Tirzepatide: what SURMOUNT and SURPASS found

Tirzepatide produces more weight loss than any licensed obesity drug before it. In SURMOUNT-1, the top 15 mg dose cut body weight by 20.9% over 72 weeks, against 3.1% on placebo [1], and a head-to-head trial found it beat semaglutide by about six percentage points [3]. It carries the same family of side effects as other GLP-1 drugs, and the weight returns if you stop [4].

What it is

Tirzepatide is a single 39-amino-acid peptide that activates two hormone receptors: GLP-1, the target of semaglutide, and GIP (glucose-dependent insulinotropic polypeptide), a second gut hormone released after eating [8]. Eli Lilly's design includes a 20-carbon fatty acid that binds albumin in the blood [8]. The result has a half-life of roughly five days, so it's injected once a week [8].

Why hitting GIP as well as GLP-1 should add weight loss is still debated. The FDA label puts it cautiously: GLP-1 regulates appetite, and animal studies suggest the GIP component "may further contribute" to food intake regulation [8]. What the trials show is that people eat less and lose more weight than with GLP-1 drugs alone; the precise contribution of GIP in humans is not pinned down.

It is sold as Mounjaro (type 2 diabetes, and weight management in the UK) and Zepbound (weight management and sleep apnoea in the US).

The human evidence

Lilly ran two large programmes: SURPASS in type 2 diabetes and SURMOUNT in obesity. Both are double-blind or open-label randomised trials with thousands of participants, funded by the manufacturer.

SURMOUNT-1: the main obesity trial

Mean starting weight was 104.8 kg, so the 15 mg group lost around 22 kg on average [1]. Those numbers use a treatment-regimen analysis, which counts people who stopped the drug. Discontinuation due to side effects ranged from 4.3% to 7.1% across doses, against 2.6% on placebo [1].

SURPASS-2 and SURMOUNT-5: against semaglutide

Two trials put tirzepatide directly against semaglutide. In SURPASS-2 (n = 1,879, type 2 diabetes, 40 weeks, open-label), all three tirzepatide doses lowered HbA1c more than semaglutide 1 mg: 2.30 percentage points on 15 mg against 1.86 on semaglutide [2]. Weight fell by an extra 1.9 to 5.5 kg with tirzepatide depending on dose [2]. Serious adverse events were a little more common on tirzepatide (5–7%) than semaglutide (3%) [2]. Note that semaglutide 1 mg is lower than the 2.4 mg used for obesity, so this was never a fair test of weight loss.

SURMOUNT-5 closed that gap. It randomised 751 adults with obesity, no diabetes, to the highest tolerated dose of each drug for 72 weeks [3].

SURMOUNT-5 was open-label, so participants knew which drug they were on, and Lilly paid for it [3]. Even so, a 6.5-point gap in a randomised comparison is hard to explain away.

Stopping the drug

SURMOUNT-4 gave 783 people 36 weeks of open-label tirzepatide, during which they lost 20.9% on average, then randomised 670 of them to keep going or switch to placebo for a further 52 weeks [4]. Those who continued lost another 5.5%; those switched to placebo regained 14.0% [4]. At 88 weeks, 89.5% of continuers had kept at least 80% of their initial loss, against 16.6% on placebo.

Beyond weight

The sleep apnoea result is worth unpacking. SURMOUNT-OSA was two parallel 52-week trials: one in people not using a CPAP machine and one in people who were [5]. Participants started with around 50 breathing interruptions an hour, which is severe. In the first trial the count fell by 25.3 events an hour on tirzepatide against 5.3 on placebo; in the second, by 29.3 against 5.5 [5]. The placebo groups improved a little too, which is why the between-group difference of 20 to 24 events an hour is the fairer number to quote [5]. A starting average near 50 minus about 25 still leaves many people with apnoea that would normally be treated, so read this as a large reduction rather than a cure. It became the first drug the FDA approved for the condition [11].

SUMMIT also measured how people felt. On the Kansas City Cardiomyopathy Questionnaire, a 0–100 score of heart-failure symptoms and limits, the tirzepatide group improved by 19.5 points against 12.7 on placebo at 52 weeks [6]. Side effects led 6.3% of the tirzepatide group to stop, against 1.4% on placebo [6].

SURPASS-CVOT deserves a closer read, because it is often summarised as a heart-protection win. Tirzepatide was compared against dulaglutide, an older GLP-1 drug with its own proven heart benefit, not against placebo. It met the test for non-inferiority, meaning it was not worse, but the superiority test was not significant (p = 0.09) [7]. So we know tirzepatide protects the heart at least as well as dulaglutide; a clean "better than" result was not shown. In SUMMIT, the benefit came from fewer worsening heart failure events, while cardiovascular deaths were few and similar (8 vs 5) [6].

What the animal and lab work suggests

The animal finding that matters most for people is a safety one. In rats, tirzepatide caused thyroid C-cell tumours, so the US label carries a boxed warning and rules the drug out for people with a personal or family history of medullary thyroid cancer [8]. Whether it happens in humans has not been determined [8].

Safety and side effects

Gut. Nausea, diarrhoea, vomiting and constipation are the main complaints. In SURPASS-2, nausea affected 17–22% on tirzepatide against 18% on semaglutide [2], so the two drugs look broadly similar here. Most events happen during dose escalation [1].

Gallbladder. Across the Zepbound trials, gallbladder inflammation was reported in 0.7% on tirzepatide against 0.2% on placebo, and gallstones in 1.1% against 1% [8].

Pancreatitis. In the diabetes trials, 13 people on tirzepatide had adjudicated acute pancreatitis (0.23 per 100 patient-years) against 3 on comparator drugs (0.11 per 100 patient-years) [8]. The label says to stop if pancreatitis is suspected.

Eyes. The label warns about diabetic retinopathy complications in people with type 2 diabetes and says tirzepatide has not been studied in people with more severe existing retinopathy [8].

Lean mass. The FDA label states tirzepatide lowers fat mass more than lean mass [8]. A 2024 review of the GLP-1 class found very inconsistent lean-mass data across studies and warned that DXA "lean mass" includes water and organs as well as muscle [9]. Nobody yet knows how much functional muscle people lose, especially older adults.

Legal and regulatory status

NICE advises reviewing treatment if less than 5% of weight has been lost after 6 months on the highest tolerated dose [12]. Tirzepatide sold outside a prescription is not the licensed product.

What we still don’t know

• Whether tirzepatide outperforms older GLP-1 drugs on heart attacks and deaths, rather than simply matching them [7].
• How long people need to stay on it, and whether any tapering strategy prevents regain [4].
• What share of lost lean tissue is muscle, and whether it affects strength or falls in older users [9].
• How much of the extra weight loss comes from GIP itself in humans [8].
• Long-term safety beyond the three to four years covered by the largest trials.

Educational content only — not medical advice. Many peptides discussed on HPR are not approved for human use. Talk to a qualified clinician before making any decision about your health.

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