Which weight-loss medications (GLP-1) are best: semaglutide or tirzepatide, and how do they differ?

Both tirzepatide and semaglutide are proven effective agents for weight loss and blood sugar control, but tirzepatide performs better on virtually every measured outcome. The difference lies in how the medications work: semaglutide activates only the GLP-1 receptor, whereas tirzepatide simultaneously targets the GIP receptor as well (glucose-dependent insulinotropic peptide). This dual action is presumably the reason tirzepatide produces greater weight loss and lowers blood sugar more effectively.

In people with overweight or obesity without diabetes, a network meta-analysis of 27 trials (n=15,584) shows that tirzepatide 15 mg results in an average weight loss of 16.53% of body weight compared with placebo, versus a lower percentage for semaglutide 2.4 mg. In another meta-analysis of randomised trials, 78% of tirzepatide users achieved at least 5% weight loss, 56% at least 10%, and 32% at least 15%. A large observational study using real-world patient data (n=18,386 after matching) confirmed this picture: tirzepatide users were 1.76 times more likely to achieve at least 5% weight loss, 2.54 times more likely to achieve at least 10%, and 3.24 times more likely to achieve at least 15% weight loss compared with semaglutide users. At 12 months, the average difference in weight loss was 6.9 percentage points in favour of tirzepatide.

In people with type 2 diabetes, a network meta-analysis of 28 randomised trials (n=23,622) confirms that tirzepatide at all doses is more effective than semaglutide for both blood sugar control and weight loss. In the head-to-head SURPASS-2 trial (n=1,879, 40 weeks), tirzepatide reduced HbA1c (a measure of average blood sugar over the preceding months) by 2.01 to 2.30 percentage points depending on dose, compared with 1.86 percentage points for semaglutide 1 mg. In terms of weight, tirzepatide users lost 1.9 to 5.5 kg more than semaglutide users, also depending on dose. All three tirzepatide doses (5, 10, and 15 mg weekly) were statistically superior to semaglutide 1 mg.

In terms of side effects, both medications are broadly comparable for the most common complaints. Gastrointestinal symptoms such as nausea, diarrhoea, and vomiting occur with both and are generally mild to moderate in severity. The rates in the SURPASS-2 trial were close: nausea 17-22% (tirzepatide) versus 18% (semaglutide), diarrhoea 13-16% versus 12%, vomiting 6-10% versus 8%. At higher tirzepatide doses, gastrointestinal complaints were reported more frequently than at lower doses, which is a consideration when choosing a dose.

There is one point that warrants attention: in the SURPASS-2 trial, serious adverse events were reported slightly more often with tirzepatide (5-7%) than with semaglutide (3%). What exactly causes this difference is not clear from the available research summaries. Broader meta-analyses simultaneously found that neither medication increases the risk of serious adverse events compared with placebo. This is therefore a point to discuss with the treating physician, not a reason to rule out tirzepatide in advance, but also not something to ignore.

Practically speaking: anyone choosing one of these medications and aiming for maximum weight loss has, based on current research, the strongest evidence behind tirzepatide, particularly at higher doses (10-15 mg weekly). Semaglutide has the advantage of a longer market history and has been available for certain indications at higher doses (2.4 mg for weight management) for longer. The experimental retatrutide scored even higher than tirzepatide in one network meta-analysis, but has not yet been approved and falls outside the scope of everyday clinical decision-making. The final choice also depends on reimbursement, availability, and individual tolerability, something a physician is best placed to assess.