What pharmacological classes do Tirzepatide, Retatrutide, and Ozempic (semaglutide) belong to?

Pharmacological Classes and Mechanisms of Tirzepatide, Retatrutide, and Ozempic (Semaglutide)

Pharmacological Classification

Tirzepatide (Mounjaro/Zepbound) is a dual GIP/GLP-1 receptor co-agonist, semaglutide (Ozempic/Wegovy) is a selective GLP-1 receptor agonist, and retatrutide is a triple GIP/GLP-1/glucagon receptor agonist. 1, 2, 3

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Detailed Pharmacology

Semaglutide (Ozempic)

Mechanism of Action:

• Selective GLP-1 receptor agonist that binds to GLP-1 receptors expressed in multiple organs including pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid 2
• Glucose-dependent insulin secretion: Potentiates prandial insulin release from pancreatic β-cells in a glucose-dependent manner, minimizing hypoglycemia risk 1, 2
• Glucagon suppression: Reduces inappropriate glucagon secretion in a glucose-dependent fashion, preventing hepatic glucose production 2
• Central appetite suppression: Acts on hypothalamic centers to suppress appetite and increase satiety 2
• Delayed gastric emptying: Reduces gastric motility, contributing to weight loss effects 1
• β-cell preservation: May promote pancreatic β-cell proliferation and protect against apoptosis 2

Clinical Efficacy:

• Weight loss: Achieves 14.9% mean body weight reduction at 68 weeks in non-diabetic patients with obesity 2
• Glycemic control: Reduces HbA1c by 1.48-1.86 percentage points 2, 4
• Cardiovascular protection: Demonstrated 26% reduction in composite cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) in SUSTAIN-6 trial 2

Dosing:

• Ozempic (diabetes): Lower doses up to 1 mg weekly 2
• Wegovy (obesity): Titrated from 0.25 mg weekly up to maintenance dose of 2.4 mg weekly over 16 weeks 2

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Tirzepatide (Mounjaro/Zepbound)

Mechanism of Action:

• Dual GIP/GLP-1 receptor co-agonist - the first approved medication in this class 1, 3, 5
• GIP receptor activation: Stimulates glucose-dependent insulinotropic polypeptide receptors, which potentiate the anorexigenic effects of GLP-1 and increase lipolysis, lipid oxidation, and energy expenditure 1
• GLP-1 receptor activation: Binds GLP-1 receptors with approximately five times less affinity than endogenous GLP-1, but achieves therapeutic effect through dual mechanism 2
• Synergistic insulin response: The dual incretin activation produces synergistic effects on insulin secretion and glucagon suppression beyond either hormone alone 2
• Enhanced metabolic effects: Improves insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, associated with lower prandial insulin and glucagon concentrations 3
• Multiple weight loss pathways: Central appetite suppression, delayed gastric emptying, increased energy expenditure, and enhanced lipolysis 1, 2

Clinical Efficacy:

• Superior weight loss: Achieves 20.9% mean body weight reduction at 72 weeks with 15 mg dose, representing 6% absolute advantage over semaglutide 2, 4
• Unprecedented glycemic control: Reduces HbA1c by 1.87-2.24 percentage points, with 23.0-62.4% of patients achieving HbA1c <5.7% (normoglycemia) 2, 3
• Greater cardiometabolic benefits: Superior waist circumference reduction, triglyceride reduction, and fasting glucose control compared to semaglutide 2
• Liver fat reduction: Significantly reduces both hepatic steatosis and visceral adipose tissue in patients with type 2 diabetes 1

Dosing:

• Starting dose: 5 mg weekly subcutaneously 2
• Titration: Increase every 4 weeks based on tolerance to maximum 15 mg weekly 2

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Retatrutide (Investigational)

Mechanism of Action:

• Triple GIP/GLP-1/glucagon receptor agonist - the most advanced triple co-agonist in development 1, 6, 7
• GLP-1 and GIP activation: Shares the dual incretin mechanisms of tirzepatide 1
• Glucagon receptor activation: Adds glucagon receptor stimulation, which potentiates anorexigenic effects and has additional peripheral effects including increased lipolysis, lipid oxidation, and energy expenditure 1
• Magnitude comparable to bariatric surgery: The triple agonist mechanism can induce weight loss similar in magnitude to bariatric surgery 1

Clinical Efficacy (Phase 2 Data):

• Dose-dependent weight loss: Ranged from -7.2% to approximately -18% as dose increased from 1 mg to 12 mg at 24 weeks 6
• Promising preliminary results: Early data suggest potential superiority to dual agonists, though head-to-head comparisons with semaglutide and tirzepatide are lacking 6, 7

Development Status:

• Phase 2 completed for obesity and type 2 diabetes 6, 7
• Phase 3 trials ongoing for metabolic dysfunction-associated steatotic liver disease (MASLD) 1
• Not yet FDA approved - still investigational 6, 7

Safety Considerations:

• Heart rate increase: Consistent with GLP-1 receptor agonism, heart rate increased by up to 6.7 beats/min, which may offset some cardiovascular benefits of weight loss 6
• Gastrointestinal effects: Most frequent adverse events were nausea, diarrhea, and vomiting, similar to other incretin-based therapies 6

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Comparative Safety Profile

Common to All Three Agents:

• Gastrointestinal effects predominate: Nausea (17-22% tirzepatide, 18-40% semaglutide), diarrhea (13-16% tirzepatide, 12% semaglutide), vomiting (6-10% tirzepatide, 8-16% semaglutide) 2, 4
• Severity: Typically mild-to-moderate, dose-dependent, and decrease over time 2
• Mitigation strategy: Slow titration increases gastrointestinal tolerability 2

Serious but Rare Risks (All Agents):

• Pancreatitis: Reported in clinical trials, though causality not definitively established 2
• Gallbladder disease: Including cholelithiasis and cholecystitis 2
• Thyroid cancer: Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 2

Hypoglycemia Risk:

• Minimal as monotherapy: Glucose-dependent mechanism results in low hypoglycemia risk (0.2-1.7% tirzepatide, 0.4% semaglutide) 2, 4

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Summary Table with Key Comparisons

Feature	Semaglutide (Ozempic)	Tirzepatide (Mounjaro)	Retatrutide
Class	GLP-1 receptor agonist	Dual GIP/GLP-1 receptor agonist	Triple GIP/GLP-1/glucagon receptor agonist
Receptor Targets	GLP-1 only	GIP + GLP-1	GIP + GLP-1 + Glucagon
FDA Status	✅ Approved (diabetes & obesity)	✅ Approved (diabetes & obesity)	❌ Investigational (Phase 2)
Weight Loss (%)	14.9% at 68 weeks	20.9% at 72 weeks	~18% at 24 weeks (Phase 2)
HbA1c Reduction	-1.48 to -1.86%	-1.87 to -2.24%	Data pending
Dosing	0.25-2.4 mg weekly	5-15 mg weekly	1-12 mg weekly (investigational)
CV Outcomes	✅ Proven benefit (HR 0.74)	⏳ SURPASS-CVOT ongoing	❓ Unknown
Nausea Rate	18-40%	17-22%	Similar (Phase 2)
Unique Advantage	Proven CV protection	Greatest weight loss & HbA1c reduction	Potential bariatric surgery-level weight loss
Key Concern	Lower weight loss vs tirzepatide	Higher diarrhea incidence	Heart rate increase (↑6.7 bpm)

Legend: ✅ = Established/Approved, ⏳ = In Progress, ❌ = Not Approved, ❓ = Unknown/Pending

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Clinical Decision Algorithm

For Type 2 Diabetes with Obesity:

1. First-line: Tirzepatide (superior HbA1c reduction and weight loss) 2
2. If established CVD: Consider semaglutide 2.4 mg (proven cardiovascular benefit) 2
3. If tirzepatide unavailable/not tolerated: Semaglutide 2.4 mg 2

For Obesity without Diabetes:

1. First-line: Tirzepatide 15 mg (greatest weight loss and cardiometabolic benefits) 2
2. If established CVD: Semaglutide 2.4 mg (proven cardiovascular risk reduction) 2
3. Retatrutide: Not yet available; await Phase 3 results and FDA approval 6, 7

Monitoring Requirements:

• Blood pressure (may require antihypertensive adjustment) 2
• Signs of pancreatitis (persistent severe abdominal pain) 2
• Gallbladder symptoms 2
• Thyroid function 2
• Nutritional status 2