Tirzepatide and semaglutide: different twins?

Abstract

Incretin-based therapies currently represent one of the cornerstones in the management of type 2 diabetes mellitus and obesity, owing to their ability to integratively modulate cardiometabolic risk. Semaglutide, a selective agonist of the glucagon-like peptide-1 (GLP-1) receptor, has consolidated its clinical role through an efficacy profile that combines marked improvement in glycaemic control, substantial body weight reduction, and well-established cardiovascular and renal benefits. Tirzepatide, the first dual agonist of the glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has introduced a new generation of incretin-based agents, characterized by a superior impact on weight loss and insulin sensitivity, with a potential expansion of therapeutic indications. Although both molecules share a remarkable ability to reduce body weight and HbA1c levels, they differ in their mechanisms of action, current therapeutic indications, and the robustness of available evidence on cardiovascular outcomes. Their integration into clinical practice therefore requires a personalized approach that balances metabolic efficacy, safety, and individual patient risk profiles. Within this context, the incretin revolution offers new perspectives for cardio–reno–metabolic prevention.

Introduction

Incretin-based therapies have profoundly transformed the management of type 2 diabetes mellitus (T2DM) and, more recently, obesity, redefining the role of gut-derived hormones in cardiometabolic pathophysiology. These therapies include agents that enhance or mimic the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), hormones that, in response to nutrient intake, coordinate glucose-dependent insulin secretion, glucagon suppression, appetite regulation, and energy balance through integrated effects on the pancreas, liver, autonomic nervous system, and hypothalamic centres.

The clinical evolution of these therapies has been progressive. From early exendin-4-based GLP-1 receptor agonists (GLP-1RAs), such as exenatide and lixisenatide—effective in glycaemic control but with limited effects on body weight—the field advanced to ‘human-like’ GLP-1RAs, including liraglutide and dulaglutide, characterized by greater efficacy and improved tolerability. The class reached full maturity with semaglutide, available in both once-weekly injectable and once-daily oral formulations, which combines potent metabolic effects with documented cardiovascular benefits.

The introduction of tirzepatide, the first dual GIP/GLP-1 receptor agonist, has further expanded this landscape. The synergistic activation of both incretin receptors enables a depth of response in body weight reduction and metabolic parameters that has not been achieved with traditional GLP-1RAs. Although both molecules induce significant reductions in body weight, HbA1c, and cardiometabolic risk, they differ in pharmacological class, primary indications, mechanisms of action, and the level of available cardiovascular evidence. Their comparison therefore provides insight into how incretin modulation can be strategically leveraged in obesity management, glycaemic control, and cardiovascular prevention.

Molecular basis and mechanisms of action

Semaglutide is a human GLP-1 analogue with 94% sequence homology, modified by the addition of a C18 lipid side chain that promotes albumin binding and confers a half-life of approximately 7 days, allowing for once-weekly administration or daily oral dosing.

Selective activation of the GLP-1 receptor—expressed in multiple tissues, including the pancreas, brainstem, hypothalamus, cardiomyocytes, and endothelial cells—results in increased glucose-dependent insulin secretion, suppression of glucagon release, delayed gastric emptying, and anorexigenic effects mediated through modulation of hypothalamic pathways. At the vascular level, GLP-1 receptor agonism reduces oxidative stress, improves endothelial function, and attenuates inflammatory processes involved in the progression of atherosclerosis.

Tirzepatide, by contrast, is not merely a ‘potentiated GLP-1’. Although it activates the GLP-1 receptor, its affinity for this receptor is lower than that of semaglutide. Its distinguishing feature is the concomitant activation of the GIP receptor, historically considered of secondary importance but now recognized as a key modulator of adipocyte physiology. GIP promotes lipid uptake in adipocytes, participates in the regulation of energy metabolism, and interacts with central appetite pathways. Dual agonism therefore generates a synergistic effect: GLP-1 reduces caloric intake and improves glycaemic regulation, whilst GIP appears to mitigate GLP-1–induced nausea, enhance anorexigenic effects, and favourably modulate adipocyte metabolism towards greater fat mass loss (Figure 1). This dual mechanism allows tirzepatide to achieve, in many patients, a greater degree of weight loss than that observed with pure GLP-1 receptor agonists.

Figure 1.

Mechanisms of action of semaglutide and tirzepatide.

Cardio–renal–metabolic benefits: evidence from clinical trials

Semaglutide in diabetes

The cardiovascular benefit and safety of semaglutide in patients with T2DM have been demonstrated across several randomized clinical trials. The first pillar of this evidence derives from the SUSTAIN-6 trial (Study to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes), conducted in patients with T2DM at high cardiovascular risk. In this study, subcutaneous semaglutide administered at doses of 0.5 or 1 mg significantly reduced the first occurrence of the composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 26% compared with placebo [6.6% vs. 8.9%; hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.58–0.95; P < 0.001 for non-inferiority].¹ Although the effect was primarily driven by a reduction in non-fatal stroke, the relatively short median follow-up (2.1 years) was sufficient to demonstrate an early cardiovascular benefit, likely mediated by improvements in glycaemic control, body weight reduction, blood pressure lowering, and favourable endothelial anti-inflammatory effects.¹

A second key contribution comes from the PIONEER-6 trial (Peptide Innovation for Early Diabetes Treatment), designed to evaluate the cardiovascular safety of oral semaglutide. This study enrolled 3183 patients with T2DM and high cardiovascular risk, randomized to oral semaglutide 14 mg once daily or placebo, with a median follow-up of 15.9 months.² Semaglutide demonstrated non-inferiority to placebo with respect to major adverse cardiovascular events (MACE) (3.8% vs. 4.8%; HR 0.79; 95% CI 0.57–1.11; P < 0.001 for non-inferiority).² Although not powered to test superiority, the trial revealed a particularly noteworthy finding: a 51% reduction in cardiovascular mortality (0.9% vs. 1.9%; HR 0.49; 95% CI 0.27–0.92).² Whilst not definitive, this signal contributed to consolidating the cardiovascular safety profile of oral semaglutide and laid the groundwork for subsequent outcome-focused investigations.

The SOUL trial (Semaglutide Cardiovascular Outcomes Trial) was therefore specifically designed to assess the cardiovascular efficacy of the oral formulation. This randomized, double-blind study included 9650 patients aged ≥50 years with T2DM and established atherosclerotic cardiovascular disease, chronic kidney disease (CKD), or both.³ Participants received oral semaglutide 14 mg once daily or placebo on top of standard care. After a median follow-up of 49.5 months, semaglutide reduced the risk of MACE by 14% compared with placebo (12.0% vs. 13.8%; HR 0.86; 95% CI 0.77–0.96; P = 0.006).³ These findings align the cardiovascular profile of oral semaglutide with that previously observed for the subcutaneous formulation.

Beyond cardiovascular outcomes, SOUL also documented improvements in metabolic parameters: patients treated with semaglutide experienced an average additional weight loss of approximately 3 kg compared with placebo and achieved significant reductions in HbA1c.³

A further important aspect concerns the effect of semaglutide on the progression of CKD. The recently completed FLOW trial (Evaluate Renal Function with Semaglutide Once Weekly) enrolled 3533 patients with T2DM and moderate CKD, assessing the impact of once-weekly subcutaneous semaglutide 1 mg vs. placebo. Over extended follow-up, semaglutide reduced the risk of a composite of clinically relevant renal outcomes—including sustained ≥50% decline in estimated glomerular filtration rate, progression to end-stage kidney disease, or death from renal causes—by 24%, with 331 events in the semaglutide group compared with 410 in the placebo group (HR 0.76; 95% CI 0.66–0.88; P = 0.0003). This result positions semaglutide as the first GLP-1 receptor agonist to demonstrate robust evidence of renal protection independent of glycaemic control, thereby expanding its role in cardio–renal risk management.

Taken together, SUSTAIN-6, PIONEER-6, SOUL, and FLOW define a coherent and consistent body of evidence: semaglutide exhibits a well-documented cardiovascular and renal efficacy profile that extends beyond simple glycaemic modulation. In parallel, ongoing studies such as SURPASS-CVOT (Study of Tirzepatide Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes) will clarify whether tirzepatide, through its dual mechanism of action, will be able to match or surpass these benefits in patients with T2DM and established atherosclerotic cardiovascular disease.

Semaglutide in obesity

The STEP programme (Semaglutide Treatment Effect in People with Obesity) investigated the effects of semaglutide in individuals with obesity without diabetes. In STEP-1, which enrolled 1961 adults, mean body weight reduction reached 14.9% at 68 weeks, accompanied by significant improvements in quality of life and cardiometabolic parameters.⁴

The most striking evidence, however, comes from the SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity), a cardiovascular outcomes study conducted in more than 17 600 individuals with obesity and established but stable cardiovascular disease, without T2DM. Over a median follow-up of nearly 41 months, semaglutide 2.4 mg reduced the incidence of MACE by 20% compared with placebo (HR 0.80; 95% CI 0.72–0.90; P < 0.001).⁵ This finding is particularly relevant, as it demonstrates that cardiovascular risk reduction does not necessarily require improvements in glycaemic control, but may instead derive from weight loss and global improvement in the cardiometabolic profile.

Tirzepatide in diabetes

The SURPASS programme has clearly documented the high metabolic potency of tirzepatide. In the SURPASS-2 trial (Study of Tirzepatide Compared With Semaglutide in Patients With Type 2 Diabetes), the dual agonist, administered at weekly doses of 5, 10, or 15 mg, was directly compared with semaglutide 1 mg in nearly 1900 patients with T2DM receiving background metformin therapy.⁶ Over 40 weeks of follow-up, tirzepatide achieved significantly greater reductions in HbA1c than semaglutide: −2.01%, −2.24%, and −2.30% with tirzepatide 5, 10, and 15 mg, respectively, vs. −1.86% with semaglutide 1 mg.⁶

Weight loss also confirmed the superiority of the dual agonist, reaching approximately 10–12 kg with tirzepatide compared with the 6–7 kg average reduction observed with semaglutide.⁶

An important feature emerging from the SURPASS trials is the consistency of tirzepatide’s effects. Regardless of background therapy, tirzepatide demonstrated a highly stable efficacy profile, accompanied by a clinically meaningful reduction in systolic blood pressure, which in some trials exceeded 5 mmHg in participants achieving the greatest weight loss. This blood pressure reduction anticipates potential cardiovascular benefits, which will be formally tested in the SURPASS-CVOT trial, comparing tirzepatide with dulaglutide in a population with T2DM at high cardiovascular risk.

Tirzepatide in obesity

In individuals without T2DM, tirzepatide has shown even more impressive results. The SURMOUNT-1 trial (A Study of Tirzepatide in Participants With Obesity or Overweight), which enrolled 2539 adults without diabetes but with obesity or overweight associated with comorbidities, represented the first large-scale evaluation of tirzepatide’s weight-loss potential in a non-diabetic population.⁷ Participants were assigned to one of three weekly doses of tirzepatide (5, 10, or 15 mg) or placebo and followed for 72 weeks, a duration sufficient to robustly assess treatment efficacy.

The magnitude of weight reduction was remarkable: approximately 15% with the lowest dose and exceeding 20% with the highest dose, compared with only 3.1% in the placebo group (P < 0.001).⁷ In addition to weight loss, treatment resulted in consistent improvements in cardiometabolic profiles, including reductions in systolic blood pressure, LDL cholesterol, triglycerides, and several inflammatory markers. This constellation of effects has fuelled interest in a potential indirect cardiovascular benefit, consistent with the profound transformation of the metabolic phenotype observed in treated participants. It should be emphasized, however, that SURMOUNT-1 was not designed to assess major cardiovascular events and therefore cannot provide definitive conclusions regarding the impact of tirzepatide on cardiovascular outcomes.

The high efficacy of tirzepatide in obesity management was further confirmed by the SURMOUNT-5 trial, the first true head-to-head comparison with semaglutide in a population of adults with obesity without diabetes.⁸ In this study, which enrolled 670 participants and included a 72-week follow-up, once-weekly tirzepatide 15 mg induced a mean body weight reduction of 20.2%, significantly greater than the 13.7% achieved with semaglutide 2.4 mg (P < 0.001) (Table 1).⁸ Beyond weight loss, tirzepatide exerted a more favourable effect on waist circumference and lipid profile, outlining a particularly broad cardiometabolic improvement.

Table 1.

Comparison between semaglutide and tirzepatide in adults with obesity without diabetes (SURMOUNT-5).

Characteristic	Semaglutide	Tirzepatide
Patient phenotype	Individuals with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with ≥1 obesity-related comorbidity (hypertension, dyslipidaemia, obstructive sleep apnoea syndrome, cardiovascular disease), without diabetes
Number of participants	339	338
Maximum planned dose	1.7–2.4 mg subcutaneously once weekly	10–15 mg subcutaneously once weekly
Primary endpoint (% change in body weight at 72 weeks)	−13.7% (95% CI −14.9 to −12.6)	−20.2% (95% CI −21.4 to −19.1); P < 0.001
Patients achieving ≥10% weight loss	60.5%	81.6%
Patients achieving ≥15% weight loss	40.1%	64.6%
Patients achieving ≥20% weight loss	27.3%	48.4%
Patients achieving ≥25% weight loss	16.1%	31.6%
Patients achieving ≥30% weight loss	6.9%	19.7%
Absolute weight reduction (kg)	−15.0 kg	−22.8 kg
Waist circumference reduction	−13.0 cm (95% CI −14.3 to −11.7)	−18.4 cm (95% CI −19.6 to −17.2); P < 0.001
Overall treatment discontinuation	8.0%	6.1%
Discontinuation due to gastrointestinal adverse events	5.6%	2.7%
Main reasons for discontinuation	Persistent nausea, vomiting, diarrhoea	Nausea; injection-site reactions
Most common adverse events	Nausea (44%), diarrhoea (23.4%), constipation (28.5%), vomiting (21.3%)	Nausea (43.6%), diarrhoea (23.5%), constipation (27%), vomiting (15%)
Serious adverse events	3.5%	4.8%
Injection-site reactions	0.3%	8.6%
Study completion rate	∼85%	∼85%
Overall tolerability	More pronounced gastrointestinal profile; higher discontinuation rate	Better gastrointestinal tolerability; higher rate of local reactions
Clinical conclusion	Effective in achieving clinically meaningful weight loss	Superior to semaglutide in body weight and waist circumference reduction

Abbreviations: BMI, body mass index; OSAS, obstructive sleep apnoea syndrome; GI, gastrointestinal; CI, confidence interval.

It is important to note, however, that SURMOUNT-5, like most trials evaluating anti-obesity medications, did not include cardiovascular events amongst its endpoints. Whilst representing a crucial step in understanding the relative clinical potency of these two agents, the trial does not allow conclusions as to whether the greater weight loss achieved with tirzepatide translates into a corresponding reduction in cardiovascular risk.

Safety profile

The safety profiles of semaglutide and tirzepatide are consistent with those of the incretin class, with nausea and vomiting occurring more frequently during the initial dose-escalation phase. In the SURMOUNT-5 trial, these adverse events led to fewer treatment discontinuations with tirzepatide, plausibly owing to GIP receptor agonism, which appears to mitigate gastrointestinal symptoms.⁸ The incidence of cholelithiasis is slightly increased with both therapies, largely attributable to the rapidity of weight loss, whereas no significant increase in the risk of acute pancreatitis has been observed.

Sub-analyses using dual-energy X-ray absorptiometry and magnetic resonance imaging have shown that weight reduction predominantly reflects loss of fat mass, although a concomitant reduction in lean mass is also observed. This finding warrants a cautious clinical approach in older individuals or in patients at increased risk of musculoskeletal frailty.

Clinical practice guidelines

American and European guidelines for the management of T2DM position GLP-1 receptor agonists with proven cardiovascular benefit—particularly semaglutide, liraglutide, and dulaglutide—amongst first-line therapies for patients with T2DM and established cardiovascular disease or at high cardiovascular risk, irrespective of baseline HbA1c levels.^9,10 In this context, the therapeutic priority is not merely glycaemic control but cardiovascular prevention, and the choice of GLP-1RA is guided by an organ-protective strategy rather than glucose-lowering alone.

The European Society of Cardiology guidelines for the management of patients with chronic coronary syndromes assign semaglutide a central role in the treatment of patients with coronary artery disease and T2DM, particularly in the presence of overweight or obesity.¹¹

Finally, major international guidelines for the management of obesity recognize semaglutide 2.4 mg and tirzepatide as first-line pharmacological options for the treatment of chronic obesity.^12,13 This positioning reflects not only their superior efficacy compared with previous generations of anti-obesity medications, but also the growing recognition of obesity as a chronic, progressive disease requiring long-term and multidimensional management.

Conclusions

Tirzepatide and semaglutide may appear as ‘twin’ drugs: both are administered once weekly, induce marked reductions in body weight and HbA1c, and improve the cardiometabolic profile. Beneath this apparent similarity, however, lie substantial differences. Semaglutide represents the most advanced evolution of the GLP-1 receptor agonist class, with a developmental trajectory that has progressed from optimization of glycaemic control to robust demonstration of cardiovascular benefit and a central role in the treatment of obesity at high cardiovascular risk.

Tirzepatide, by contrast, inaugurates a new generation of incretin-based therapies, in which combined GIP/GLP-1 receptor agonism enables a greater depth of metabolic response, particularly with respect to weight loss.

From a cardiologist’s perspective, the message is clear: semaglutide currently remains the most established option for reducing cardiovascular risk in patients with T2DM and obesity with atherosclerotic disease, whereas tirzepatide is particularly well suited when maximal weight reduction represents the primary clinical objective. In the near future, the results of SURPASS-CVOT and SURMOUNT-MMO (Study of Tirzepatide on the Reduction of Morbidity and Mortality in Adults With Obesity) will clarify whether these ‘different twins’ will also converge in terms of cardiovascular outcomes. In both cases, for those committed to ‘knowing and caring for the heart,’ the incretin revolution is destined to remain at centre stage.

Funding

None.

Data availability

No new data were generated or analyzed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Tirzepatide e semaglutide: gemelli diversi?’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.