Semaglutide vs Tirzepatide: what trials show

In the head-to-head trial in adults with obesity but without type 2 diabetes, tirzepatide beat injectable semaglutide: -20.2% versus -13.7% body weight at 72 weeks.^[1] Both drugs are approved prescription medicines with large randomised trials behind them. Both bring common stomach side effects, and the weight tends to return when treatment stops.^[2][3][4][5]

The head-to-head trials

SURMOUNT-5 enrolled adults with obesity but without type 2 diabetes. Tirzepatide at 10 or 15 mg weekly (maximum tolerated dose) gave -20.2% weight change, versus -13.7% for injectable semaglutide at 1.7 or 2.4 mg weekly. The trial was open-label, and tirzepatide was superior on weight (P<0.001).^[1]

In type 2 diabetes, SURPASS-2 compared tirzepatide 5, 10 or 15 mg with semaglutide 1 mg in 1,879 adults. HbA1c fell 2.01 to 2.30 points on tirzepatide versus 1.86 on semaglutide. Weight loss was larger on tirzepatide by 1.9, 3.6 and 5.5 kg.^[6]

Nausea was similar in SURPASS-2: 17 to 22% on tirzepatide versus 18% on semaglutide 1 mg. Serious adverse events were 5 to 7% versus 3%.^[6]

Weight loss in each drug's own trials

These trials had different designs, so the numbers are not a fair race. Still, they show the size of the effect.

• STEP 1: 1,961 adults with obesity or overweight and no diabetes lost 14.9% on semaglutide 2.4 mg weekly versus 2.4% on placebo over 68 weeks.^[3]
• STEP 5: weight change at 104 weeks was -15.2% on semaglutide 2.4 mg.^[7]
• SURMOUNT-1: 2,539 adults with obesity and no diabetes lost 15.0%, 19.5% and 20.9% on tirzepatide 5, 10 and 15 mg weekly, versus 3.1% on placebo over 72 weeks.^[2]
• Among people with type 2 diabetes, semaglutide 2.4 mg gave -9.6% versus -3.4% on placebo in STEP 2.^[8]
• In SURMOUNT-2, tirzepatide gave -12.8% on 10 mg and -14.7% on 15 mg versus -3.2% on placebo.^[9]

Semaglutide also comes as a daily tablet. In OASIS 1, oral semaglutide 50 mg daily gave -15·1% versus -2.4% on placebo at 68 weeks.^[10]

Stopping the drug

The weight comes back with both drugs. In the STEP 1 extension, people who stopped semaglutide and lifestyle support regained 11.6 percentage points of body weight within a year. That was about two-thirds of what they had lost.^[5]

In STEP 4, switching to placebo gave +6.9% weight change, versus -7.9% for those who continued semaglutide.^[11]

SURMOUNT-4 shows the same pattern for tirzepatide. Continuing gave a further 5.5% loss, while switching to placebo gave a 14.0% regain.^[4]

Heart, kidney and sleep apnoea

The two drugs have different outcome trials, and they were not tested against each other. Our sources don't cover a head-to-head heart trial.

• Semaglutide, SELECT (17,604 adults with heart disease and overweight or obesity, no diabetes): heart death, non-fatal heart attack or non-fatal stroke occurred in 6.5% versus 8.0% on placebo (hazard ratio 0.80).^[12]
• Semaglutide, SUSTAIN 6 (adults with type 2 diabetes at high heart risk): 6.6% versus 8.9% on placebo (hazard ratio 0.74).^[13]
• Semaglutide, FLOW (adults with type 2 diabetes and chronic kidney disease): major kidney events had a hazard ratio of 0.76 versus placebo.^[14]
• Tirzepatide, SUMMIT (adults with heart failure with preserved ejection fraction and obesity): cardiovascular death or worsening heart failure occurred in 9.9% versus 15.3% on placebo (hazard ratio 0.62).^[15]
• Tirzepatide, SURPASS-CVOT versus dulaglutide: 12.2% versus 13.1%. It was noninferior, but superiority was not shown.^[16]
• Tirzepatide, SURMOUNT-OSA: the apnoea-hypopnoea index fell by 25.3 events an hour versus 5.3 on placebo in the first trial.^[17]

The labels differ too. The Zepbound label lists moderate to severe obstructive sleep apnoea in adults with obesity.^[18] The Wegovy label lists fewer major heart events in adults with heart disease plus obesity or overweight.^[19]

Side effects and safety

Stomach problems are common with both. In STEP 1, discontinuation because of gastrointestinal events was 4.5% on semaglutide versus 0.8% on placebo.^[3] In SELECT, stopping the drug because of side effects was 16.6% versus 8.2%.^[12]

In SURMOUNT-1, stopping because of adverse events was 4.3% on 5 mg, 7.1% on 10 mg and 6.2% on 15 mg, versus 2.6% on placebo. Most gastrointestinal events were mild to moderate and came during dose escalation.^[2]

Two other findings come from single trials, and our sources don't compare them across the two drugs. In SUSTAIN 6, eye complications of diabetic retinopathy were more common on semaglutide (hazard ratio 1.76).^[13] In a STEP 1 sub-analysis, about one-third (≈35%) of the weight lost on semaglutide was lean mass. Lean mass includes water and connective tissue as well as muscle, so this is not the same as muscle lost.^[20] Our sources don't cover a matching lean-mass figure for tirzepatide.

The Zepbound label carries a boxed warning for thyroid C-cell tumours, based on rat studies. Whether this happens in humans has not been determined.^[18] Our sources don't compare the two drugs on thyroid risk.

The bottom line

On weight, the best direct evidence favours tirzepatide over injectable semaglutide in adults with obesity.^[1] In type 2 diabetes, tirzepatide also lowered HbA1c and weight more in a head-to-head trial.^[6] Semaglutide and tirzepatide each have heart results from their own trials, and tirzepatide also has sleep apnoea results.^[12][15][17]

For both, the benefit is tied to staying on the drug, and stomach side effects are common.^[5][4] Compounded or 'research' vials are not FDA-reviewed products.^[21] This is not medical advice. A prescriber who knows your health history is the right person to weigh these trade-offs.