Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes

ABSTRACT

Introduction

The glucagon-like peptide-1 (GLP-1) receptor agonists (RA) have increasingly gained prominence in the treatment of type 2 diabetes (T2D) based on their glycemic benefits and favorable body weight and cardiorenal effects. Despite this, continued development of therapeutics with superior efficacy is important to help address persistent challenges in the attainment of metabolic goals in many patients with T2D.

Areas covered

Tirzepatide is an unimolecular dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA in development for the treatment of T2D. This review summarizes key characteristics of tirzepatide and Phase 1 and Phase 2 clinical trial efficacy and safety results. Additionally, it provides an overview of the ongoing Phase 3 clinical trial program in T2D and briefly summarizes recently initiated studies in patients with obesity and nonalcoholic steatohepatitis. Information in this review comes primarily from published clinical trials, manufacturer’s websites, and ClinicalTrials.gov.

Expert opinion

Based on data from Phase 2 trials, tirzepatide has the potential to be the most efficacious therapy in T2D with respect to both glucose and body weight control. Data from the ongoing Phase 3 clinical trial program should start to become available in late 2020 and will determine the future course of this promising therapeutic agent.

KEYWORDS:

• Dual GIP/GLP-1 receptor agonist
• glucagon-like peptide-1 (GLP-1)
• glucose-dependent insulinotropic polypeptide (GIP)
• incretin hormones
• LY3298176
• tirzepatide
• type 2 diabetes

Article highlights

• Tirzepatide is a 39-amino acid linear synthetic peptide based on the sequence of native GIP, with agonist activity at both GIP and GLP-1 receptors.

• In a 26-week Phase 2 trial in patients with T2D suboptimally controlled with diet and exercise with or without metformin tirzepatide demonstrated a dose-dependent effect on HbA_1c and bodyweight lowering, which was superior to the selective GLP-1 RA dulaglutide.

• The most common adverse events were GI in nature and included nausea, vomiting, and diarrhea.

• A 12-week Phase 2 trial, which assessed slower and more gradual tirzepatide dose-escalation regimens, concluded that GI tolerability could be improved with a lower starting dose and more gradual and slower increase to maximally effective doses.

• A large-scale Phase 3 clinical development program in T2D (SURPASS), a Phase 3 trial of tirzepatide in overweight and obese individuals without diabetes (SURMOUNT 1, n=2400), and a Phase 2 trial assessing tirzepatide in patients with NASH (SYNERGY-NASH, n=196) are currently ongoing.

• Given the published timelines of the Phase 3 clinical development program for T2D, regulatory submission is anticipated in 2021 with potential commercial availability of tirzepatide for T2D in 2022.

Declaration of interest

J Frias has received research support from Allergan, AstraZaneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, Madrigal, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi and Theracos. J Frias is on the advisory boards of and has received consulting fees from Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Eli Lilly, Gilead, Merck, Novo Nordisk and Sanofi. J Frias is on the speaker bureau for Merck and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

Eli Lilly provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This paper was not funded.