Tirzepatide for weight loss — what it is, how it works, and what the trials show
Tirzepatide (brand names include Mounjaro for diabetes and Zepbound for obesity in some markets) is a novel, dual-agonist peptide that activates two incretin hormone receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. It was developed by Eli Lilly and has produced unusually large, dose-dependent weight loss in clinical trials — both in people with type 2 diabetes and in people with obesity without diabetes.
PubMed
+1
How tirzepatide works
Dual incretin agonism. Tirzepatide is designed to stimulate both the GIP receptor and the GLP-1 receptor. GLP-1 agonism reduces appetite, slows gastric emptying, and improves glucose-dependent insulin secretion. GIP previously was thought to be less useful for weight loss, but combined activation (sometimes called “twincretin” activity) appears to enhance weight-loss and glycemic effects beyond GLP-1 activation alone.
PubMed
+1
Appetite and energy balance. By acting in brain regions that regulate appetite and by slowing gut emptying, tirzepatide reduces caloric intake. There is also evidence that its metabolic effects on fat metabolism and insulin sensitivity help reshape body composition during weight loss.
PubMed
Glycemic control plus weight loss. The incretin effects improve insulin secretion when glucose is high, lowering blood glucose and HbA1c, while simultaneously producing marked weight loss — a combination that makes tirzepatide attractive for treating both diabetes and obesity.
PubMed
Key clinical trials and what they found
Below are the major programs and representative trial findings.
SURPASS program — tirzepatide for type 2 diabetes
A set of Phase 3 trials (SURPASS-1 through SURPASS-5 and others) examined tirzepatide’s effects in people with type 2 diabetes, often comparing it with placebo, insulin, or semaglutide. Across these trials tirzepatide produced greater reductions in HbA1c and greater weight loss compared with many comparators (including semaglutide in some trials). The SURPASS-2 trial showed tirzepatide was non-inferior and superior to semaglutide for glycemic control and produced larger mean weight loss at the tested timepoints.
PubMed
+1
SURMOUNT program — tirzepatide for obesity (no diabetes)
SURMOUNT-1 (published in NEJM) tested once-weekly tirzepatide (5, 10, 15 mg) versus placebo for 72 weeks in adults with obesity or overweight and without diabetes. Treatment produced substantial, dose-dependent weight loss: mean percent weight loss was large (and clinically meaningful) compared with placebo, and many participants reached ≥15–20% weight loss thresholds at higher doses. This trial established tirzepatide’s potential as a powerful anti-obesity medication.
New England Journal of Medicine
Other SURMOUNT analyses and follow-up trials showed additional benefits on cardiometabolic risk factors (blood pressure, lipids, glycemia in those with prediabetes) and documented the pattern of weight regain after stopping therapy in some studies. One randomized study of treatment withdrawal reported that discontinued treatment was associated with substantial weight regain, while continued therapy maintained weight loss.
PubMed
Safety and tolerability across trials
Common adverse effects are similar to GLP-1 receptor agonists: nausea, vomiting, diarrhea, constipation, and decreased appetite, generally most intense during dose escalation and often diminishing with time. Hypoglycemia risk is low when tirzepatide is used alone but can increase when combined with insulin or sulfonylureas. Longer-term cardiovascular outcome and safety data are being collected in dedicated trials.
PubMed
+1
How big is the weight loss?
In SURMOUNT-1 and related reports, the magnitude of weight reduction at higher tirzepatide doses often exceeded what has typically been achieved with earlier GLP-1 monotherapies:
Dose-dependent mean percent weight losses in SURMOUNT-1 were large (statistically and clinically significant) versus placebo at 72 weeks, with higher doses producing the largest effects. Many participants on 10–15 mg achieved ≥15% or ≥20% weight loss.
New England Journal of Medicine
(Exact numbers vary by dose group and trial; for precise figures check the SURMOUNT-1 NEJM report and published supplementary materials.)
New England Journal of Medicine
Comparisons with other drugs
Tirzepatide vs semaglutide: In diabetes trials and in more recent head-to-head studies, tirzepatide has often produced greater weight loss and larger HbA1c reductions than semaglutide at the doses tested. Head-to-head data in obesity and diabetes continue to accumulate; the clinical choice depends on efficacy, side-effect profile, patient preference, cost, and access.
PubMed
+1
Tirzepatide vs older therapies: Across the SURPASS and SURMOUNT programs, tirzepatide typically outperformed older classes (insulin, GLP-1 monotherapy) for weight loss and glycemic control, but direct comparisons, safety monitoring, and longer follow-up remain important.
PubMed
+1
Safety considerations and unanswered questions
Gastrointestinal effects are common and sometimes limit tolerability. Slow dose escalation can reduce early GI symptoms.
PubMed
Hypoglycemia: risk increases when tirzepatide is combined with insulin or sulfonylureas; clinicians must adjust other glucose-lowering drugs when initiating tirzepatide.
PubMed
Cardiovascular outcomes: large outcome trials are ongoing to establish long-term CV safety/benefit in people with diabetes and obesity.
PubMed
Weight regain after stopping: evidence shows substantial regain occurs in many people who discontinue tirzepatide after losing weight, underscoring that obesity is often a chronic condition requiring ongoing management.
PubMed
Selected key references & PubMed links
(Clicking the citations will take you to PubMed / NEJM pages for each item.)
Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. NEJM 2022 (SURMOUNT-1). PubMed:
New England Journal of Medicine
Nauck MA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist — review. PubMed (mechanism and early data).
PubMed
Rosenstock J, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist (tirzepatide). Lancet / Diabetes & Endocrinology 2021 (SURPASS initial reports). PubMed:
PubMed
Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). NEJM 2021. PubMed:
PubMed
Aronne LJ, et al. The SURMOUNT-4 Randomized Clinical Trial (treatment withdrawal and weight regain analyses). PubMed 2024.
PubMed
For research uses only not for human or animal use.
