Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study

Beverley M. Shields, John M. Dennis, Catherine D. Angwin, Fiona Warren, William E. Henley, Andrew J. Farmer, Naveed Sattar, Rury R. Holman, Angus G. Jones, Ewan R. Pearson, Andrew T. Hattersley (Lead / Corresponding author), TriMaster Study group

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Abstract

Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. We tested two 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. 525 people with type 2 diabetes participated in 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 pioglitazone 59.6 mmol/mol , sitagliptin 60.0 mmol/mol, canagliflozin 60.6 mmol/mol (p=0.2). 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). There were 2201 adverse events reported, and 447/525 (85%) randomised participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple routinely available clinical measures to identify the drug class most likely to deliver the greatest glycaemic reduction for a given patient. ClinicalTrials.gov registration: NCT02653209; ISRCTN registration12039221.
Original languageEnglish
Number of pages26
JournalNature Medicine
Early online date7 Dec 2022
DOIs
Publication statusE-pub ahead of print - 7 Dec 2022

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