Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective

Abstract

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (-1.87 to -2.59%, -20 to -28 mmol/mol) and body weight (-6.2 to -12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

FIGURE 1

Gluco‐regulatory actions of GIP and GLP‐1 proposed based on preclinical and clinical studies, and actions of tirzepatide in adults with type 2 diabetes. GIP, glucose‐dependent insulinotropic polypeptide; GLP‐1, glucagon‐like peptide‐1; T2D, type 2 diabetes

FIGURE 2

Overview of the Phase 3 SURPASS 1‐5 clinical programme, , , , presenting population, baseline therapeutics, comparators and key baseline demographics for SURPASS 1‐5 reflecting the progression of disease; molecule structure (tirzepatide is a 39 amino acid synthetic peptide, GIP/GLP‐1 receptor agonist conjugated to a C20 fatty diacid moiety); and dose esclation sheme (doses initiated at 2.5 mg once weekly and increased by 2.5 mg every 4 weeks until assigned dose was reached and maintained for duration of trial). BMI, body mass index; CV, cardiovascular; GIP, glucose‐dependent insulinotropic polypeptide; GLP‐1, glucagon‐like peptide‐1; HbA1c, glycosylated haemoglobin A1c; OAM, oral antihyperglycaemic medication; SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitor; SU, sulphonylurea

FIGURE 3

Glycaemic efficacy of tirzepatide in SURPASS 1‐5., , , , , Data are estimated mean (SE) or percentage and from the modified intention‐to‐treat population (efficacy analysis set) of each study. (A) HbA1c change from baseline to the primary study endpoint; proportion of participants achieving HbA1c targets (B) <7.0%, (C) ≤6.5% and (D) <5.7%. *p < .05 versus placebo or active comparator. HbA1c, glycosylated haemoglobin A1c; IDeg, insulin degludec; IGlar, insulin glargine 100 U/ml; MET, metformin; N, number of patients who were randomly assigned and received at least one dose of study drug; PBO, placebo; Sema, semaglutide; SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitor; SU, sulphonylurea

FIGURE 4

Body weight loss with tirzepatide in SURPASS 1‐5., , , , , Data are estimated mean (SE) or percentage and from the modified intention‐to‐treat population (efficacy analysis set) of each study. (A) Body weight change from baseline to the primary study endpoint; (B) proportion of participants achieving ≥5% weight loss at the primary study endpoint; (C) body weight change from baseline over time in SURPASS‐4. Solid line indicates baseline values. *p < .05 versus placebo or active comparator. IDeg, insulin degludec; IGlar, insulin glargine 100 U/ml; MET, metformin; N, number of patients who were randomly assigned and received at least one dose of study drug; PBO, placebo; Sema, semaglutide; SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitor; SU, sulphonylurea

FIGURE 5

Incidence of nausea, vomiting and diarrhoea in SURPASS‐2. Data are percentage of participants who reported a new event relative to participants at risk during a time interval (incidence) and from the modified intention‐to‐treat population (safety analysis set). Dose escalation indicates the time period before reaching the maintenance dose of tirzepatide 5 mg (4 weeks), 10 mg (12 weeks), and 15 mg (20 weeks) and semaglutide 1 mg (8 weeks)