirzepatide, would help validate the adipokine hypothesis and fully assess tirzepatide's potential benefits in different types of heart failure. Among visceral fat depots, epicardial adipose tissue (EAT) plays a unique role in obesity-related HFpEF, acting both as a metabolically active site secreting inflammatory cytokines and as a space-occupying structure impairing ventricular relaxation 23. GLP-1RAs have been shown to significantly reduce EAT volume 24, whereas EAT depletion, commonly observed in HFrEF, is associated with greater risk of left ventricular dysfunction and adverse prognosis 23. This finding is consistent with previous trials that failed to demonstrate beneficial effects of classic GLP-1RAs in HFrEF and even raised concerns about increased cardiac adverse events with liraglutide treatment 25, 26. Notably, both GLP-1R and GIPR are expressed in EAT, with GIPR expression levels approximately 1100 times higher than those of GLP-1R 27. The relatively low expression of GLP-1R in EAT raises the possibility that GLP-1 mediates its effects largely through systemic metabolic improvements, whereas GIP acts through direct receptor activation. Interestingly, GLP-1R expression in EAT correlates with genes promoting fatty acid oxidation and white-to-brown adipose tissue differentiation, whereas GIPR expression is associated with adipogenesis 27. Whether this paradox reflects a regulatory balance between GIP and GLP-1 signaling that promotes healthy adipose tissue remodeling while preventing pathological fat accumulation or cardiac cachexia warrants further investigation. SURPASS-CVOT provided a head-to-head comparison of tirzepatide and dulaglutide at a time when dulaglutide and liraglutide dominated the GLP-1RA market. However, prescribing patterns have shifted substantially in recent years, with semaglutide and tirzepatide now accounting for the majority of incretin-based therapy use 28. The limited current use of dulaglutide among patients with type 2 diabetes restricts the generalizability of the trial's findings in contemporary clinical practice. Interestingly, a recently published database study, benchmarked against the SURPASS-CVOT trial, helps address this issue 29. In this study, benchmarking yielded results consistent with the trial. The authors then extended the analysis to a broader real-world population and compared tirzepatide with semaglutide, ultimately demonstrating comparable effects between the two drugs on myocardial infarction, stroke, or all-cause mortality. Although randomized clinical trials remain the gold standard for evaluating drug efficacy, the rapidly evolving therapeutic landscape of diabetes can limit the generalizability of trial data for clinical decision-making over time. The study conducted by Krüger et al. highlights the potential of nonrandomized database studies to provide a complementary approach for extending trial findings and assessing the real-world effectiveness of different incretin-based therapies, although residual confounding remains an inherent concern. In summary, the SURPASS-CVOT trial represents a pivotal head-to-head comparison demonstrating the noninferiority of tirzepatide to dulaglutide with respect to cardiovascular outcomes. Database studies rooted in trial benchmarking further enhance the relevance of these findings. Future studies aimed at elucidating the complex and highly context-dependent biological roles of GIP in cardiovascular and metabolic diseases will be essential for identifying patients who are most likely to benefit from GLP-1/GIP dual agonists. A deeper understanding of GIP signaling and its interaction with GLP-1 in insulin secretion, lipid metabolism, and adipose tissue remodeling will also lay the groundwork for the next generation of incretin-based therapies, including triple GLP-1/GIP/glucagon receptor agonists such as retatrutide. Chao Xue drafted the manuscript and approved the final version to be published. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Chao Xue (Wed,) studied this question.