What is the difference between Ozempic (semaglutide) and Mounjaro (tirzepatide)?

Key Differences Between Ozempic and Mounjaro

Mounjaro (tirzepatide) is superior to Ozempic (semaglutide) for both weight loss and glycemic control, achieving 20.9% weight loss versus 14.9% with semaglutide 2.4mg, and should be prioritized as first-line therapy when maximum metabolic benefit is the goal. 1

Mechanism of Action

Tirzepatide (Mounjaro) is a dual GIP/GLP-1 receptor agonist, while semaglutide (Ozempic) is a selective GLP-1 receptor agonist only. 1 This fundamental difference explains tirzepatide's superior efficacy:

• Tirzepatide activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, providing enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, improved insulin secretion, and increased energy expenditure 1, 2
• Semaglutide binds only to GLP-1 receptors, though it has greater albumin affinity resulting in prolonged action 1
• Both medications stimulate insulin secretion and reduce glucagon secretion in a glucose-dependent manner, improving satiety and promoting weight loss 1

Weight Loss Efficacy

Tirzepatide demonstrates statistically significant superior weight loss compared to semaglutide across all doses. 2, 3

• Tirzepatide 15mg weekly achieves 20.9% weight loss at 72 weeks 1, 2
• Semaglutide 2.4mg weekly (Wegovy) achieves 14.9% weight loss at 68 weeks 2
• The mean difference is 4.23kg (95% CI: 3.22-5.25) favoring tirzepatide 4
• Real-world data confirms these findings: tirzepatide produced -17.2kg weight loss versus -14.6kg with semaglutide 2.4mg after 1 year 5
• The weight loss effect is dose-dependent for both medications, with higher doses producing greater results 2, 4

Glycemic Control

Tirzepatide provides superior HbA1c reduction compared to semaglutide at all dose levels. 1, 3

• Tirzepatide 15mg reduces HbA1c by 2.30 percentage points versus 1.86 percentage points with semaglutide 1mg 6
• All tirzepatide doses (5mg, 10mg, 15mg) were noninferior and superior to semaglutide 1mg for glycemic control 6
• Tirzepatide 15mg weekly is recommended as first-line choice for maximum glycemic control in type 2 diabetes 1
• In indirect comparisons, tirzepatide 10mg and 15mg were associated with statistically significant greater HbA1c reductions versus semaglutide 2.4mg 3

Cardiometabolic Benefits

Semaglutide has more established cardiovascular outcome trial (CVOT) data showing MACE reduction, while tirzepatide shows superior improvements in multiple cardiometabolic risk factors. 1, 2

Semaglutide's Cardiovascular Evidence:

• Reduces composite incidence of cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80,95% CI 0.72-0.90) in patients with cardiovascular disease and BMI ≥27 2
• The SUSTAIN-6 trial demonstrated 26% reduction in composite outcome (HR 0.74,95% CI 0.58-0.95) 2
• For patients with established cardiovascular disease, semaglutide 2.4mg may be preferred due to proven cardiovascular benefit 1

Tirzepatide's Cardiometabolic Advantages:

• Greater waist circumference reduction compared to semaglutide 1, 3
• Superior triglyceride reduction 1, 3
• Better fasting glucose control 1, 3
• Improved blood pressure, lipid profiles, and insulin sensitivity 1

Dosing and Administration

Both medications are administered as subcutaneous injections once weekly, but differ in their dosing schedules. 2

Semaglutide (Ozempic) Dosing:

• Available in 0.5mg, 1.0mg, or 2.0mg formulations 1
• For weight loss (Wegovy): start at 0.25mg weekly, titrate to 2.4mg weekly over 16 weeks 1
• Dose titration required to minimize gastrointestinal side effects 1

Tirzepatide (Mounjaro) Dosing:

• FDA-approved starting dose is 5mg weekly 1
• Can be titrated up to 10mg or 15mg weekly based on response and tolerability 1
• In real-world data, only 25.9% of tirzepatide patients reached maximum 15mg dose, while 83.5% of semaglutide patients reached maximum 2.4mg dose 5

Safety Profile and Side Effects

Both medications demonstrate comparable safety profiles with predominantly gastrointestinal adverse events. 1, 2

Common Side Effects:

• Nausea: 17-22% with tirzepatide versus 18-40% with semaglutide 6
• Diarrhea: 13-16% with tirzepatide versus 12% with semaglutide 6
• Vomiting: 6-10% with tirzepatide versus 8-16% with semaglutide 6
• Gastrointestinal effects are typically mild-to-moderate and decrease over time 1, 2

Serious Adverse Events:

• Both carry identical risks of pancreatitis and gallbladder disease (cholelithiasis, cholecystitis) 2
• Minimal hypoglycemia risk when used as monotherapy due to glucose-dependent mechanisms 1, 2
• Both are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 2
• Semaglutide shows 38% higher rate of serious adverse events versus placebo (95% CI 1.10-1.73) 2

Treatment Discontinuation:

• Semaglutide has higher discontinuation rates: 34 more discontinuations per 1000 patients compared to placebo 1
• Both medications show comparable discontinuation rates in head-to-head comparisons 6

Clinical Decision Algorithm

For maximum glycemic control and weight loss in type 2 diabetes, prioritize tirzepatide 15mg weekly as first-line choice. 1

Choose Tirzepatide When:

• Maximum weight loss is the primary goal (20.9% weight loss) 1, 2
• Maximum HbA1c reduction is needed 1, 3
• Patient requires superior cardiometabolic benefits including triglyceride and waist circumference reduction 1, 3

Choose Semaglutide When:

• Patient has established cardiovascular disease without diabetes (proven MACE reduction) 1, 2
• Tirzepatide is unavailable or not tolerated 1
• Insurance authorization barriers exist for tirzepatide 1

Important Considerations:

• Never combine either medication with DPP-4 inhibitors or other GLP-1 receptor agonists 1
• Both medications must be used in conjunction with lifestyle modifications (reduced-calorie diet and increased physical activity) 2
• Insurance coverage restrictions often limit access to specific agents, and formulary inclusion of both prevents treatment delays 1

Cost Considerations

Both medications have similar high costs, though specific pricing may vary. 2

• Average wholesale price for semaglutide: approximately $1,600 per 30-day supply 2
• Average wholesale price for tirzepatide: approximately $1,272 per 30-day supply 2
• Cost-effectiveness analyses show variable results depending on comparator and willingness-to-pay thresholds 1

Long-Term Treatment Requirements

Both medications require lifelong treatment to maintain weight loss and metabolic benefits. 1

• Sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 1
• After semaglutide cessation, significant weight regain occurs (11.6% of lost weight regained after 52 weeks) 2
• Patients should be counseled that these medications must be used lifelong for sustained benefits 2