Tirzepatide

Tirzepatide is a first-in-class dual agonist that activates both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1) receptors. ^{[1] [2]} It is an acylated peptide engineered to activate the GIP and GLP-1 receptors, which are key mediators of insulin secretion that are also expressed in brain regions regulating food intake. ^[3] Tirzepatide (Mounjaro) is approved as a once-weekly subcutaneous injection as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes, and it is approved at the same 5, 10 and 15 mg doses for chronic weight management. ^{[2] [4]}

GIP and GLP-1 are incretin hormones released in the intestine in response to nutrient intake that stimulate pancreatic beta-cell insulin secretion. ^[1] GLP-1 in particular reduces food intake and delays gastric emptying, and tirzepatide has also been shown to reduce low-density lipoprotein cholesterol and triglycerides and to improve blood pressure. ^[1] Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, associated with lower prandial insulin and glucagon concentrations. ^[3]

Across the phase III SURPASS 1-5 trials in type 2 diabetes, tirzepatide at 5-15 mg per week reduced HbA1c by 1.24 to 2.58% and body weight by 5.4-11.7 kg, amounts unprecedented for a single agent. ^[3] In a network meta-analysis, tirzepatide induced the largest reduction of HbA1c among GLP-1 receptor agonists and was the most effective agent for glycaemic control compared with placebo. ^[5] In a systematic review of adults with overweight or obesity and without diabetes, tirzepatide at 15 mg once weekly produced weight loss of up to 17.8% after 72 weeks of therapy. ^[6] In the phase 3 SURMOUNT program many participants achieved at least 20% weight loss, and tirzepatide produced clinically important improvements in obesity-related complications including sleep apnea, metabolic dysfunction-associated steatohepatitis, and heart failure with preserved ejection fraction. ^[4]

The most common adverse events with tirzepatide are gastrointestinal, mainly nausea, diarrhoea, decreased appetite and vomiting, and these are generally mild to moderate and more common at higher doses. ^{[2] [3]} Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. ^[2] Potent GLP-1-based therapies such as tirzepatide achieve greater overall weight loss but are associated with a significant reduction in lean mass. ^[7] After discontinuation, weight is regained in proportion to the amount originally lost, and participants taking semaglutide or tirzepatide regained a pooled mean of 9.69 kg, so these agents are considered chronic therapy. ^[8]