Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program

Abstract

Objective: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers.

Research design and methods: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia.

Results: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide.

Conclusions: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

Graphical abstract

Figure 1

Change from baseline in HbA_1c, BW, and cardiometabolic parameters at week 40 in people with early-onset vs. later-onset T2D in SURPASS-2. Analysis based on data from participants while on assigned treatment without rescue medication (efficacy estimand). Data are LSM and 95% CIs within subgroups and treatment arms derived from MMRM, adjusted for baseline values and study stratification factors. Lipid profiles were analyzed on the log scale and then converted back to the percent change. The interactions between the treatment and onset of T2D were assessed using the same MMRM model applied to the overall population with additional terms for onset of T2D (early-onset or later-onset), treatment-by-onset of T2D, time-by-onset of T2D, and treatment-by-time-by-onset of T2D terms. Background therapy was metformin. (A) Change from baseline in HbA_1c in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.436. (B) Percent change from baseline in BW in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.011. (C) Change from baseline in WC in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.300. (D) Change from baseline in systolic BP in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.032. (E) Percent change from baseline in triglycerides in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.837. (F) Percent change from baseline in HDL-C in people with early-onset vs. later-onset T2D at week 40 in SURPASS-2. The treatment-by-early-onset interaction at week 40 was P = 0.811.

Figure 2

Change from baseline in HbA_1c, BW, and cardiometabolic parameters in people with early-onset vs. later-onset T2D in SURPASS-1. Analysis based on data from participants while on assigned treatment without rescue medication (efficacy estimand). Data are LSM and 95% CIs within subgroups and treatment arms derived from MMRM, adjusted for baseline values and study stratification factors. Lipid profiles were analyzed on the log-scale and then converted back to the percent change. The interactions between the treatment and onset of T2D were assessed using the same MMRM model applied to the overall population with additional terms for onset of T2D (early-onset and later-onset), treatment-by-onset of T2D, time-by-onset of T2D, and treatment-by-time-by-onset of T2D terms. (A) Change from baseline in HbA_1c in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.378. (B) Percent change from baseline in BW in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.292. (C) Change from baseline in WC in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.284. (D) Change from baseline in systolic BP in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.569. (E) Percent change from baseline in triglycerides in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.794. (F) Percent change from baseline in HDL-C in people with early-onset vs. later-onset T2D at week 40 in SURPASS-1. The treatment-by-early-onset interaction at week 40 was P = 0.476. Early-onset means diagnosis of T2D before age 40 years. n is the number of participants in the subgroup across all treatment arms.

Figure 3

Change from baseline in HbA_1c, BW, and cardiometabolic parameters in people with early-onset vs. later-onset T2D in SURPASS-3. Analysis based on data from participants while on assigned treatment without rescue medication (efficacy estimand). Data are LSM and 95% CIs within subgroups and treatment arms derived from MMRM, adjusted for baseline values and study stratification factors. Lipid profiles were analyzed on the log scale and then converted back to the percent change. The interactions between the treatment and onset of T2D were assessed using the same MMRM model applied to the overall population with additional terms for onset of T2D (early-onset and later-onset), treatment-by-onset of T2D, time-by-onset of T2D, and treatment-by-time-by-onset of T2D terms. Background therapy was metformin with or without SGLT2i. (A) Change from baseline in HbA_1c in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.132. (B) Percent change from baseline in BW in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.521. (C) Change from baseline in WC in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.692. (D) Change from baseline in systolic BP in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.681. (E) Percent change from baseline in triglycerides in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.280. (F) Percent change from baseline in HDL-C in people with early-onset vs. later-onset T2D at week 52 in SURPASS-3. The treatment-by-early-onset interaction at week 52 was P = 0.320.