Effect of tirzepatide on the counter-regulatory response to hypoglycaemia during a hypoglycaemic clamp in people with type 2 diabetes

We explored the effects of tirzepatide (TZP) on counter-regulatory response during a hypoglycemic clamp. Patients with type 2 diabetes (N=42) were randomized to TZP (15 mg) or placebo (PBO) for 12 wk, in a crossover design, with a wash-out period of 8 to 12 wk. The primary objective was the change in glucagon (GCG) during clamp-induced hypoglycemia (HG) from plasma glucose (PG) 100 mg/dL to nadir PG (45 mg/dL). Secondary measures were changes in other counter-regulatory hormones, insulin, and C-peptide during clamp-induced HG and PG recovery from nadir PG to 72 mg/dL. Time to recovery and HG symptom scores were assessed. At 12 wk, HbA1c change from baseline was -1.5% with TZP vs +0.5% with PBO. Increases in GCG from PG 100 mg/dL to nadir PG and during recovery did not differ between treatments (p=0.756 and p=0.565, respectively) (Table). Growth hormone and adrenaline responses did not differ between treatments, while increases in cortisol and noradrenaline responses were delayed with TZP, which explains a lower HG symptom score with TZP vs PBO at nadir (p=0.007). The proportion of patients aware of HG did not differ between treatments. Mean time to recovery from HG was 47 min with TZP and 43 min with PBO (p=0.002); however, nadir PG was lower with TZP (44 vs 47 mg/dL; p=0.015). In conclusion, the response of glucagon to hypoglycemia is maintained with TZP. Disclosure T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Consultant; Lilly, Research Support; AstraZeneca, Novo Nordisk A/S, Sanofi, Speaker's Bureau; Roche Diagnostics. E.Svehlikova: Other Relationship; Mylan. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. C.Zhou: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. Funding Eli Lilly and Company