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

What is Tirzepatide?

Tirzepatide is a first-in-class, once-weekly injectable dual agonist that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors, approved by the FDA for treating type 2 diabetes and obesity, demonstrating superior efficacy over single-receptor GLP-1 agonists like semaglutide. 1

Mechanism of Action

Tirzepatide works through dual receptor activation that produces complementary metabolic effects:

• Binds to both GIP and GLP-1 receptors, though its affinity for the GLP-1 receptor is approximately five times less than endogenous GLP-1, while maintaining strong GIP receptor binding 1
• Stimulates glucose-dependent insulin secretion from pancreatic β-cells, meaning insulin release only occurs when blood glucose rises, explaining the low risk of hypoglycemia 1
• Suppresses glucagon secretion in hyperglycemia through GLP-1 receptor activation, while GIP receptor activation paradoxically augments glucagon in euglycemia or hypoglycemia but inhibits it during high glucose states 1
• Delays gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone through vagal nerve-mediated mechanisms 1
• Reduces appetite and increases satiety through actions on GLP-1 and GIP receptors in the hypothalamus and brainstem nuclei that regulate energy intake and expenditure 1

Clinical Efficacy

Weight Loss

Tirzepatide produces unprecedented weight reduction that surpasses all other pharmacologic agents:

• Achieves 20.9% mean weight loss at 72 weeks with the 15 mg dose in patients with obesity without diabetes, representing a 6% absolute advantage over semaglutide 2.4 mg (14.9% weight loss) 1, 2
• Produces 15-22.4% weight loss across different doses (5-15 mg) in the SURMOUNT trials, with greater reductions at higher doses 1, 3
• Weight loss comparable to bariatric surgery outcomes, marking a paradigm shift in obesity pharmacotherapy 1

Glycemic Control

In type 2 diabetes management, tirzepatide demonstrates superior glucose-lowering effects:

• Reduces HbA1c by 1.87-3.02% across the SURPASS clinical trial program, with dose-dependent effects 3
• 23.0-62.4% of patients achieve HbA1c <5.7% (normoglycemia range), an unprecedented proportion for pharmacologic therapy 4
• Superior to semaglutide 1 mg, dulaglutide, and basal insulin in head-to-head comparisons 1, 3

Cardiovascular and Metabolic Benefits

Beyond glucose and weight control, tirzepatide improves multiple cardiometabolic parameters:

• Reduces cardiovascular risk factors including blood pressure, lipid profiles, and liver fat content 3
• Improves insulin sensitivity to a greater extent than semaglutide, with lower prandial insulin and glucagon concentrations 4
• Cardioprotective effects mediated through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, and reduced systemic vascular resistance 1

Dosing and Administration

Start at 5 mg subcutaneously once weekly, then titrate upward every 4 weeks based on tolerance to 10 mg, then to a maximum of 15 mg weekly 2

• The gradual titration minimizes gastrointestinal side effects while maintaining therapeutic benefit 2
• Administered as a once-weekly subcutaneous injection, providing convenience compared to daily medications 1, 2

Safety Profile and Adverse Effects

The side effect profile resembles GLP-1 receptor agonists but with some distinctions:

• Gastrointestinal effects predominate: nausea, vomiting, diarrhea, and constipation are most common, typically mild-to-moderate and transient 1, 2
• Diarrhea may be more frequent with tirzepatide compared to selective GLP-1 agonists 5
• Serious but rare risks include pancreatitis, gallbladder disease (cholelithiasis, cholecystitis), and potential thyroid effects 2
• Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 2

Important Perioperative Consideration

• May increase risk of delayed gastric emptying and pulmonary aspiration during anesthesia, even with extended fasting periods, due to effects on gastric motility 1

Clinical Positioning

Tirzepatide represents the most effective single pharmacologic agent for both type 2 diabetes and obesity management, with efficacy that exceeds all comparators in clinical trials:

• First-line consideration for patients requiring maximal weight loss and glycemic control, particularly those with type 2 diabetes and obesity 2
• Superior to semaglutide in direct comparison studies, though semaglutide has more established cardiovascular outcome data in certain populations 2
• Must be combined with lifestyle modifications including reduced-calorie diet and increased physical activity for optimal results 2
• Requires long-term use, as significant weight regain occurs after cessation 2