Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management

Abstract

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

Keywords: Diabetes mellitus; Gastric inhibitory polypeptide; Glucagon-like peptide 1; Obesity; Tirzepatide; type 2.

Figure 1

Pancreatic and exopancreatic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide‐1 (GLP-1). *Evidence from preclinical studies.

Figure 2

Mechanisms of action (white background boxes) and clinical outcomes (colored background boxes) with tirzepatide in SURPASS program. *Transient effect, MACE-4 (cardiovascular death, myocardial infarction, stroke, and hospitalisation for unstable angina), composite kidney outcome: time to first occurrence of estimated glomerular filtration rate (eGFR) decline of at least 40% from baseline, end-stage kidney disease, death due to kidney failure, or new-onset macroalbuminuria. VAT, visceral adipose tissue; ASAT, abdominal subcutaneous adipose tissue; WL, weight loss; T2DM, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; TIR, time in range; MACE-4, major adverse cardiovascular event; HR, hazard ratio; CVD, cardiovascular disease; ACR, albumin-creatinine ratio.

Figure 3

(A) Change in glycosylated hemoglobin (HbA1c) with different doses of tirzepatide and comparators in SURPASS programme. (B) Change in weight with different doses of tirzepatide and comparators in SURPASS programme and SURMOUNT-1 study. All data is presented as efficacy estimand. *P< 0.05 for the estimated treatment difference with each dose of tirzepatide vs. placebo and/or active comparator. T2DM, type 2 diabetes mellitus; Met, metformin; SGLT2i, sodium-glucose co-transporter 2 inhibitor; SU, sulfonylurea; OAD, oral antidiabetic drug; Tirz, tirzepatide; Pbo, placebo; Sema, semaglutide; Degl, insulin degludec; Glar, insulin glargine; Dula, dulaglutide.

Figure 4

Selected ongoing clinical trials with tirzepatide (SURPASS program [green boxes], SURMOUNT program [red boxes], and other studies [blue boxes]). SURMOUNT-MMO, A Study of Tirzepatide on the Reduction on Morbidity and Mortality in Adults With Obesity; CV, cardiovascular; SURPASS-CVOT, A Study of Tirzepatide Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes; T2DM, type 2 diabetes mellitus; BMI, body mass index; SURPASSSWITCH, A Study of Tirzepatide in Adult Participants With Type 2 Diabetes Switching From Dulaglutide; HbA1c, glycosylated hemoglobin; SYNERGY-NASH, A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH); NASH, nonalcoholic steatohepatitis; SURMOUNT-OSA, Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide in Participants With Obstructive Sleep Apnea; SUMMIT, A Study of Tirzepatide in Participants With Heart Failure With Preserved Ejection Fraction and Obesity; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; SURPASS-AP-Combo, A Study of Tirzepatide in Participants With Type 2 Diabetes on Metformin With or Without Sulfonylurea; SURMOUNT-CN, A Study of Tirzepatide in Chinese Participants Without Type 2 Diabetes Who Have Obesity or Overweight.