Semaglutide vs tirzepatide: what the SURMOUNT-5 head-to-head trial showed

Semaglutide and tirzepatide are both approved for type 2 diabetes and weight management, mainly as weekly injections (semaglutide also comes as a tablet). Semaglutide acts on the receptor for one gut hormone, GLP-1, while tirzepatide acts on two, GIP and GLP-1. In SURMOUNT-5, a large head-to-head trial in people with obesity, those on tirzepatide lost more weight on average (20.2% versus 13.7% at 72 weeks), but the trial was not designed to measure effects on heart attacks, strokes or deaths.^1,2,4,5,11

At a glance

How they work

Semaglutide is a modified version of GLP-1 (glucagon-like peptide-1), a hormone made in the gut, with 94% sequence similarity (homology) to human GLP-1. It increases insulin release and lowers glucagon only when blood sugar is high (a glucose-dependent effect), slightly slows stomach emptying, and acts on brain areas that regulate appetite.^1,2,10

Tirzepatide is a single molecule that activates the receptors for both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide), another gut hormone, with the same glucose-dependent effects on insulin and glucagon. Its label says nonclinical (laboratory and animal) studies suggest the added GIP action may further contribute to the regulation of food intake. Both drugs bind to albumin, a blood protein, which slows their removal and gives them long half-lives.^1,2,4,5,10

Approved products and uses

• US, semaglutide: Ozempic injection and Rybelsus or Ozempic tablets for type 2 diabetes, with added heart-risk reduction (and, for Ozempic, kidney-risk reduction) in specific groups; Wegovy injection and tablets for long-term weight management and to lower major heart-event risk in adults with cardiovascular disease and obesity or overweight. Wegovy injection is also approved from age 12 and, under accelerated approval, for a fatty liver disease with scarring (MASH with moderate to advanced fibrosis).
• US, tirzepatide: Mounjaro for type 2 diabetes (adults and children 10 and older) and to lower major heart-event risk in high-risk adults with type 2 diabetes; Zepbound for long-term weight management and for moderate to severe obstructive sleep apnea in adults with obesity.
• EU, semaglutide: Ozempic and Rybelsus for type 2 diabetes; Wegovy for weight management in adults (injection or tablets) and adolescents 12 and older (injection). Heart results appear in the product information, not as a separate use.
• EU, tirzepatide: one brand, Mounjaro, for type 2 diabetes (from age 10) and weight management in adults, with sleep apnea and heart failure results in the product information rather than as separate uses.^{1,2,3,4,5,6,7,8,9}

SURMOUNT-5: the large head-to-head trial

SURMOUNT-5 (New England Journal of Medicine, 2025) randomly assigned 751 adults with obesity, or overweight with a weight-related condition, and without diabetes to weekly injections of tirzepatide or semaglutide for 72 weeks, each at the highest dose the person tolerated. It was open-label, meaning participants and doctors knew which drug was given, and it was funded by Eli Lilly, which makes tirzepatide.^11,18

On average, body weight fell by 20.2% with tirzepatide and 13.7% with semaglutide, and waist size by 18.4 cm versus 13.0 cm. More people on tirzepatide reached every weight-loss milestone: 81.6% versus 60.5% lost at least 10% of their body weight, and 31.6% versus 16.1% lost at least 25%.^11,18

Side effects in both groups were mostly gastrointestinal, mild to moderate, and happened mainly while the dose was being increased. Lilly reported that 6.1% of people on tirzepatide and 8.0% on semaglutide stopped treatment because of side effects, but noted that the trial was not designed (powered) to compare safety and tolerability.^11,18

In type 2 diabetes, an earlier open-label trial funded by Lilly, SURPASS-2 (1,879 patients, 40 weeks), found that tirzepatide lowered HbA1c (a measure of average blood sugar) more than semaglutide, by 2.01 to 2.30 percentage points across three doses versus 1.86, and led to more weight loss.¹²

Heart outcomes

Semaglutide has a placebo-controlled heart trial in people without diabetes. SELECT (New England Journal of Medicine, 2023) enrolled 17,604 adults aged 45 or older with established cardiovascular disease and overweight or obesity. Over a mean follow-up of 39.8 months, cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo (hazard ratio 0.80, a 20% lower risk). Side effects led 16.6% on semaglutide and 8.2% on placebo to stop permanently. This trial supports Wegovy's US heart-risk indication.^13,1

Tirzepatide's heart trial, SURPASS-CVOT (New England Journal of Medicine, 2025), had no placebo group. It compared tirzepatide with dulaglutide, another GLP-1 drug already shown to reduce heart events, in 13,299 adults with type 2 diabetes and atherosclerotic cardiovascular disease (heart or artery disease caused by plaque), followed for a median of about four years. The same combined outcome occurred in 12.2% on tirzepatide and 13.1% on dulaglutide (hazard ratio 0.92, 95.3% confidence interval 0.83 to 1.01). That met the goal of being no worse (non-inferior), but superiority to dulaglutide was not established.^14,5

Mounjaro's US label now includes lowering the risk of major heart events in adults with type 2 diabetes at high risk. In the EU, the EMA accepted that tirzepatide reduces this risk in people with type 2 diabetes and cardiovascular disease, but decided a separate indication was not needed because these patients are already covered by the diabetes indication, and added the data to the product information instead.^5,10

No trial has reported a direct comparison of the two drugs on heart outcomes. SELECT and SURPASS-CVOT differ in who took part (no diabetes versus type 2 diabetes) and in the comparison (placebo versus an active drug), so their results are not directly comparable. A placebo-controlled trial of tirzepatide's effect on illness and death in adults with obesity, SURMOUNT-MMO (15,374 enrolled), is still running, with completion estimated for October 2027.^13,14,15

Side effects and warnings

The most common side effects on both US weight-management labels are digestive: nausea, diarrhea, vomiting, constipation, abdominal pain and indigestion (dyspepsia). Both also list fatigue, burping, acid reflux and hair loss. The labels share the same main warnings:^1,4

• Boxed warning: both caused thyroid C-cell tumors in rodents, and it is unknown whether they do so in humans. Neither should be used by people with a personal or family history of medullary thyroid cancer or with multiple endocrine neoplasia type 2 (MEN 2).
• Acute pancreatitis and acute gallbladder disease.
• Acute kidney injury from fluid loss (volume depletion) and severe gastrointestinal reactions.
• Serious allergic (hypersensitivity) reactions, and low blood sugar (hypoglycemia), especially with insulin or sulfonylureas (drugs that make the pancreas release insulin).
• Worsening diabetic eye disease (retinopathy) in people with type 2 diabetes, and inhaling stomach contents (pulmonary aspiration) during general anesthesia or deep sedation.
• Wegovy's label also carries a separate warning about increased heart rate.^1,4,5

In the EU, the EMA has listed NAION, a loss of blood flow to the optic nerve that may cause loss of vision, as a very rare side effect of semaglutide (up to 1 in 10,000 people). Anyone with sudden vision loss or rapidly worsening eyesight on semaglutide should contact a doctor without delay.¹⁷

What SURMOUNT-5 does not tell us

• Whether either drug better prevents heart attacks, strokes or deaths: its main outcomes were weight and waist size over 72 weeks.
• How the drugs compare in people with type 2 diabetes, who were not included.
• Which is safer or better tolerated: it was not powered to compare safety.
• How tirzepatide compares with the higher-dose semaglutide injection (Wegovy HD) that the FDA approved in March 2026, or with semaglutide tablets. Both arms used weekly injections.
• How any one person will respond. These are averages with a lot of overlap: 60.5% of people on semaglutide lost at least 10% of their weight, while 18.4% of people on tirzepatide did not.
• How well the results carry over to other settings: the trial was open-label, sponsored by the maker of tirzepatide, and run only in the US and Puerto Rico.^11,16,18