Predictors of Initial and Sustained Glycemic and Weight Response to Tirzepatide: A Post Hoc Analysis of SURPASS-4

Abstract

This post hoc analysis assessed sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in people with type 2 diabetes and increased cardiovascular risk. Participants achieving HbA1c ≤48 mmol/mol (6.5%) or weight loss ≥10% at 52 weeks were evaluated for sustained glycemic or weight control and predictors of initial and sustained efficacy. For tirzepatide-treated participants achieving HbA1c ≤48 mmol/mol (6.5%) at 52 weeks, 75-84% sustained this until study end (median 81 weeks). Factors predicting achievement were higher tirzepatide dose, shorter diabetes duration, and lower HbA1c, higher HOMA of β-cell function (HOMA-B), metformin alone, and absence of albuminuria at baseline. Factors predicting sustained glycemic control were greater weight loss, smaller fasting glucose decrease, no sulfonylurea, and higher HOMA-B at 52 weeks. For participants achieving ≥10% weight loss at 52 weeks, 79-82% maintained weight loss. Factors predicting achievement were higher tirzepatide dose, female sex, no cardiovascular disease history, and lower baseline HbA1c, estimated glomerular filtration rate, and triglycerides. Greater decrease in LDL-cholesterol to 52 weeks predicted maintained weight loss. Greater weight loss and better β-cell function achieved with tirzepatide were the main predictors for sustained glycemic control in this post hoc analysis; no clinically meaningful predictor was identified for sustained weight control.

Article highlights: We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.

Graphical abstract

Figure 1

Sustainability of HbA_1c ≤48 mmol/mol (6.5%) in SURPASS-4. A: Achievement of HbA_1c ≤48 mmol/mol (6.5%) at week 52 and sustainability in the 2nd year. B: Change from baseline in HbA_1c over time in participants who achieved HbA_1c ≤48 mmol/mol (6.5%) at week 52. Analyses were conducted in participants in the modified intention-to-treat population with at least one on-treatment HbA_1c measurement after week 52. Data are shown as the percentage (95% CI) of participants or mean percentage change over time based on observed values. Sustainability was defined as at HbA_1c target at week 52 and the last post–52 weeks on-treatment HbA_1c measurement did not increase by >2 mmol/mol (0.2%). The asterisk (*) denotes a scheduled study visit but without preplanned HbA_1c measurement. The triangle (Δ) denotes mean change from the week 52 measurement based on observed values. BL, baseline; iGlar, insulin glargine; TZP, tirzepatide.

Figure 2

Sustainability of HbA_1c <39 mmol/mol (5.7%) in SURPASS-4. A: Achievement of HbA_1c <39 mmol/mol (5.7%) at week 52 and sustainability in the 2nd year. B: Change from baseline in HbA_1c over time in participants who achieved HbA_1c <39 mmol/mol (5.7%) at week 52. Analyses were conducted in participants in the modified intention-to-treat population with at least one on-treatment HbA_1c measurement after week 52. Data are shown as the percentage (95% CI) of participants or mean percentage change over time based on observed values. For HbA_1c, sustainability was defined as at HbA_1c target at week 52 and the last post–52 weeks on-treatment HbA_1c measurement did not increase by >2 mmol/mol (0.2%). The asterisk (*) denotes a scheduled study visit but without preplanned HbA_1c measurement. The triangle (Δ) denotes mean change from the week 52 measurement based on observed values. BL, baseline; iGlar, insulin glargine; TZP, tirzepatide.

Figure 3

Predictors of achieving HbA_1c ≤48 mmol/mol (6.5%) at week 52 and sustaining this goal in the 2nd year in SURPASS-4. A: Predictors of achieving HbA_1c ≤48 mmol/mol (6.5%) at week 52. B: Predictors of sustaining HbA_1c ≤48 mmol/mol (6.5%) in the 2nd year. Analyses were conducted in tirzepatide-treated participants in the modified intention-to-treat population. Data are shown as odds ratio (95% CI). Age, sex, and tirzepatide dose were included in all models as standard. The sustainability model was also adjusted for the estimated probability of achieving the goal at week 52. Sustainability was defined as HbA_1c target at week 52 and the last post–52 weeks on-treatment HbA_1c measurement did not increase by >2 mmol/mol (0.2%). BL, baseline; CFB, change from baseline; FSG, fasting serum glucose; MET, metformin; OAM, oral glucose-lowering medication; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZP, tirzepatide; UACR, urine albumin-to-creatinine ratio.

Figure 4

Predictors of achieving HbA_1c <39 mmol/mol (5.7%) at week 52 and sustaining this goal in the 2nd year in SURPASS-4. A: Predictors of achieving HbA_1c <39 mmol/mol (5.7%) at week 52. B: Predictors of sustaining HbA_1c <39 mmol/mol (5.7%) in the 2nd year. Analyses were conducted in tirzepatide-treated participants in the modified intention-to-treat population. Data are shown as odds ratio (95% CI). Age, sex, and tirzepatide dose were included in all models as standard. The sustainability model was also adjusted for the estimated probability of achieving the goal at week 52. For HbA_1c, sustainability was defined as at HbA_1c target at week 52 and the last post–52 weeks on-treatment HbA_1c measurement did not increase by >2 mmol/mol (0.2%). BL, baseline; CFB, change from baseline; CV, cardiovascular; MET, metformin; OAM, oral glucose-lowering medication; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TG, triglycerides; TZP, tirzepatide; UACR, urine albumin-to-creatinine ratio.

Figure 5

Sustainability of weight loss ≥10% in SURPASS-4. A: Achievement of ≥10% body weight reduction at week 52 and sustainability in the 2nd year. B: Change from baseline in body weight over time in participants who achieved ≥10% weight loss at week 52. Analyses were conducted in participants in the modified intention-to-treat population with at least one on-treatment weight measurement after week 52. Data are shown as the percentage (95% CI) of participants or mean percentage change over time based on observed values. Sustainability was defined as at weight loss target at week 52 and the average of the last two post–52 weeks on-treatment weight measurements were not higher than (≤) 2-kg increase from their 52-week measurement. In cases where a participant had only one on-treatment weight measurement after week 52, this single value was used to define sustainability. The triangle (Δ) denotes mean change from the week 52 measurement based on observed values. Avg., average; BL, baseline; TZP, tirzepatide.

Figure 6

Predictors of achieving ≥10% weight loss at week 52 and sustaining this goal in the 2nd year in SURPASS-4. A: Predictors of achieving ≥10% body weight loss at week 52. B: Predictors of sustaining ≥10% weight loss in the 2nd year. Analyses were conducted in tirzepatide-treated participants in the modified intention-to-treat population. Data are shown as odds ratio (95% CI). Age, sex, and tirzepatide dose were included in all models as standard. The sustainability model was also adjusted for the estimated probability of achieving the goal at week 52. Sustainability was defined as at weight loss target at week 52 and the average of the last two post–52 weeks on-treatment weight measurements was not higher than a (≤) 2-kg increase from their 52-week measurement. In cases where a participant had only one on-treatment weight measurement after week 52, this single value was used to define sustainability. BL, baseline; CFB, change from baseline; CV, cardiovascular; TZP, tirzepatide.