What classification are Tirzepatide, Retatrutide, and Ozempic (semaglutide) under in terms of their therapeutic usage?

Therapeutic Classification of Tirzepatide, Retatrutide, and Ozempic (Semaglutide)

These medications are classified as incretin-based therapies, specifically GLP-1 receptor agonists (semaglutide/Ozempic), dual GIP/GLP-1 receptor co-agonists (tirzepatide), and triple GIP/GLP-1/glucagon receptor agonists (retatrutide). 1

Primary Pharmacological Classifications

Semaglutide (Ozempic)

• GLP-1 receptor agonist - Semaglutide is a selective GLP-1 receptor agonist that binds to GLP-1 receptors expressed in multiple organs including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid 1
• Acts through glucose-dependent insulin secretion mechanism that potentiates prandial insulin release from pancreatic β-cells while minimizing hypoglycemia risk 1
• FDA-approved for both type 2 diabetes management (lower doses) and chronic weight management (2.4mg weekly formulation) 2, 3

Tirzepatide

• Dual GIP/GLP-1 receptor co-agonist - Tirzepatide is the first dual incretin receptor agonist, stimulating both glucose-dependent insulinotropic polypeptide (GIP) receptors and GLP-1 receptors 1, 4
• This dual mechanism potentiates anorexigenic effects of GLP-1 and increases lipolysis, lipid oxidation, and energy expenditure beyond either hormone alone 1
• FDA-approved for type 2 diabetes (November 2023) and obesity treatment, offering superior weight loss (20.9%) compared to semaglutide (14.9%) 2

Retatrutide

• Triple GIP/GLP-1/glucagon receptor agonist - Retatrutide adds glucagon receptor stimulation to the dual GIP/GLP-1 mechanism, representing the most comprehensive incretin-based approach currently in development 1, 5
• The glucagon receptor stimulation potentiates anorexigenic effects and provides additional peripheral effects including increased lipolysis, lipid oxidation, and energy expenditure with magnitude comparable to bariatric surgery 1
• Demonstrated superior weight loss (22.10% with 12mg dose) compared to other incretin-based therapies in clinical trials 6

Therapeutic Indications

Type 2 Diabetes Management

• All three agents function as antihyperglycemic medications through glucose-dependent insulin secretion and glucagon suppression 2, 1
• Tirzepatide achieves HbA1c reductions of 1.24-2.58%, with 23.0-62.4% of patients reaching HbA1c <5.7% (normal range) 2, 4
• Semaglutide reduces HbA1c by approximately 1.48% compared to placebo 2

Obesity/Weight Management

• All three are classified as anti-obesity medications when used at higher doses 2, 5
• Tirzepatide (15mg) is first-line for obesity management due to greatest weight loss (20.9%) and superior cardiometabolic benefits 2
• Semaglutide 2.4mg (Wegovy) is second-line with 14.9% mean weight loss at 68 weeks 2
• Retatrutide shows emerging evidence with up to 22.10% weight loss in clinical trials 6

Cardiovascular Risk Reduction

• Semaglutide has established cardioprotective classification, reducing composite cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80) in patients with cardiovascular disease and BMI ≥27 2, 1
• GLP-1 receptor agonists demonstrate cardiovascular benefits through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, and improved lipid profiles 2

Mechanism-Based Classification

Incretin Mimetics

• All three drugs are incretin-based therapies that leverage the natural incretin system, where GIP and GLP-1 are incretin hormones released from intestinal cells in response to nutrient intake 2, 7
• They produce synergistic effects on insulin response and glucagon suppression through glucose-dependent mechanisms 1

Appetite Suppressants

• Function as centrally-acting appetite suppressants by acting on hypothalamic regions that regulate food intake 2, 1
• Delay gastric emptying and increase satiety, contributing to weight loss effects 2, 7

Clinical Decision Algorithm for Classification Context

For type 2 diabetes with obesity:

• Tirzepatide is classified as first-line dual incretin agonist due to superior HbA1c reduction and weight loss 1
• Semaglutide 2.4mg is alternative GLP-1 agonist for patients with established cardiovascular disease 1

For obesity without diabetes:

• Tirzepatide 15mg is first-line dual incretin anti-obesity agent 1
• Semaglutide 2.4mg is alternative for established cardiovascular disease with proven cardiovascular risk reduction 1

For cardiovascular protection:

• Semaglutide is the only agent with established cardiovascular outcome trial data showing 26% reduction in composite cardiovascular outcomes (HR 0.74,95% CI 0.58-0.95) 2

Important Classification Caveats

• Not classified as insulin - These agents work through incretin pathways, not direct insulin replacement 1
• Not classified as insulin secretagogues - Their glucose-dependent mechanism distinguishes them from sulfonylureas, with minimal hypoglycemia risk when used as monotherapy 2, 1
• Contraindicated in specific populations - All three are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 2, 1, 3