Tirzepatide: A Systematic Update

Int J Mol Sci. 2022 Nov 23;23(23):14631. doi: 10.3390/ijms232314631.


Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.

Keywords: GIP; GLP-1; LY3298176; SUMMIT; SURMOUNT; SURPASS; SYNERGY; Tirzepatide; cardiovascular medicine; diabetes; glucagon; hypertension; incretins; meta-analysis; obesity.

Publication types

  • Review

MeSH terms

  • Diabetes Mellitus, Type 2* / metabolism
  • Gastric Inhibitory Polypeptide / metabolism
  • Gastric Inhibitory Polypeptide / therapeutic use
  • Glucagon-Like Peptide 1* / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / therapeutic use
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Incretins / therapeutic use


  • Glucagon-Like Peptide 1
  • Gastric Inhibitory Polypeptide
  • Incretins
  • Glucagon-Like Peptide-1 Receptor
  • Glucose
  • Hypoglycemic Agents

Grant support

The Santulli’s Lab is supported in part by the National Institutes of Health (NIH): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823), National Heart, Lung, and Blood Institute (NHLBI: R01-HL159062, R01HL164772, R01-HL146691, T32-HL144456), National Center for Advancing Translational Sciences (NCATS: UL1TR002556-06) (to G.S.), the Diabetes Action Research and Education Foundation (to G.S.), and the Monique Weill-Caulier and Irma T. Hirschl Trusts (to G.S). F.V. is supported by a postdoctoral fellowship of the American Heart Association (AHA-22POST995561); S.S.J. is supported by a postdoctoral fellowship of the American Heart Association (AHA-21POST836407).