Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: A joint modelling approach

Objective: Precision medicine drug therapy seeks to maximise efficacy and minimise harm for individual patients. This will be difficult if drug response and side-effects are positively associated, meaning patients likely to respond best are at increased risk of side-effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and risk of side-effects (survival outcome) for patients initiating type 2 diabetes therapy.

Study Design and Setting: Participants were randomised to metformin, sulfonylurea or thiazolidinedione therapy in the ADOPT drug-efficacy trial (n=4,351). Joint models were parameterised for: 1) current HbA1c response (change from baseline in HbA1c); 2) cumulative HbA1c response (total HbA1c change).

Results: With metformin, greater HbA1c response did not increase risk of gastrointestinal events (Hazard ratio (HR) per 1% absolute greater current response 0.82 (95% confidence interval 0.67,1.01); HR per 1% higher cumulative response 0.90 (0.81,1.00)). With sulfonylureas, greater current response was associated with increased risk of hypoglycaemia (HR 1.41 (1.04,1.91)). With thiazolidinediones, greater response was associated with increased risk of oedema (current HR 1.45 (1.05,2.01); cumulative 1.22 (1.07,1.38)) but not fracture.

Conclusion: Joint modelling provides a useful framework to evaluate the association between response to a drug and risk of developing side-effects. There may be great potential for widespread application of joint modelling to evaluate the risks and benefits of both new and established medications.