Tirzepatide: A Systematic Update

Abstract

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.

Impact of a dual glucose‐dependent insulinotropic peptide/glucagon‐like peptide‐1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta‐analysis

“…However, the chosen doses of GLP‐1RAs might not be the reason that we did not find an impact of GLP‐1RAs in increasing heart rate because the GLP‐1RAs doses included in this study were dulaglutide 0.75 to 1.5 mg and semaglutide 1.0 mg per week, which are the maximum dosages widely used in clinical practice to treat diabetes mellitus. TZP has better efficacy in reducing HbA1c and body weight and increasing gastrointestinal adverse events than GLP‐1RAs, 15,21 which might indicate that the chosen TZP doses have a stronger activation effect on GLP‐1 receptors 44 . Additionally, GIP could increase heart rate directly, and its potential impact on vasodilation may also lead to an increase in heart rate 45,46 .…”

“…16 Research has shown that TZP is more efficient in lowering blood glucose and reducing body weight than GLP-1RAs, and potentially decreases the risk of cardiovascular events. 15,17,18 However, the published TZP product monograph showed that it could cause a mean increase in heart rate from 2 to 4 bpm. 19 Although previous studies had revealed a dose-response relationship of TZP in its effect on glucose control and weight loss, [20][21][22] a summary of the heart rate data from different studies, with specific effect and confidence intervals (CIs) and data on a possible dose-response relationship with regard to heart rate, were not provided in the monograph.…”

“…Tirzepatide (LY3298176, TZP), a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, is undergoing a large number of clinical trials for the treatment of T2DM. 15 The SURPASS clinical trial programme aimed to assess the efficacy and safety of once-weekly TZP doses of 5, 10 and 15 mg as a treatment to improve glycaemic control in people with T2DM in comparison with placebo and other glucoselowering medications, including GLP-1RAs and basal insulin. 16 Research has shown that TZP is more efficient in lowering blood glucose and reducing body weight than GLP-1RAs, and potentially decreases the risk of cardiovascular events.…”

“…The SURPASS clinical trial programme aimed to assess the efficacy and safety of once‐weekly TZP doses of 5, 10 and 15 mg as a treatment to improve glycaemic control in people with T2DM in comparison with placebo and other glucose‐lowering medications, including GLP‐1RAs and basal insulin 16 . Research has shown that TZP is more efficient in lowering blood glucose and reducing body weight than GLP‐1RAs, and potentially decreases the risk of cardiovascular events 15,17,18 . However, the published TZP product monograph showed that it could cause a mean increase in heart rate from 2 to 4 bpm 19 .…”

Novel Molecules in Diabetes Mellitus, Dyslipidemia and Cardiovascular Disease

“…which analysed the benefits of a novel medication, tirzepatide, a molecule that acts by the dual agonism of GLP-1/GIP receptors. Tirezepatide’s efficacy in reducing blood glucose, weight, and blood pressure values was confirmed in five clinical trials in patients with type 2 diabetes mellitus, while in non-diabetic obese patients, a weekly administration of the drug, in various concentrations, produced remarkable results in reducing body weight [ 6 ].…”