DUAL GIP-GLP-1 RECEPTOR AGONIST TIRZEPATIDE IMPROVES GLUCOSE CONTROL AND INSULIN SENSITIVITY IN MIXED MEAL TESTS IN PEOPLE WITH TYPE 2 DIABETES

Background and aim Tirzepatide, a dual GIP and GLP-1 receptor agonist, produced superior glycemic control and body weight reductions as compared with selective GLP-1 receptor agonists in type 2 diabetes (T2D) clinical trials. We explored the effects of tirzepatide on glucose control and on measures of insulin sensitivity during standardized mixed-meal tolerance testing (sMMTT).

Methods Within a randomized, double-blind, Phase 1 trial including placebo, tirzepatide-15mg, and active comparator semaglutide-1mg in T2D, sMMTT was conducted at baseline and 28-weeks, with measurement of blood glucose and insulin. Insulin sensitivity indices were calculated (Matsuda, OGIS and Stumvoll).

Results At 28-weeks, tirzepatide reduced HbA1c by 2.05% and body weight by 11.2kg. Reduction of glucose total AUC 0-240 min was significantly greater with tirzepatide (41%) than with semaglutide (34%) or with placebo (increased by 1%) at 28-weeks (both p≤0.002). Greater glucose AUC reduction with tirzepatide was paralleled by greater reduction in fasting glucose (p≤0.006), while incremental AUC was not significantly different between tirzepatide and semaglutide (p=0.11). The three sMMTT insulin sensitivity indices improved more with tirzepatide than with placebo or semaglutide. For instance, Matsuda index increased by 164% with tirzepatide vs 14% with placebo and 77% with semaglutide (both p<0.001).

Conclusions Treatment with tirzepatide substantially improved glucose control and sMMTT insulin sensitivity in people with T2D, consistent with hyperinsulinemic-euglycemic clamp M-values. Insulin sensitivity improvement is a likely factor contributing to the better sMMTT glucose control seen with tirzepatide than with semaglutide.

Conflict of Interest

Disclosure: This study will be presented at the 15th International Conference on Advanced Technologies & Treatments for Diabetes from 27-30 April 2022 in Barcelona & Online.

COI of Authors:

AM has received financial support from Eli Lilly and Company and is a consultant for Eli Lilly and Company. TH is an employee and shareholder of Profil. TH received speaker honoraria and travel grants from Eli Lilly and Company. J. DeVries: Research Support; Self; Dexcom, Inc., Medtronic, Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Sanofi. Research Support; Self; Senseonics. Speaker's Bureau; Self; Senseonics. Advisory Panel; Self; Zealand Pharma A/S. JK, SU, JL, TC, KJM, AH, EJP, ZM, and MKT are employees and minor shareholders/stakeholders of Eli Lilly and Company

Publication History

Article published online:
26 May 2022