What is Terzepatide (Dual GIP and GLP-1 receptor agonist)?

What is Tirzepatide?

Tirzepatide is a first-in-class, once-weekly injectable dual agonist that simultaneously activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, delivering unprecedented reductions in both HbA1c and body weight that surpass all other single-agent diabetes medications. 1, 2

Mechanism of Action

Dual Receptor Activation:

• Tirzepatide activates G-protein coupled GLP-1 receptors on pancreatic β cells, increasing intracellular calcium and triggering insulin exocytosis in a glucose-dependent manner, though with approximately five times less binding affinity than endogenous GLP-1. 1

• It simultaneously activates GIP receptors, which have a dual effect on glucagon: augmenting secretion during euglycemia/hypoglycemia while inhibiting it during hyperglycemia. 1

• The glucose-dependent nature of insulin stimulation by both receptors explains the remarkably low risk of hypoglycemia with this agent. 1

Central Nervous System Effects:

• Both GLP-1 and GIP receptors located in the hypothalamus and brainstem nuclei mediate appetite, satiety, energy intake, and expenditure, contributing to substantial weight loss. 3, 1

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, though this effect shows tachyphylaxis with continuous exposure. 1

Clinical Efficacy

Glycemic Control:

• Tirzepatide at doses of 5-15 mg weekly reduces HbA1c by 1.24% to 2.58%, with 23.0% to 62.4% of patients achieving normoglycemia (HbA1c < 5.7%). 2

• This represents superior efficacy compared to selective GLP-1 receptor agonists like semaglutide 1.0 mg weekly and titrated basal insulin. 2, 4

Weight Loss:

• Mean weight loss ranges from 5.4 to 11.7 kg across the SURPASS trials, with 20.7% to 68.4% of patients losing more than 10% of baseline body weight. 2

• At 72 weeks, tirzepatide produced mean weight loss of 15% in non-diabetic obese patients, with greater reductions (20.9%) at the 15 mg dose. 3

• This degree of weight loss was previously only reported with bariatric surgery. 3

Mechanism of Superior Efficacy:

• Tirzepatide improves both insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, associated with lower prandial insulin and glucagon concentrations. 2

• The complementarity of action between the two incretins (GIP and GLP-1) produces dose-dependent improvements beyond what selective GLP-1 agonists achieve. 5

Cardiovascular Safety

• Meta-analysis of cardiovascular events across the SURPASS program showed no hazard ratio > 1.0 versus pooled comparators for any cardiovascular event analyzed. 2

• Upper bounds of confidence intervals for major adverse cardiovascular events (MACE) were < 1.3, fulfilling conventional definitions of cardiovascular safety. 2

• MACE-4 events (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospital admission for angina) tended to be reduced over up to 2 years, though with low event numbers. 2

Adverse Effects

Gastrointestinal Effects:

• Adverse events are similar to selective GLP-1 receptor agonists: nausea, vomiting, diarrhea, and constipation, occurring more commonly at higher doses. 2, 4

• Diarrhea appears more frequent with tirzepatide compared to GLP-1 analogues. 5

• Withdrawal rates in active treatment arms remain relatively low despite gastrointestinal side effects. 4

Management Strategies:

• Start at low doses and titrate upward slowly to improve gastrointestinal tolerability. 3

• Reduce meal size, limit alcohol and carbonated drinks, and avoid high-fat diet. 3

Clinical Positioning

• The American Diabetes Association and European Association for the Study of Diabetes recognize tirzepatide as a dual GIP/GLP-1 receptor agonist in their 2022 consensus report on type 2 diabetes management. 3

• Tirzepatide will likely be recommended as a preferred option for patients with compelling need for high glucose-lowering effects, low hypoglycemia risk, and weight loss. 4

• Final positioning in treatment algorithms depends on results of the ongoing cardiovascular outcomes trial (SURPASS-CVOT). 5, 4