A real-world comparison finds tirzepatide beating semaglutide and liraglutide

Randomized trials have established that tirzepatide, semaglutide, and liraglutide each produce meaningful weight loss, generally in that order of magnitude. A retrospective study published this month in Diabetes, Metabolic Syndrome and Obesity asks whether that ranking holds up in routine clinical practice, using electronic medical records from a single internal medicine clinic in Istanbul [s1].

The design

This was a single-center, retrospective, observational study of consecutively treated adults aged 18 to 75 with overweight or obesity but without diabetes, drawn from clinic records between September 2023 and September 2024 [s1]. Patients had received liraglutide, semaglutide, or tirzepatide for at least 36 weeks, with drug choice made through routine clinical decision-making rather than randomization — meaning this study cannot separate the drugs' effects from whatever led a clinician and patient to choose one over another [s1]. The primary outcome was percent change in body weight from baseline to week 36; secondary outcomes included waist circumference, lipid profile, liver enzymes, pancreatic enzymes, HbA1c, insulin resistance (via HOMA-IR), and adverse events [s1]. Baseline hepatic steatosis was assessed by ultrasound, and mild elevations in amylase and lipase — pancreatic enzymes — were pre-defined as up to three times the upper limit of normal [s1].

What it found

All three drugs produced statistically significant reductions in body weight and waist circumference by week 36 (p < 0.01 for each) [s1]. Weight loss was greater with tirzepatide than with either liraglutide or semaglutide [s1] — the study's summary does not give the specific percentage figures for each drug, reporting the comparison directionally rather than numerically in its abstract. Lipid parameters improved across all three groups, with the largest triglyceride reduction seen in the tirzepatide group [s1]. Liver enzyme improvements were similar across all three drugs [s1].

On tolerability, gastrointestinal adverse events were common across the board but particularly frequent with liraglutide [s1]. No clinically confirmed cases of pancreatitis occurred in any group [s1].

Why "real-world" data matters alongside trials

Randomized trials measure efficacy under controlled conditions — fixed dosing schedules, close monitoring, and often more motivated or selected participants. Real-world observational studies like this one capture something different: how drugs perform amid the messier realities of routine practice, including dose escalation pacing, adherence, and whatever mix of patients actually gets prescribed each drug outside a trial setting. The tirzepatide-ahead ranking found here broadly tracks what head-to-head randomized trials — comparing tirzepatide against semaglutide, and both against liraglutide — have previously shown, which is itself a modestly reassuring consistency check, though it's also possible clinicians preferentially chose tirzepatide for patients they expected to respond better, a selection effect observational data can't rule out.

The limits

This is a single clinic in Istanbul, with treatment assignment made by clinical judgment rather than randomization — the core limitation of any real-world comparative study, since patients starting each drug may have differed systematically in ways that also affect weight loss and side effects, independent of which drug they took. The study's own authors describe the findings as "observational and hypothesis-generating," explicitly calling for prospective or randomized comparative studies to confirm them [s1]. The sample size and exact patient counts per drug arm are not reported in the available summary, which limits how precisely the reported statistical comparisons can be evaluated.

What to watch

Larger, multi-site real-world comparisons, and whether prospective randomized head-to-head trials comparing all three drugs directly — rather than each against placebo — confirm the same ranking with quantified effect sizes. This article is not medical advice.

Sources

1. Real-World Effectiveness and Safety of Tirzepatide, Semaglutide, and Liraglutide in Adults with Overweight or Obesity without Diabetes: A Comparative Study — Diabetes, Metabolic Syndrome and Obesity, 31 March 2026