Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: A framework for evaluating stratification using routine clinical and individual trial data
American Diabetes Association
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OBJECTIVE The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side-effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycaemic response or risk of side-effects differ markedly. We assessed if simple clinical characteristics could identify patients with differing glycemic response and side-effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased one-year HbA1c fall with one therapy class and reduced with the second. We then assessed if pre-specified patient subgroups defined by the differential clinical factors showed differing five-year glycemic response and side-effects with sulfonylureas and thiazolidinediones using individual randomised trial data from ADOPT (first-line therapy, n=2,725) and RECORD (second-line therapy, n=2,222). Further replication was conducted using routine clinical data from the GoDARTS (n=1,977). RESULTS In CPRD male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both p<0.001). In ADOPT and RECORD non-obese males had a greater overall HbA1c reduction with sulfonylureas than thiazolidinediones (p<0.001); in contrast obese females had a greater HbA1c reduction with thiazolidinediones than sulfonylureas (p<0.001). Weight gain and oedema risk with thiazolidinediones were greatest in obese females however hypoglycaemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS Patient subgroups defined by sex and BMI have a different pattern of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.
The MASTERMIND consortium is supported by the Medical Research Council (UK) (MR/N00633X/1). ATH and RHH are NIHR Senior Investigators. ERP is Wellcome Trust New Investigator (102820/Z/13/Z), ATH is a Wellcome Trust Senior Investigator. ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. AGJ is supported by an NIHR Clinician Scientist award. NS acknowledges support by Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115372, the resources of which comprise financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution.
This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.
Published online 2 August 2018.