Ozempic vs. Mounjaro: Key Differences
Mounjaro (tirzepatide) produces superior weight loss (20.9%) compared to Ozempic (semaglutide 1mg for diabetes, achieving approximately 7% weight loss), while the higher-dose formulation Wegovy (semaglutide 2.4mg) achieves 14.9% weight loss—still less than tirzepatide. 1
Mechanism of Action
Tirzepatide is a dual-hormone agonist that activates both GLP-1 receptors and glucose-dependent insulinotropic polypeptide (GIP) receptors, providing enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, improved insulin secretion, and increased energy expenditure 1, 2. In contrast, semaglutide is a selective GLP-1 receptor agonist only, acting on the hypothalamus to suppress appetite, delay gastric emptying, increase glucose-dependent insulin release, decrease glucagon secretion, and increase pancreatic β-cell growth 1, 2.
Notably, tirzepatide's affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1, yet its dual-receptor activation compensates for this through synergistic effects 1.
Glycemic Control
For maximum glycemic control in type 2 diabetes, tirzepatide 15mg weekly is the first-line choice, providing the greatest HbA1c reduction 2. In the SURPASS-2 trial, tirzepatide at 5mg, 10mg, and 15mg reduced HbA1c by -2.01%, -2.24%, and -2.30% respectively, compared to semaglutide 1mg at -1.86%, with all tirzepatide doses demonstrating superiority (P<0.001 for 10mg and 15mg doses) 3.
Both medications reduce HbA1c by 1.87-3.02% for tirzepatide and approximately 1.48% for semaglutide, with 23.0-62.4% of tirzepatide-treated patients achieving HbA1c <5.7% (normal range) 1, 4.
Weight Loss Efficacy
Tirzepatide demonstrates superior weight loss across all doses:
- Tirzepatide 15mg: 20.9% weight loss at 72 weeks 1
- Semaglutide 2.4mg (Wegovy): 14.9% weight loss at 68 weeks 1
- Semaglutide 1mg (Ozempic): approximately 7% weight loss in patients with type 2 diabetes 1
In real-world data, after 1 year of treatment, tirzepatide produced -17.2 kg (-16.5%) weight loss compared to semaglutide 2.4mg at -14.6 kg (-14.1%) 5. The mean difference between tirzepatide and semaglutide 2.4mg is 4.23kg (95% CI: 3.22-5.25) 1.
Cardiovascular Benefits
Semaglutide has more established cardiovascular outcome data, demonstrating a 26% reduction in composite cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN-6 trial 1, 6. The SELECT study showed semaglutide 2.4mg reduced cardiovascular events by 20% (HR 0.80) in patients with cardiovascular disease and BMI ≥27 1.
Tirzepatide lacks robust cardiovascular outcome data but showed favorable trends with MACE-4 events having hazard ratios <1.0 and upper confidence bounds <1.3, meeting cardiovascular safety criteria 6, 4. Importantly, tirzepatide does not reduce all-cause mortality compared to usual care (low to high certainty), while semaglutide reduces all-cause mortality with high certainty 6.
Cardiometabolic Advantages of Tirzepatide
Tirzepatide 15mg has statistically significant advantages over semaglutide 2.4mg including:
- Greater waist circumference reduction 1
- Superior triglyceride reduction 1, 7
- Better fasting glucose control 1, 7
- Greater improvements in lipid profiles 7
Safety Profile and Side Effects
Both medications share similar gastrointestinal adverse effect profiles, with nausea, vomiting, diarrhea, and constipation being the most common 1, 2. Specific rates from clinical trials:
- Nausea: 17-22% (tirzepatide) vs. 18-40% (semaglutide) 1
- Diarrhea: 13-16% (tirzepatide) vs. 12% (semaglutide) 1, 3
- Vomiting: 6-10% (tirzepatide) vs. 8-16% (semaglutide) 1, 3
Semaglutide has higher discontinuation rates due to adverse events, with 34 more discontinuations per 1000 patients compared to placebo 1. In direct comparison, semaglutide has fewer serious adverse events than tirzepatide (moderate certainty), with a relative risk of 0.57 (0.34-0.96) 6.
Both medications carry identical serious but rare risks:
- Pancreatitis (causality not definitively established) 1, 4
- Gallbladder disease (cholelithiasis, cholecystitis) 1
- Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1, 2
Hypoglycemia risk is minimal when used as monotherapy due to glucose-dependent mechanisms: tirzepatide RR 1.32 (0.78-2.22) vs. semaglutide RR 1.02 (0.92-1.15) compared to usual care 6, 3.
Administration and Dosing
Both medications are administered as subcutaneous injections once weekly 1, 2.
Tirzepatide titration schedule:
- Start: 5mg weekly 1
- Titrate upward every 4 weeks to maximum 15mg weekly 1
- In real-world data, only 25.9% of patients reached the maximum 15mg dose 5
Semaglutide titration schedule (for 2.4mg formulation):
- Week 1-4: 0.25mg weekly 1
- Week 5-8: 0.5mg weekly 1
- Week 9-12: 1.0mg weekly 1
- Week 13-16: 1.7mg weekly 1
- Week 17+: 2.4mg weekly (maintenance) 1
- In real-world data, 83.5% of patients reached the maximum 2.4mg dose 5
Cost Considerations
Average wholesale prices are approximately:
Insurance authorization may be challenging for both medications, particularly for obesity management without diabetes, with tirzepatide facing more authorization barriers 1.
Clinical Decision Algorithm
For type 2 diabetes with obesity, prioritize tirzepatide 15mg weekly when maximum glycemic control and weight loss are primary goals, achieving superior HbA1c reduction and 20.9% weight loss 1, 2.
For patients with established cardiovascular disease, semaglutide 2.4mg may be preferred due to proven cardiovascular outcome benefits, reducing composite cardiovascular death, nonfatal MI, or nonfatal stroke by 20% 1, 6.
For patients requiring both glycemic control and weight loss without established CVD, tirzepatide provides superior efficacy across multiple outcomes, with 6% absolute advantage in weight loss over semaglutide 2.4mg 1, 7.
Avoid combining either medication with DPP-4 inhibitors or other GLP-1 receptor agonists, as clinical guidelines uniformly prohibit co-administration due to overlapping mechanisms 1, 2.
Critical Considerations
Both medications require lifelong treatment to maintain weight loss and glycemic benefits, as sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 1. Patients must be counseled that these medications must be used in conjunction with lifestyle changes including a 500-kcal reduction below daily requirements and minimum 150 minutes/week of physical activity 1.
Perioperative aspiration risk exists with both medications due to delayed gastric emptying, with retained gastric contents documented even after extended fasting periods 1. For weight loss patients (non-diabetic), discontinue semaglutide for at least 3 weeks before surgery 1.