Tirzepatide is a single synthetic peptide that acts as a co-agonist at both the glucose-dependent insulinotropic polypeptide receptor and the glucagon-like peptide-1 receptor. This dual agonism produces glucose lowering and weight loss that substantially exceeds what is achievable with glucagon-like peptide-1 receptor agonism alone, making tirzepatide the most effective pharmacological agent for both glycemic control and weight reduction currently approved.

Glucose-dependent insulinotropic polypeptide is the other major incretin hormone alongside glucagon-like peptide-1, secreted from intestinal K cells in response to fat and carbohydrate ingestion. In healthy individuals, glucose-dependent insulinotropic polypeptide is responsible for roughly half of the postprandial incretin effect. In type 2 diabetes mellitus, the glucagon-like peptide-1 response is preserved but blunted, while the glucose-dependent insulinotropic polypeptide response is largely intact — making the glucose-dependent insulinotropic polypeptide receptor an important pharmacological target. Tirzepatide exploits this by combining glucose-dependent insulinotropic polypeptide receptor agonism (which amplifies insulin secretion and may enhance glucagon-like peptide-1 receptor sensitivity) with glucagon-like peptide-1 receptor agonism to produce additive or synergistic effects.

The SURPASS clinical trial program established tirzepatide's superiority over semaglutide. In the head-to-head SURPASS-2 trial, tirzepatide 15 mg reduced glycated hemoglobin by 2.46 percent and body weight by 12.4 kg over 40 weeks, compared with 2.09 percent and 6.2 kg for semaglutide 1 mg — representing approximately double the weight loss with superior glucose lowering. In the SURMOUNT obesity trials, tirzepatide 15 mg produced approximately 20 to 22 percent body weight reduction in patients without diabetes — the largest pharmacological weight reduction reported in a randomized controlled trial at the time of approval. The SURPASS-CVOT trial (2025) demonstrated superiority of tirzepatide over dulaglutide for major adverse cardiovascular event reduction in type 2 diabetes mellitus with established cardiovascular disease.

The clinical success of tirzepatide has driven rapid development of next-generation incretin therapies targeting additional receptor systems. The pipeline includes triple agonists (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptor co-agonists), amylin analogs combined with glucagon-like peptide-1 receptor agonists, and oral small-molecule glucagon-like peptide-1 receptor agonists that overcome the bioavailability limitations of peptide-based oral formulations.

Retatrutide is a triple agonist targeting glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors simultaneously. Phase 2 trials have reported approximately 24 percent body weight reduction — exceeding tirzepatide — with the glucagon receptor component contributing additional energy expenditure and hepatic fat reduction. Glucagon receptor agonism independently reduces liver fat and increases energy expenditure, at the cost of potential glucose elevation if not adequately offset by the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide components. Phase 3 trials are ongoing.

Cagrilintide is a long-acting amylin analog. Amylin is co-secreted with insulin from beta cells and acts centrally to reduce food intake and slow gastric emptying. Cagrilintide combined with semaglutide (the combination called CagriSema) has shown additive weight loss approaching 25 percent in phase 2 trials, suggesting complementary central mechanisms between amylin and glucagon-like peptide-1 receptor signaling. Orforglipron is an oral non-peptide small-molecule glucagon-like peptide-1 receptor agonist that does not require an absorption enhancer, potentially offering greater convenience and lower cost than peptide-based oral formulations. Phase 2 data showed glycated hemoglobin reduction of approximately 1.5 percent and weight loss of 9 to 10 percent.