Efficacy and Safety of Tirzepatide Once Weekly Versus Placebo in Participants Who Are Either Obese or Overweight With Weight-Related Comorbidities (SURMOUNT-1)

Efficacy and Safety of Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-1)

This Phase 3 study evaluates the efficacy and safety of once-weekly subcutaneous tirzepatide (a dual GIP and GLP-1 receptor agonist) at 5 mg, 10 mg, or 15 mg versus placebo, each used with a reduced-calorie diet and increased physical activity, in adults without type 2 diabetes who have obesity or are overweight with weight-related comorbidities. The primary efficacy assessment is at Week 72. Participants with prediabetes at randomization may continue in an additional long-term treatment period to assess progression to type 2 diabetes and longer-term weight outcomes.

After screening, eligible participants are randomized in a 1:1:1:1 ratio to receive tirzepatide 5 mg, 10 mg, 15 mg, or placebo once weekly by subcutaneous injection using an autoinjector. All participants receive lifestyle counseling focused on a reduced-calorie diet and increased physical activity. The main treatment period is 72 weeks. Participants identified with prediabetes at randomization can continue study treatment for up to 176 weeks (plus follow-up), allowing evaluation of longer-term weight management and time to onset/progression to type 2 diabetes. Safety is monitored throughout, including adverse events and laboratory testing.

Inclusion Criteria:

• BMI ≥30 kg/m², OR BMI ≥27 kg/m² with ≥1 weight-related comorbidity (e.g., hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease)
• History of at least one unsuccessful dietary effort to lose weight (self-reported)
• Investigator judges participant capable and willing to self-inject (or have assistance), follow lifestyle advice, maintain a diary, and complete questionnaires
• Age ≥18 years
• Meets protocol contraception/pregnancy criteria (as applicable) and provides written informed consent

Exclusion Criteria:

• Type 1 or type 2 diabetes, history of ketoacidosis/hyperosmolar state, or screening labs diagnostic of diabetes
• Recent significant weight change (>5 kg within 3 months prior to screening)
• Prior/planned bariatric surgery; recent/ongoing endoscopic or device-based obesity therapies
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Clinically significant gastric emptying abnormality or chronic use of drugs that directly affect GI motility
• History of chronic or acute pancreatitis
• Clinically significant thyroid abnormalities at screening (e.g., TSH outside protocol range) or anticipated need to initiate thyroid replacement during study
• Obesity due to other endocrinologic disorders (e.g., Cushing syndrome) or monogenic/syndromic obesity (e.g., MC4R deficiency, Prader-Willi syndrome)
• Significant unstable major depressive disorder/severe psychiatric disorder, lifetime suicide attempt, or concerning suicidality screening (PHQ-9/C-SSRS criteria)
• Uncontrolled hypertension; recent major cardiovascular events; NYHA class IV heart failure
• Active or significant liver disease or certain elevated liver tests at screening (per protocol thresholds)
• Elevated calcitonin above protocol thresholds; personal/family history of medullary thyroid carcinoma or MEN2
• Active/untreated malignancy or remission <5 years (with specified exceptions)
• Any other condition contraindicating GLP-1 receptor agonist therapy