The mechanistic foundations of the three drugs explain much of their divergent behaviour. Semaglutide is a human GLP-1 analog with 94 percent sequence identity to the native hormone, engineered with an Aib substitution at position 8 to resist degradation by the enzyme DPP-4 and a C18 fatty diacid side chain at position 26 that binds albumin and extends its half-life to roughly seven days. Liraglutide, with 97 percent homology, carries a shorter C16 palmitic acid chain that yields a half-life of about 13 hours, confining it to once-daily injection. Tirzepatide, a 39-amino-acid synthetic ‘twincretin’, activates both the GIP and GLP-1 receptors and carries a C20 fatty diacid moiety that prolongs systemic exposure to approximately five days. These structural choices dictate dosing convenience, adherence and, ultimately, how patients experience therapy.

Formulation differences add a practical dimension to drug selection. Semaglutide is the only agent in the class available as an oral tablet, made possible by the absorption enhancer SNAC, though oral bioavailability is only about one percent and the tablet must be taken fasting with water only. Subcutaneous semaglutide achieves roughly 89 percent bioavailability. Liraglutide requires daily subcutaneous injection, which may deter some patients, while tirzepatide is delivered exclusively as a once-weekly autoinjector. Real-world data show semaglutide achieves approximately 40 percent treatment persistence at one year, higher than liraglutide, and tirzepatide’s weekly dosing is expected to support strong adherence, though long-term real-world outcomes remain pending. Notably, liraglutide is the only one of the three approved for adolescents with both type 2 diabetes and obesity.

On glycaemic control, the review’s synthesis of trial data reveals a clear hierarchy. Subcutaneous semaglutide at 0.5 to 1.0 mg reduced HbA1c by 1.3 to 1.8 percent across the SUSTAIN program, outperforming placebo, sitagliptin, exenatide and basal insulin, while oral semaglutide achieved reductions of 1.3 to 2.0 percent in the PIONEER trials, edging out subcutaneous liraglutide 1.8 mg in PIONEER 4. Liraglutide, tested in the LEAD program at 1.2 and 1.8 mg, produced HbA1c reductions of 0.7 to 1.5 percent. Tirzepatide, however, set a new benchmark: in SURPASS-2, doses of 5, 10 and 15 mg lowered HbA1c by approximately 2.01, 2.24 and 2.30 percent respectively, surpassing semaglutide 1 mg, which achieved 1.86 percent. Pooled analyses indicate more than 90 percent of tirzepatide recipients reached the HbA1c target below 7.0 percent.

Weight outcomes follow a similar pattern. Semaglutide 2.4 mg weekly produced mean weight losses of up to 14.9 percent at 68 weeks in the STEP program and 10.2 percent over four years in the SELECT trial, accompanied by a 7.7 cm reduction in waist circumference. Liraglutide at 3.0 mg daily achieved approximately 4.91 kg of weight loss in meta-analysis, with BMI declines and waist reductions around 3.55 cm. Tirzepatide again led the field: SURPASS trials recorded weight reductions ranging from 5.3 to 17.1 kg depending on dose and comparator, and in the SURMOUNT-4 trial participants with obesity maintained mean reductions of approximately 20.9 percent at 88 weeks. A SURPASS-3 substudy further showed tirzepatide reduced hepatic fat and visceral adipose tissue, with waist circumference falling by up to 18.5 cm at the highest dose.

Lipid modulation, a subtler but clinically relevant domain, also favoured the dual agonist. Semaglutide produced modest reductions of roughly 3 to 6 percent in total cholesterol, 5 to 10 percent in LDL cholesterol and 10 to 15 percent in triglycerides, with slight HDL increases, mechanisms attributed to reduced free fatty acid influx to the liver and enhanced lipoprotein lipase activity. Liraglutide showed mild improvements, particularly in triglycerides and apolipoprotein B, with dose-dependent variability. Tirzepatide delivered the most pronounced effects: meta-analytic estimates showed triglyceride reductions of 13 to 22 percent, total cholesterol reductions of roughly 5 to 7 percent, and HDL increases of 4 to 7 percent, alongside reductions in large triglyceride-rich lipoproteins and small LDL particles. The authors caution, however, that these are surrogate markers whose translation into fewer cardiovascular events remains unproven.

Where hard clinical outcomes exist, the picture becomes more differentiated. In the SUSTAIN-6 cardiovascular outcomes trial, semaglutide reduced three-point major adverse cardiovascular events—cardiovascular death, nonfatal myocardial infarction and nonfatal stroke—by 26 percent, with post hoc analyses suggesting a roughly 35 percent reduction in stroke incidence, the strongest cerebrovascular signal in the class. Liraglutide, in the landmark LEADER trial, achieved a 13 percent MACE reduction driven primarily by significant reductions in cardiovascular death, making it particularly relevant for patients whose dominant risk is mortality. Tirzepatide has not yet completed a dedicated outcomes trial, but a pre-specified meta-analysis of pooled SURPASS data, including the high-risk SURPASS-4 cohort, reported a 27 percent relative risk reduction in three-point MACE and a 46 percent reduction in four-point MACE—promising signals awaiting confirmation from the ongoing SURPASS-CVOT.

Kidney outcomes reveal mechanistic distinctions with direct clinical implications. Semaglutide cut the risk of new or worsening nephropathy by 36 percent in SUSTAIN-6, slowed eGFR decline in pooled analyses, and extended renal protection to non-diabetic individuals with cardiovascular disease in the SELECT trial, suggesting partially glucose-independent benefit. Liraglutide reduced nephropathy risk by 22 percent in LEADER, but its effect appears largely mediated by improved glycaemic control and blood pressure rather than direct nephroprotection. Tirzepatide, studied in SURPASS-4’s chronic kidney disease cohort, attenuated eGFR decline and reduced macroalbuminuria across all doses, and causal mediation analysis indicated that only 40 to 60 percent of the renal benefit was explained by traditional factors such as HbA1c, blood pressure and weight—implying a substantial glucose-independent component that may make it especially valuable for patients with diabetic kidney disease.

Safety profiles across the class are broadly favourable, dominated by gastrointestinal effects. Nausea, vomiting and diarrhoea are common with all three agents, typically arising during dose escalation and subsiding within four to eight weeks with gradual titration. Tirzepatide produces the highest frequency and severity of gastrointestinal events, including constipation, likely reflecting its GIP receptor activity, followed by semaglutide and then liraglutide, which tends to cause milder, more gradual symptoms. Gallbladder events such as cholelithiasis have been observed with all agents, largely associated with rapid weight loss, and pancreatitis is rare. Hypoglycaemia is uncommon unless the drugs are combined with insulin or sulfonylureas. All three are contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. In renal impairment, tirzepatide maintains stable pharmacokinetics even in dialysis patients, an advantage over semaglutide and liraglutide, which require caution in end-stage renal disease.

The review’s overarching conclusion is a call for calibrated clinical judgement rather than a declaration of winners. Tirzepatide demonstrably offers the greatest HbA1c and weight reductions, semaglutide combines substantial efficacy with formulation flexibility and the best stroke evidence, and liraglutide provides a proven mortality benefit with the broadest paediatric indication. Yet because every comparison in the analysis is indirect—drawn from separate trials with different populations, comparators and endpoints—the authors insist the findings should be treated as hypothesis-generating, not definitive proof of superiority. They identify direct head-to-head trials, particularly tirzepatide versus higher-dose semaglutide, long-term cardiovascular and renal outcome data for tirzepatide, and evidence in underrepresented populations as critical gaps. Until those trials report, treatment decisions must remain individualized, weighing comorbidities, renal function, tolerability, dosing preferences and each patient’s therapeutic priorities.

Subject of Research: Comparative cardiometabolic effects of the incretin-based therapies semaglutide, liraglutide and tirzepatide in type 2 diabetes and obesity

Article Title: Impact of Semaglutide, Liraglutide and Tirzepatide on Cardiometabolic Outcomes: A Comparative Narrative Review

Article References: Bawadi, H., Abuhijleh, H., Nofal, M., Zakaria, Z. Z., & Al‐Asmakh, M. (2026). Impact of Semaglutide, Liraglutide and Tirzepatide on Cardiometabolic Outcomes: A Comparative Narrative Review. Endocrinology, Diabetes & Metabolism, 9(5), Article e70338. https://doi.org/10.1002/edm2.70338

Image Credits: AI Generated

DOI: 10.1002/edm2.70338

Keywords: semaglutide, liraglutide, tirzepatide, GLP-1 receptor agonists, type 2 diabetes, obesity, HbA1c, weight loss, cardiovascular outcomes, renal function, lipid profile, incretin therapies