Tirzepatide Matches Trulicity on Heart Safety, and Does More

For millions living with type 2 diabetes and heightened cardiovascular risk, every new treatment brings a question of hope: Can it do more than just control blood sugar? The latest results from the SURPASS-CVOT trial offer a reassuring answer. Tirzepatide (Mounjaro) not only matched the heart safety of dulaglutide (Trulicity), a trusted standard in care, but went further, delivering meaningful gains in weight reduction, glycemic control, all-cause mortality, and renal protection. These findings signal a new era where managing diabetes means addressing the whole patient, not just the numbers.

Study Background and Objectives

SURPASS‑CVOT is a randomised, double‑blind, event‑driven Phase III cardiovascular outcomes trial comparing once‑weekly tirzepatide (Mounjaro), a dual GIP/GLP‑1 agonist, with dulaglutide (Trulicity), a selective GLP‑1 receptor agonist, in adults with type 2 diabetes and established atherosclerotic cardiovascular disease. The primary endpoint was non‑inferiority in major adverse cardiovascular events (MACE‑3: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke).

Study Cohort and Duration

A total of 13,299 participants across approximately 30 countries were enrolled, with follow-up spanning approximately 4.5 to 5 years, the largest and longest clinical trial conducted for tirzepatide to date.

Results: Cardiovascular Efficacy

MACE‑3: The comparative hazard ratio for MACE‑3 with tirzepatide vs dulaglutide was approximately 0.92 (95.3% CI: 0.83–1.01), meeting the predefined non‑inferiority threshold (upper CI < 1.05). This corresponds to an 8% relative risk reduction in cardiovascular events.
All‑Cause Mortality: Tirzepatide was associated with a 16% reduction in all‑cause mortality compared to dulaglutide (HR 0.84; 95% CI: 0.75–0.94).

Additional Cardiometabolic Effects

Glycemic Control and Weight Loss: Patients on tirzepatide achieved superior reductions in HbA1c and body weight compared to dulaglutide.
Renal Function: A subgroup with high or very high risk of chronic kidney disease experienced a slower decline in eGFR (mean difference ~3.5 mL/min/1.73 m² at 36 months) under tirzepatide vs dulaglutide

Safety and Tolerability

Both agents had comparable overall safety profiles, with the most frequently reported adverse events being mild‑to‑moderate gastrointestinal symptoms.
Treatment discontinuations due to adverse effects were slightly higher with tirzepatide (13.3%) versus dulaglutide (10.2%).

Regulatory and Clinical Significance

SURPASS‑CVOT achieved its primary non‑inferiority endpoint and indicated added benefits in mortality, glycemic control, weight reduction, and renal preservation, suggesting tirzepatide’s potential as a preferred first‑line incretin-based agent in patients with type 2 diabetes and cardiovascular disease.
Eli Lilly aims to submit these data to regulatory authorities by year‑end 2025, with the expectation of label expansion to include cardiovascular protection, targeting FDA approval in 2026.

Overview of Tirzepatide

What Is Tirzepatide?

Tirzepatide is a once-weekly injectable medication developed by Eli Lilly and Company. It is approved for the treatment of type 2 diabetes under the brand name Mounjaro, and for chronic weight management under the brand name Zepbound. Tirzepatide represents a new class of medication known as a dual incretin agonist, targeting two hormone pathways involved in metabolic regulation.

Mechanism of Action: Dual Incretin Agonist

Tirzepatide mimics the activity of two key metabolic hormones:

GLP-1 (Glucagon-Like Peptide-1)
GIP (Glucose-Dependent Insulinotropic Polypeptide)

Together, these hormones are called incretins. They help the body regulate blood sugar levels, appetite, and fat metabolism. Tirzepatide binds to and activates both GLP-1 and GIP receptors, enhancing their natural effects.

GLP-1 Effects

GLP-1 increases insulin secretion when blood sugar levels are high, suppresses glucagon (a hormone that raises blood sugar), delays gastric emptying, and reduces appetite. GLP-1 receptor agonists have been used for years to treat type 2 diabetes and promote weight loss.

GIP Effects

GIP also stimulates insulin secretion in response to meals. In the presence of GLP-1 receptor activation, GIP appears to further enhance weight loss and improve fat metabolism, although GIP’s effects on its own are less well understood.

Tirzepatide’s “twincretin” mechanism leads to superior glycemic control and greater weight loss compared to existing GLP-1-only medications like semaglutide (Ozempic, Wegovy).

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic profile of Tirzepatide is designed for convenient once-weekly administration, enhancing patient adherence.

Absorption and Distribution: Following subcutaneous injection, Tirzepatide is slowly absorbed, reaching peak plasma concentrations within 24 to 72 hours. Its bioavailability is high, approximately 80%. Once in circulation, it is extensively bound (around 99%) to plasma albumin, which protects it from rapid degradation and renal clearance, contributing to its long duration of action.
Metabolism and Elimination: Tirzepatide is a large peptide molecule and is too large for direct renal filtration. Its metabolism occurs through general proteolytic cleavage of the peptide backbone, followed by beta-oxidation of the C20 fatty acid moiety and amide hydrolysis. These metabolic processes do not rely on the cytochrome P450 (CYP) enzyme system, which significantly reduces the potential for drug-drug interactions with medications metabolised by CYP pathways.
Half-Life and Dosing: The most significant pharmacokinetic feature of Tirzepatide is its long elimination half-life of approximately 5 days (around 120 hours). This extended half-life is what permits a once-weekly dosing schedule. A steady-state concentration is achieved after approximately 4 weeks of consistent weekly administration.

Comparison with Other GLP-1 Receptor Agonists

While sharing a common pathway with selective GLP-1 receptor agonists like Semaglutide and Dulaglutide, Tirzepatide’s dual GIP agonism sets it apart, leading to superior clinical outcomes in head-to-head trials.

Mechanism: The primary distinction is Tirzepatide’s dual GIP/GLP-1 agonism versus the selective GLP-1 agonism of drugs like Semaglutide, Dulaglutide, and Liraglutide. This dual action is believed to create a synergistic effect on both glycaemic control and weight reduction.
Efficacy (HbA1c and Weight Loss): In the SURPASS-2 trial, published in the New England Journal of Medicine, Tirzepatide demonstrated statistically significant and clinically superior reductions in both HbA1c and body weight across all tested doses when compared directly to the maximum dose of Semaglutide (1 mg).
Half-Life: Tirzepatide’s half-life of ~5 days is comparable to that of once-weekly Semaglutide (~7 days) and Dulaglutide (~5 days), and significantly longer than the once-daily Liraglutide (~13 hours), underpinning its convenient dosing regimen.

Efficacy Across Patient Subgroups and Clinical Significance

A key finding from pooled analyses of the SURPASS programme is the consistent efficacy of Tirzepatide across different patient subgroups, regardless of baseline age, sex, race, BMI, or duration of diabetes. The magnitude of the observed effects is highly clinically significant. For instance, in SURPASS-2, over 50% of participants on the 15 mg dose of Tirzepatide achieved an HbA1c of less than 5.7%, which is the threshold for normal blood glucose levels in individuals without diabetes—a remarkable outcome for a diabetes therapy. The profound weight loss also addresses a core pathophysiological driver of type 2 diabetes and its comorbidities.

Furthermore, Tirzepatide has shown beneficial effects on other cardiometabolic risk factors, including significant reductions in systolic blood pressure and improvements in lipid profiles (e.g., reduced triglycerides, increased HDL cholesterol), as documented across the trial programme.

Warnings and Contraindications

The official prescribing information, as detailed by regulatory bodies like the U.S. Food and Drug Administration (FDA), includes specific warnings and contraindications.

Thyroid C-Cell Tumours: Like other GLP-1 receptor agonists, Tirzepatide carries a boxed warning regarding the risk of thyroid C-cell tumours. This is based on findings in rodents; however, the relevance to humans is unknown. It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Pancreatitis and Gallbladder Events: Cases of acute pancreatitis have been reported in clinical trials. Patients should be counselled on the signs and symptoms (e.g., persistent severe abdominal pain) and the drug should be discontinued if pancreatitis is suspected. There have also been reports of acute gallbladder disease, such as cholelithiasis or cholecystitis.
Other Precautions: Caution is advised in patients with a history of severe gastrointestinal disease, such as gastroparesis, as Tirzepatide delays gastric emptying.

Clinicians should monitor patients for adverse events and manage them proactively, primarily through patient education and a gradual dose-escalation strategy.

Cardiovascular Implications of Tirzepatide (Mounjaro)

Emerging data suggest that tirzepatide’s apparent cardiovascular benefits may be attributed to its dual incretin receptor agonism, targeting both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. This dual mechanism is thought to provide enhanced metabolic and anti-inflammatory effects compared to GLP-1 receptor agonists alone, such as dulaglutide (Trulicity).

In clinical trials, participants receiving tirzepatide demonstrated not only superior reductions in HbA1c levels but also greater weight loss, improved blood pressure control, and favourable changes in lipid parameters. These effects collectively contribute to reduced cardiovascular risk, particularly in patients with preexisting cardiovascular comorbidities.

Additionally, tirzepatide may exert cardioprotective effects by improving insulin sensitivity and attenuating chronic low-grade inflammation, both of which are established risk factors for atherosclerotic cardiovascular disease in individuals with type 2 diabetes.

These findings support the evolving perspective that antihyperglycemic therapies should be assessed not solely on glycemic endpoints, but also on their capacity to mitigate cardiovascular risk. Tirzepatide represents a potential advancement in the paradigm of diabetes management, emphasising both metabolic control and cardiovascular protection.

Clinical Implications for Patients and Healthcare Providers

For individuals with type 2 diabetes and coexisting cardiovascular disease, recent trial findings related to tirzepatide (Mounjaro) offer a promising therapeutic advancement. Rather than managing glycemic control and cardiovascular risk in isolation, tirzepatide supports a more integrated, comprehensive approach to cardiometabolic care, potentially improving both survival and quality of life.

Nonetheless, these developments raise important clinical questions. Should tirzepatide be considered the preferred agent for all high-risk patients? Are there specific subpopulations that derive greater benefit? What are the implications for long-term safety, particularly in broader, real-world populations?

While tirzepatide has demonstrated a favourable safety profile in clinical trials, ongoing post-marketing surveillance will be essential to assess adverse events over time. Common side effects, particularly gastrointestinal disturbances, are generally mild to moderate but must be carefully balanced against potential reductions in cardiovascular morbidity and mortality.

As with any therapeutic decision, shared decision-making between patients and providers remains essential. Discussions should centre around the individual’s risk profile, therapeutic goals, and prior response to treatment, including consideration of transitions from existing GLP-1 receptor agonists.

Finally, addressing barriers to access will be critical. As awareness of tirzepatide’s potential cardiovascular benefits grows, healthcare systems and policymakers must work to ensure equitable access, particularly among historically underserved populations who are disproportionately affected by both diabetes and cardiovascular disease.

Conclusion

In the SURPASS‑CVOT Phase III trial, tirzepatide (Mounjaro) demonstrated non‑inferior cardiovascular protection compared with dulaglutide (Trulicity) and provided additional advantages in reducing all‑cause mortality, achieving superior glycemic and weight outcomes, and slowing renal decline. The incidence of treatment discontinuation due to adverse effects was modestly higher, primarily gastrointestinal in nature, but the overall benefit‑risk profile appears favourable for tirzepatide’s use in high‑risk cardiometabolic populations