Mounjaro (tirzepatide): what it is, how it works, the evidence

Complete guide: GLP-1 drugs: a complete guide to semaglutide and beyond

Mounjaro (tirzepatide): what it is

Mounjaro is the brand name of tirzepatide, a synthetic once-weekly subcutaneous peptide developed by Eli Lilly. Its distinguishing feature is that it activates two incretin receptors at once: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor⁵. The FDA described it in its approval announcement as a first-in-class medicine that activates both receptors¹.

The FDA approved it on May 13, 2022 to improve glycemic control in adults with type 2 diabetes, as an adjunct to diet and exercise¹. Approval rested on nine clinical trials with 7,769 adults with type 2 diabetes; five of them, with 6,263 patients, assessed efficacy². The European Medicines Agency (EMA) authorized Mounjaro on September 15, 2022³.

Mounjaro and Zepbound: are they the same drug?

Yes: both contain tirzepatide. The difference is the indication and the brand. In the United States, Mounjaro was approved for type 2 diabetes and Zepbound for chronic weight management in adults with obesity, or overweight with at least one weight-related condition; the FDA approved Zepbound on November 8, 2023⁴. In the European Union, the EMA authorizes Mounjaro for both type 2 diabetes and weight management³.

Mechanism of action: why two receptors

Incretins are gut hormones released after eating. GLP-1 increases glucose-dependent insulin secretion, lowers glucagon and reduces appetite. GIP also stimulates insulin. Tirzepatide is a single molecule acting on both receptors⁵. In cells it was described as an "imbalanced and biased" agonist: it favors the GIP receptor and, at the GLP-1 receptor, recruits β-arrestin less⁶.

The exact role of GIP is still being studied and carries its own scientific paradox. We explain it in detail in tirzepatide mechanism of action: GIP, GLP-1 and the paradox.

Mounjaro vs Ozempic: differences and head-to-head trials

Ozempic is semaglutide, a molecule from a different company (Novo Nordisk) that activates only the GLP-1 receptor. Semaglutide for weight is marketed as Wegovy. They are two different drugs, not two brands of the same one. There are two head-to-head comparisons with semaglutide:

• SURPASS-2 (type 2 diabetes): tirzepatide lowered HbA1c more than semaglutide 1 mg; the differences were −0.15, −0.39 and −0.45 percentage points depending on the arm⁸.
• SURMOUNT-5 (obesity, 751 participants): at 72 weeks, mean weight change was −20.2% with tirzepatide and −13.7% with semaglutide¹⁵.

These are randomized-trial averages, not predictions for any one person. For the wider class, see the GLP-1 guide; the reference semaglutide obesity trial was STEP 1¹⁹.

What the SURPASS and SURMOUNT trials showed

The SURPASS program studied type 2 diabetes: against placebo as monotherapy (SURPASS-1)⁷, against insulin degludec (SURPASS-3)⁹ and against insulin glargine in patients with increased cardiovascular risk (SURPASS-4)¹⁰. The SURMOUNT program studied obesity:

• SURMOUNT-1 (2,539 adults): mean weight loss at 72 weeks of 15.0%, 19.5% and 20.9% by arm, versus 3.1% with placebo¹¹.
• SURMOUNT-1, 176-week follow-up: in people with prediabetes, progression to type 2 diabetes was 1.3% with tirzepatide versus 13.3% with placebo¹⁸.
• SURMOUNT-2: obesity with type 2 diabetes¹². SURMOUNT-3: after an intensive lifestyle intervention¹³.
• SURMOUNT-4: when tirzepatide was stopped after 36 weeks, participants regained weight; those who continued kept their loss (a further −5.5% versus +14.0% with placebo)¹⁴.
• Obstructive sleep apnea: the apnea-hypopnea index fell 20.0 to 23.8 events per hour more than with placebo in the two trials¹⁶.
• Heart failure with preserved ejection fraction (SUMMIT): lower combined risk of cardiovascular death or worsening heart failure (HR 0.62)¹⁷.

Tirzepatide side effects and safety

The most frequent effects are gastrointestinal. In SURPASS-2, nausea affected 17-22% with tirzepatide and 18% with semaglutide; diarrhea, 13-16% and 12%; vomiting, 6-10% and 8%⁸. The EMA also lists low blood glucose when combined with a sulphonylurea or insulin, abdominal pain and constipation³. In SURMOUNT-1, adverse events led to discontinuation in 4.3% to 7.1% of the tirzepatide groups and 2.6% with placebo¹¹.

On thyroid tumors, the FDA reports that in rats tirzepatide and similar medicines caused thyroid tumors, including cancer, and that it is not known whether this occurs in people². The EMA lists a post-authorization study on medullary thyroid carcinoma³. For a full review, see tirzepatide side effects: what the trials show.