Tirzepatide and Cardiovascular Outcomes: A Narrative Review of Mechanisms, Efficacy and Implications for Heart Failure Management

In SURPASS and related trials, once‐weekly tirzepatide (5–15 mg) produces modest, consistent BP reductions: systolic by ~4–6 mmHg and diastolic by ~2 mmHg over ~1 year [19]. SBP reduction was primarily weight‐loss–mediated. In SURPASS‐4, weight‐independent effects explained 33%–57% of the difference in SBP [20, 21].

A clear dose–response is seen in SURPASS‐J monotherapy, where higher doses yielded larger on‐treatment reductions (≈11/5–6 mmHg at the highest dose). In pooled SURPASS analyses, those starting with SBP > 140 mmHg had the largest reductions, whereas participants with low‐normal baseline SBP (< 122 mmHg) showed minimal change, indicating a downward shift in BP most pronounced among hypertensive patients [21, 22].

In the obesity (non‐diabetic) trial (SURMOUNT‐1), tirzepatide 72‐week treatment led to clinically significant BP improvements at the patient level. Notably, 58.0% of tirzepatide‐treated participants achieved normal BP (< 130/80 mmHg) at Week 72, compared to 35.2% on placebo [22, 23]. Mediation analysis in SURMOUNT‐1 attributed about 68% (SBP) and 71% (DBP) of these improvements to weight loss, highlighting the practical benefit of the drug on BP categories, not just mean values.

In a secondary analysis of SUMMIT, tirzepatide at 52 weeks significantly reduced SBP relative to placebo (estimated treatment difference ~−5 mmHg) and markedly reduced estimated circulating blood volume by ~0.58 L [24]. This suggests tirzepatide relieves volume overload and vascular stiffness in HFpEF, contributing to its BP‐lowering effect and symptomatic benefit.

In pooled analyses, tirzepatide‐induced BP declines did not cause symptomatic hypotension in most patients [20]. Nevertheless, clinicians should monitor for orthostatic symptoms when initiating tirzepatide in patients on multiple BP drugs (especially diuretics or SGLT2 inhibitors) and adjust co‐medications if needed. Also, small dose‐dependent increases in heart rate have been observed in trials, with no consistent increase in atrial fibrillation in meta‐analyses [25, 26].

Taken together, BP lowering plus improvements in weight and lipids likely reduce HF and stroke risk and improve HFpEF symptoms, with the greatest benefit in patients starting with higher SBP and obesity‐related haemodynamic load [19, 20, 24].

In overweight or obese patients without diabetes (SURMOUNT‐1), once‐weekly tirzepatide (up to 15 mg) induced dose‐dependent and sustained weight loss over 72 weeks: −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg) versus −3.1% with placebo. Notably, ≥ 20% loss was achieved in 50%–57% of patients at higher doses. This profound weight loss unloads the circulation, reduces visceral and cardiac fat, and improves ventricular filling pressures—all central to HFpEF pathophysiology.

In SUMMIT, tirzepatide resulted in (−13.9% vs. −2.2% in placebo) mean weight loss at 52 weeks, with corresponding improvements in symptoms and a lower rate of death from cardiovascular causes or worsening heart‐failure events (9.9% vs. 15.3% in placebo) [27]. Consistent with these clinical benefits, the SUMMIT CMR substudy found that tirzepatide significantly reduced left ventricular (LV) mass (~−11 g) and paracardiac (epicardial plus pericardial) adipose volume (~−45 mL) compared to placebo [28]. The LV mass change correlated with weight loss, supporting a weight‐mediated reverse remodelling effect.

Across SURPASS trials, tirzepatide treatment produced significant improvements in atherogenic lipids: total cholesterol fell (TC −3.8%/−4.6%/−5.9% at 5/10/15 mg) with reduced triglycerides and LDL‐C. HDL‐C was increased [19]. These lipid improvements are largely weight‐loss–mediated, as noted in SURPASS‐J.

In a post hoc analysis of SURPASS J‐mono, greater weight loss on tirzepatide was associated with larger improvements in triglycerides and HDL‐C [21]. By lowering triglyceride‐rich lipoproteins (a source of residual risk), tirzepatide can complement LDL‐cholesterol–targeted therapy to slow atherosclerotic progression.

In another post hoc analysis of the phase‐2 tirzepatide study, tirzepatide dose‐dependently reduced apoC‐III and apoB and lowered the number of large triglyceride‐rich lipoprotein and small LDL particles, consistent with decreased remnant cholesterol and an overall less atherogenic profile [29].

Complementary evidence comes from SURPASS‐CVOT, an event‐driven cardiovascular outcomes trial in > 13,000 patients with type 2 diabetes and established atherosclerotic cardiovascular disease, which compared tirzepatide (up to 15 mg weekly) with dulaglutide 1.5 mg weekly, a GLP‐1 receptor agonist with proven CV benefit [9]. The design and baseline characteristics have been published, confirming a high‐risk cohort with long‐standing diabetes and established ASCVD. According to the first peer‐reviewed report of the top‐line results, tirzepatide met the primary endpoint of non‐inferiority for 3‐point MACE (CV death, nonfatal myocardial infarction or nonfatal stroke) compared with dulaglutide, with an approximately 8% relative risk reduction (hazard ratio ~0.92; 95% CI 0.83–1.01) [30]. Thus, tirzepatide preserved at least the full cardioprotective effect of a benchmark GLP‐1 RA, with no signal of increased cardiovascular risk. Exploratory analyses reported numerically lower all‐cause mortality, larger reductions in HbA1c and body weight, and signals for slower decline in estimated glomerular filtration rate in high‐risk subgroups with tirzepatide versus dulaglutide, consistent with its broader metabolic effects.

Tirzepatide was associated with a significantly greater reduction in the urine albumin‐to‐creatinine ratio (UACR) compared with controls, with an average decrease of approximately 26.9%. Among participants with baseline UACR levels ≥ 30 mg/g, the reduction was even more pronounced at around 41.4% [31].

In a post hoc analysis of the SURPASS‐4 trial, which included patients with type 2 diabetes, a body mass index (BMI) ≥ 25 kg/m², and high cardiovascular risk, once‐weekly tirzepatide (5, 10 or 15 mg) was compared with insulin glargine. Over a median follow‐up of 85–104 weeks, tirzepatide treatment was associated with a lower incidence of the composite kidney endpoint, defined as an eGFR decline of ≥ 40%, renal death, progression to kidney failure or new‐onset macroalbuminuria [32].

Nearly 60% of enrolled patients had chronic kidney disease, and in this subgroup tirzepatide conferred similar reductions in HF events compared with patients without renal impairment. A dedicated renal analysis showed that after an initial dip in eGFR, consistent with haemodynamic adjustment, tirzepatide stabilised or improved kidney function over 52 weeks relative to placebo. A reduction in albuminuria was also observed, suggesting potential renal protective effects alongside the cardiac benefits [33] (Figure 3).

Obesity is characterised by chronic low‐grade inflammation and oxidative stress that worsen atherosclerosis and HFpEF. Across randomised human studies, tirzepatide consistently attenuates systemic inflammation (Table 1).

In SURMOUNT, 72‐week changes versus placebo were substantial: IL‐6 ↓ ~ 26%–31% and hsCRP ↓ ~51%–65%. Mediation analyses show that early (24‐week) declines are only modestly weight‐mediated (≈18%–31%), whereas by 72 weeks the reductions are largely weight‐mediated (≈57%–87%), indicating an initial partly weight‐independent signal that becomes predominantly weight‐linked with sustained treatment [34].

In a phase‐2 randomised programme, tirzepatide also lowered ICAM‐1 and YKL‐40 dose‐dependently by 26 weeks, alongside hsCRP reductions. Thus, supporting broader immunometabolic modulation beyond CRP/IL‐6 [29].

In SUMMIT, tirzepatide reduced hsCRP by ~37% and high‐sensitivity troponin‐T by ~10% and lowered systolic blood pressure by ~5 mmHg versus placebo, while NT‐proBNP showed a modest/non‐significant decline (p ≈ 0.07). Importantly, ΔCRP correlated with both improved 6‐min walk distance and lower troponin, linking reduced systemic inflammation to less myocardial injury and better functional status [24].

As context, the GLP‐1RA class shows a compatible human signal; in a randomised trial, exenatide reduced hsCRP and MCP‐1 and lowered 8‐iso‐PGF2α (oxidative stress) over 16 weeks versus placebo, and meta‐analyses confirm significant CRP reductions with GLP‐1Ras; reinforcing a class anti‐inflammatory effect relevant to tirzepatide [35, 36].

Endothelial dysfunction is central to vascular stiffness and impaired ventricular–arterial coupling in HFpEF. Across randomised trials, GLP‐1 receptor agonists improve endothelial‐dependent vasodilation and, in aggregate, show modest improvements in arterial stiffness.

A 2024 network meta‐analysis of 38 RCTs in type 2 diabetes reported significant gains in brachial flow‐mediated dilation (FMD) and reductions in pulse‐wave velocity (PWV) versus placebo, consistent with enhanced NO‐dependent vasodilation [37]. In a 12‐week randomised study in type 1 diabetes, once‐weekly semaglutide nearly doubled FMD (≈5.8% → ≈11.1%; p < 0.001) and lowered peripheral vascular resistance (~5%; p ≈ 0.046), demonstrating measurable endothelial benefit over a short horizon [38]. However, a separate 2024 meta‐analysis found no significant pooled effect of GLP‐1RAs on PWV, highlighting heterogeneity across populations, follow‐up duration and measurement methods [39].

For tirzepatide specifically, dedicated human FMD/PWV records are not yet available, but multiple signals point towards favourable vascular biology. In a phase‐2 randomised programme, tirzepatide reduced ICAM‐1 (with no change in VCAM‐1) alongside hsCRP reductions by 26 weeks. These findings are compatible with lower endothelial inflammatory activation [29].

Taken together, class effects on FMD/PWV plus tirzepatide's endothelial biomarker and haemodynamic profile support a model in which tirzepatide enhances vascular compliance indirectly (via weight loss, lower BP and reduced inflammation) and likely directly through endothelial pathways, thereby helping to reduce afterload and support diastolic filling pressures in HFpEF.

The SUMMIT trial was the first large, double‐blind outcomes study of dual‐incretin therapy in obesity‐related HFpEF. In this study, just over 700 symptomatic patients with HFpEF (LVEF ≥ 50%) and BMI ≥ 30 kg/m² were randomised to weekly tirzepatide or placebo and followed for a median of ~2 years.

Tirzepatide significantly reduced the prespecified composite of cardiovascular death or worsening heart‐failure events by 38% versus placebo—an effect driven predominantly by fewer HF hospitalizations and urgent HF visits, while all‐cause and cardiovascular mortality were neutral. Treatment was also associated with marked weight loss (≈12%–14% at 52 weeks) and clinically meaningful improvements in symptoms and exercise capacity. The magnitude of weight reduction approaches that seen after bariatric surgery in some series [1, 40].

Mechanistic analyses from SUMMIT provide insight into how tirzepatide achieves these benefits. The drug significantly reduced estimated blood volume, lowered high‐sensitivity troponin levels and attenuated systemic inflammation. These changes are consistent with relieving volume‐pressure overload and myocardial stress [24].

An expanded secondary analysis confirmed that tirzepatide's benefits extended across multiple domains of clinical status, including improved quality of life, functional class and a reduced need for HF medications [41]. Furthermore, a cardiac MRI substudy demonstrated reverse remodelling: tirzepatide therapy led to regression of left ventricular mass and a reduction in paracardiac adipose tissue (LV mass −11 g; paracardiac fat −45 mL) [28]. Such structural improvements likely translate into better diastolic function and symptomatic relief (Figure 5).

Collectively, SUMMIT offers high‐quality evidence that targeting obesity and metabolic dysfunction with a dual GIP/GLP‐1 agonist can modify the disease trajectory in HFpEF, reducing HF events while improving exercise capacity and quality of life.

Complementary real‐world evidence comes from a brief report by Kishimori et al. [42], who compared tirzepatide with semaglutide in adults with HFpEF and type 2 diabetes using the global TriNetX electronic health record network. After propensity score matching (n ≈ 5800 per group), 1‐year risks of acute heart failure, all‐cause death and all‐cause hospitalisation did not differ significantly between tirzepatide and semaglutide (HR for acute HF 0.98, 95% CI 0.89–1.07; HR for all‐cause death 0.87, 95% CI 0.67–1.13; HR for all‐cause hospitalisation 1.00, 95% CI 0.94–1.06), and gastrointestinal adverse events and hypoglycaemia were also similar. These findings suggest that in HFpEF with diabetes, tirzepatide and semaglutide provide broadly comparable short‐term HF and survival outcomes, reinforcing a class cardiometabolic benefit while allowing weight‐loss and metabolic responses to guide individual drug selection.

Recognising this evidence, new guidelines have begun to integrate obesity management into HF care. The 2025 ACC scientific statement on obesity in heart failure addresses the therapeutic role of GLP‐1 and dual GIP/GLP‐1 agonists for patients with HFpEF and obesity, and it recommends multidisciplinary care pathways to integrate anti‐obesity medications safely and effectively [43].

For clinicians managing patients with HF, who frequently have concomitant obesity, diabetes and ischemic heart disease, these data suggest that using tirzepatide for weight and glycemic control is unlikely to compromise cardiovascular outcomes and may provide incremental reductions in adverse events on top of standard HF therapies [9, 30]. When viewed alongside HFpEF trials such as SUMMIT and STEP‐HFpEF, the emerging picture is that dual incretin agonism can simultaneously improve HF‐related symptoms and haemodynamics in obesity‐related HFpEF while lowering long‐term atherosclerotic event risk without an apparent trade‐off in cardiovascular safety.

In contrast to the HFpEF findings, the role of incretin‐based therapies in heart failure with reduced ejection fraction (HFrEF) remains uncertain. Earlier trials of GLP‐1 receptor agonists in HFrEF, most notably FIGHT, showed no clinical benefit [44]. Also, the LIVE trial reported higher resting heart rate and more serious cardiac events with liraglutide versus placebo [45], supporting a cautious approach in this phenotype.

In FIGHT, liraglutide did not improve outcomes and there were signals of possible harm, such as a higher incidence of HF hospitalisation [44]. In addition, liraglutide did not improve left ventricular ejection fraction and was associated with an ≈7 bpm increase in resting heart rate and more serious cardiac adverse events compared with placebo [45]. To date, no large randomised outcomes trial of tirzepatide has been performed specifically in HFrEF, and patients with severely reduced EF or recent decompensation were generally excluded from tirzepatide's studies.

An 'obesity paradox' has been noted in HFrEF; higher body mass often correlates with better outcomes, so rapid weight loss could unmask frailty or cachexia in this population [46, 47]. Until dedicated HFrEF trials are conducted, any tirzepatide use in such patients should be very cautious and highly individualised. Consistently, a recent meta‐analysis of randomised trials in HFrEF found no improvement in key HF outcomes with GLP‐1 receptor agonists [48].

Emerging real‐world data suggest that tirzepatide may be safe, and possibly beneficial, even in patients with advanced systolic heart failure and ventricular arrhythmias, with a propensity score–matched analysis reporting lower 1‐year mortality in tirzepatide users compared with non‐users. However, these observational, arrhythmia‐focused cohorts are prone to confounding and do not overturn the neutral or negative randomised trial data; they are better interpreted as reassuring for cardiovascular safety when tirzepatide is used to treat coexisting obesity or diabetes in HFrEF rather than as evidence of HF‐specific efficacy [49].

For HFrEF patients with severe obesity, tirzepatide may still be considered on a case‐by‐case basis when excess adiposity is a clear driver of haemodynamic compromise or refractory symptoms. In such cases, a collaborative approach (involving cardiology, endocrinology, nutrition, etc.) is advised, with close monitoring and dose adjustments as weight and haemodynamic changes.

In HFpEF, where symptom burden and impaired functional capacity are often the main clinical concerns, the improvements observed with incretin therapy are particularly important. In SUMMIT, patients receiving tirzepatide reported substantially better health‐related quality of life, with Kansas City Cardiomyopathy Questionnaire (KCCQ) scores improving by nearly seven points more than placebo at 1 year, a change that exceeds the established threshold for clinical significance. This along with an average increase of ~18 m in the 6‐min walk test, a functional improvement rarely achieved with existing pharmacologic therapies in HfpEF [27]. Of note, the trajectory of benefit began within the first few months of treatment and was maintained throughout follow‐up, demonstrating both the efficacy and durability of this approach.

STEP‐HFpEF provides converging evidence with semaglutide, where patients also experienced clinically significant improvements in KCCQ scores and exercise capacity over 52 weeks. These benefits occurred alongside reductions in systemic inflammation (as reflected by high‐sensitivity CRP) and body weight, suggesting that the observed improvements in patient‐reported outcomes reflect both haemodynamic and systemic metabolic relief. Subgroup analyses further revealed that the magnitude of quality‐of‐life benefit correlated with baseline NT‐proBNP levels, indicating that patients with greater haemodynamic burden may derive disproportionate symptomatic improvement from incretin therapy [27, 40].

Trial readouts collectively support a pathway where substantial, sustained weight loss (plus anti‐inflammatory and vascular effects) improves filling pressures, exercise tolerance and daily function. SUMMIT's imaging substudy adds structure–function specificity (↓LV mass, ↓paracardiac fat), while STEP's biomarker/CRP data show important systemic anti‐inflammatory contribution. These mechanisms extended to cardiorenal syndrome indicated previously, where reduced venous congestion and improved metabolic status stabilise kidney function, consistent with SUMMIT's 52‐week eGFR findings [24, 33].

The signal hierarchy now spans (a) patient experience (KCCQ) and performance (6MWD) in STEP‐HFpEF, and (b) hard clinical events (HF worsening) plus patient‐reported outcomes in SUMMIT—together informing 2024–2025 scientific statements that place GLP‐1/dual GIP‐GLP‐1 agonists within multidisciplinary obesity management for HFpEF. Pending broader uptake with background SGLT2/MRA therapy and longer follow‐up for mortality, the consistent quality‐of‐life and functional gains justify considering incretin therapy when excess adiposity is the driver of limitation.

Tirzepatide and semaglutide share a common GLP‐1–based backbone but differ in receptor profile and, potentially, in how they modify the heart–adipose–metabolic axis relevant to HF. Semaglutide is a selective GLP‐1 receptor agonist that promotes glucose‐dependent insulin secretion, suppresses glucagon, slows gastric emptying and reduces appetite, leading to substantial weight loss and improvements in glycemic control, blood pressure and systemic inflammation [40, 50]. GLP‐1 signalling also appears to exert natriuretic, endothelial and modest direct myocardial effects that may be particularly relevant in cardiometabolic HFpEF [13, 14].

Tirzepatide is a dual GIP/GLP‐1 receptor agonist. In addition to GLP‐1–mediated effects, agonism at the GIP receptor further enhances insulin secretion, improves insulin sensitivity and amplifies weight loss beyond that typically achieved with GLP‐1 monotherapy [13, 14, 51]. This more potent metabolic effect translates into larger reductions in body weight, visceral and ectopic fat, including pericardial/epicardial adipose tissue and left‐ventricular mass, as shown in the SUMMIT CMR substudy [52]. By aggressively unloading adiposity and improving cardiometabolic risk factors (glycemia, blood pressure, inflammatory markers), tirzepatide and semaglutide both target the core pathophysiologic substrate of obesity‐related HFpEF rather than a narrow LVEF phenotype [40, 50, 53, 54].

Both tirzepatide and semaglutide have robust randomised evidence in obesity‐related HFpEF. In STEP‐HFpEF, semaglutide 2.4 mg weekly produced clinically meaningful improvements in health status and function (placebo‐corrected KCCQ‐CSS ≈ +7–8 points; 6MWD ≈ +15–20 m), ≈13% mean weight loss versus ≈2%–3% with placebo and larger reductions in NT‐proBNP (~20% vs. ~5%) [40, 50, 53, 54].

In SUMMIT (n = 731, LVEF ≥ 50%), tirzepatide (up to 15 mg weekly) lowered the composite of cardiovascular death or worsening HF from 15.3% to 9.9% (HR 0.62; 95% CI 0.41–0.95), driven by fewer HF hospitalizations/urgent visits; it also yielded greater KCCQ gains (~19.5 vs. 12.7 points), modest 6MWD increases (~15–20 m), ≈12%–15% weight loss, and CMR‐documented reductions in LV mass and paracardiac fat [27, 52].

In SURMOUNT‐5, a phase 3b, open‐label trial in adults with obesity (mean BMI ~39.5 kg/m²) without established cardiovascular disease or type 2 diabetes, tirzepatide was compared head‐to‐head with semaglutide for weight loss and modelled 10‐year cardiovascular risk reduction [55]. In a post hoc analysis, presented at ESC 2025 and including ~750 participants who completed 72 weeks of treatment, 10‐year cardiovascular disease (CVD) risk was estimated using validated BMI‐based Framingham equations. Baseline predicted risk was approximately 9%. Tirzepatide produced a larger absolute reduction in 10‐year CVD risk than semaglutide (about −2.4% vs. −1.4%; p < 0.001), corresponding to a relative risk reduction of roughly 24% versus ~14% with semaglutide. These differences were largely driven by greater weight loss and cardiometabolic improvements (blood pressure, glycemia, lipids) in the tirzepatide arm, and population‐level modelling suggested that, in an eligible U.S. population, tirzepatide could potentially prevent nearly twice as many CVD events over a decade as semaglutide. Although these estimates are based on risk modelling rather than adjudicated events, they illustrate how more intensive reductions in adiposity and risk factors may translate into larger long‐term cardioprotective gains, highly relevant given obesity's causal role in HFpEF and other cardiac phenotypes.

Overall, both agents produce similar placebo‐adjusted symptomatic and functional gains on a background of double‐digit weight loss; semaglutide offers more detailed NT‐proBNP data, while tirzepatide currently shows the clearest HF event‐reduction signal. Real‐world and emulation studies broadly corroborate lower HF and cardiorenal events with both drugs [40, 42, 51, 56].

From a clinical standpoint, tirzepatide and semaglutide can be viewed as disease‐modifying adjuncts in obesity‐driven HFpEF rather than 'HF drugs' in the traditional neurohormonal sense. Their main value lies in profound and sustained weight loss, improvement in metabolic risk factors, reduction of congestion and ectopic cardiac fat, and better functional capacity and health status [27, 40, 50, 52, 53].

In obese HFpEF with or without type 2 diabetes, either agent is reasonable in addition to guideline‐directed HF therapies (SGLT2 inhibitors, RAAS blockade, MRAs, diuretics). Tirzepatide may be favoured when very large weight loss or maximal glycemic improvement is a priority, or when the clinician wishes to leverage the HF event‐reduction signal seen in SUMMIT [27, 51, 52, 56]. Semaglutide may be preferred when a more extensive cardiovascular outcome portfolio is desired (e.g., SELECT and other CVOT data in ASCVD and obesity), or when natriuretic peptide reduction is particularly relevant [40, 50, 53, 57]. In HFrEF, use of either agent should remain individualised and metabolic‐driven (obesity, diabetes) rather than HF‐driven, pending dedicated outcome trials [44, 58].