TriMaster: randomised double-blind crossover trial of a DPP4-inhibitor, SGLT2-inhibitor and thiazolidinedione to evaluate differential glycaemic response to therapy based on obesity and renal function

Abstract

Abstract Precision medicine aims to target treatment to an individual based on their clinical features. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. We tested two specific hypotheses: 1) individuals with BMI > 30kg/m2, compared with BMI ≤ 30kg/m2, have greater glucose lowering with thiazolidinediones than DPP4-inhibitors, and 2) individuals with eGFR 60-90mls/min/1.73m2 compared with eGFR > 90mls/min/1.73m2 have greater glucose lowering with DPP4-inhibitors than SGLT2-inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. We conducted a UK based randomised, double-blind, three-way crossover trial of 16 weeks treatment with each of sitagliptin 100mg/day, canagliflozin 100mg/day and pioglitazone 30mg/day added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs. Participants with BMI > 30kg/m2, compared with BMI ≤ 30kg/m2, had a 2.88 mmol/mol (95% CI 0.98,4.79) lower HbA1c on pioglitazone than on sitagliptin (n = 356, P = 0.003). Participants with eGFR 60-90mls/min/1.73m2, compared with eGFR > 90mls/min/1.73m2, had a 2.90 mmol/mol (95% CI 1.19,4.61) lower HbA1c on sitagliptin than on canagliflozin (n = 342, P = 0.001). In this first precision medicine trial in type 2 diabetes, our findings support the use of simple routinely available measures to identify the drug likely to deliver the greatest glycaemic reduction.