What is Tirzepatide?
Tirzepatide is a first-in-class, once-weekly injectable dual GIP/GLP-1 receptor agonist approved by the FDA in November 2023 for both type 2 diabetes management and chronic weight management in adults with obesity. 1
Mechanism of Action
Tirzepatide works through a unique dual-receptor activation mechanism that distinguishes it from traditional GLP-1 receptor agonists:
Dual incretin activation: Tirzepatide simultaneously activates both glucose-dependent insulinotropic polypeptide (GIP) receptors and glucagon-like peptide-1 (GLP-1) receptors, creating synergistic metabolic effects. 1, 2
Appetite suppression: The medication acts on GIP and GLP-1 receptors in the hypothalamus and brainstem to suppress appetite, delay gastric emptying, and increase energy expenditure—producing weight loss that approaches the magnitude seen with bariatric surgery. 1, 3
Glucose regulation: Tirzepatide enhances glucose-dependent insulin secretion, decreases glucagon secretion, and promotes pancreatic β-cell growth, resulting in superior glycemic control. 1
Molecular pharmacology: Tirzepatide binds to the GIP receptor but has approximately five times less affinity for the GLP-1 receptor compared to endogenous GLP-1, creating a biased activation profile. 1, 4
Clinical Efficacy
Weight Loss
Tirzepatide demonstrates unprecedented weight loss efficacy, achieving 20.9% mean body weight reduction at 72 weeks with the 15 mg dose—superior to semaglutide's 14.9% reduction. 1
Nearly 40% of patients achieve ≥25% total body weight loss at 72 weeks with tirzepatide 15 mg. 3
Weight loss is dose-dependent, with the 5 mg, 10 mg, and 15 mg doses producing progressively greater reductions. 1, 3
Weight loss is greater in non-diabetic individuals (15–20.9%) compared to those with type 2 diabetes (4–6.2%). 3
Glycemic Control
Tirzepatide produces HbA1c reductions of 1.87% to 2.59% (20 to 28 mmol/mol) across the SURPASS clinical trial program. 5, 2
Between 23.0% and 62.4% of patients achieve an HbA1c below 5.7% (normoglycemia range). 2
Tirzepatide demonstrates superior HbA1c reduction compared to semaglutide 1 mg, with a treatment difference of -1.5% (95% CI -1.71 to -1.4). 5
Cardiometabolic Benefits
Tirzepatide reduces multiple cardiovascular risk parameters including blood pressure (1–6 mm Hg systolic reduction), visceral adiposity, circulating triglycerides, and liver fat content. 5, 6
The medication improves insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, associated with lower prandial insulin and glucagon concentrations. 2
Tirzepatide met cardiovascular safety criteria with MACE-4 hazard ratios <1.0 and upper confidence bounds <1.3, though it did not achieve superiority for MACE reduction or all-cause mortality compared to usual care. 1, 2
Administration and Dosing
Route: Subcutaneous injection once weekly. 1
Starting dose: 2.5 mg weekly for 4 weeks (tolerability assessment), then 5 mg weekly as the initial maintenance dose. 3
Titration: Increase to 10 mg after ≥4 weeks on 5 mg, then to 15 mg after ≥4 weeks on 10 mg if additional glycemic control or weight loss is needed. 3
Maximum dose: 15 mg weekly. 1
FDA-Approved Indications
Type 2 diabetes: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. 7, 5
Chronic weight management: For adults with BMI ≥30 kg/m² (obesity) or BMI ≥27 kg/m² with at least one weight-related comorbidity, as an adjunct to reduced-calorie diet and increased physical activity. 1
Safety Profile and Adverse Effects
Gastrointestinal effects: The most common adverse events are nausea (17–22%), diarrhea (13–16%), vomiting (6–10%), and constipation, which are predominantly mild-to-moderate, dose-dependent, and decrease over time. 1, 5, 2
Hypoglycemia risk: Tirzepatide has minimal intrinsic hypoglycemia risk when used as monotherapy or with metformin, but risk increases when combined with insulin or sulfonylureas. 1
Serious adverse events: Pancreatitis and gallbladder disease (cholelithiasis, cholecystitis) have been reported, though causality has not been definitively established. 1
Contraindications: Absolute contraindication in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2), based on animal studies showing thyroid C-cell tumors. 1
Comparison to Other GLP-1 Receptor Agonists
Tirzepatide offers superior weight loss (6% absolute advantage) and comparable or better glycemic control compared to semaglutide 2.4 mg weekly, though semaglutide has proven cardiovascular outcome benefits that tirzepatide has not yet demonstrated. 1
Both medications share similar adverse effect profiles, with gastrointestinal symptoms predominating. 1
Tirzepatide shows statistically significant advantages including greater waist circumference reduction, superior triglyceride reduction, and better fasting glucose control. 1
Cost is comparable, with tirzepatide averaging $1,272 per 30-day supply versus $1,600 for semaglutide. 1
Clinical Considerations
Lifestyle integration required: Tirzepatide must be combined with a reduced-calorie diet (approximately 500-kcal deficit) and minimum 150 minutes per week of physical activity for optimal results. 1
Long-term treatment necessary: Discontinuation leads to regain of one-half to two-thirds of lost weight within 1 year, making lifelong treatment necessary for sustained benefits. 1
Treatment evaluation: Assess efficacy at 12–16 weeks on the maximum tolerated therapeutic dose; discontinue if <5% weight loss after 3 months. 1, 3
Concomitant medication adjustments: Reduce basal insulin by 20% and consider discontinuing or reducing sulfonylureas by 50% when initiating tirzepatide to prevent hypoglycemia. 1
Ongoing Research
Tirzepatide is currently under investigation for additional indications including major adverse cardiovascular events, heart failure with preserved ejection fraction, and metabolic dysfunction-associated steatohepatitis (MASH). 5, 6