Discussion
diabetes, chronic kidney disease, HbA1c reduction
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, HEART FAILURE, TYPE 2 DIABETES, COMPLICATIONS, DIABETES
This randomised crossover study provides prospective trial evidence to directly support a stratified approach for therapy to manage glycaemia in type 2 diabetes. Our results demonstrate that for second- and third-line therapy in type 2 diabetes, simple predefined stratification using body mass index and renal function can determine the choice of the drug most likely to be effective for glucose-lowering.We have shown, among patients with type 2 diabetes on background metformin or combination metformin and sulfonylurea therapy, stratification based on BMI and eGFR is associated with differential glucose-lowering responses to canagliflozin, sitagliptin, and pioglitazone. For a population of people with type 2 diabetes, treating patients with the drug proposed best for their strata rather than the alternative drug could potentially lead to an overall mean improvement of ~3mmol/mol, in those who are able to tolerate the therapy. This stratification could be used to help select glucose-lowering therapies for individuals in clinical practice. For participants with a BMI>30kg/mWe found using different strata led to clinically meaningful differences (~3mmol/mol) in achieved HbA1c between glucose lowering therapies. This equates to approximately 3 years without requiring additional therapy, given the median deterioration in HbA1c in people with type 2 diabetes is 1mmol/mol per yearThese findings, based on binary, free-to-implement strata, establish the principle of stratification helping to target type 2 diabetes treatment to those most likely to benefit, and represent a step forward in the translation of type 2 diabetes precision medicine into clinical practice. However, ultimately a more sophisticated ‘precision’ approach using models that integrate multiple individual-level clinical features (eg BMI, HbA1c and eGFR) on a continuous scale will have greatest utility for clinical practiceOur findings are consistent with previous research from trial subgroup and observational data which has suggested that higher BMI may be associated with increased glucose lowering to thiazolidinedionesA key strength of this randomised controlled trial (RCT) is that we have shown that these differences are observed in the crossover setting, allowing robust assessment of differential response to therapy within individuals and therefore direct assessment of stratified treatment that cannot be undertaken from existing trials with a parallel group design. The crossover design also requires a much smaller sample size compared with parallel group trials. There were a number of limitations to our RCT. The crossover design, although more powerful for assessing within-person differences, does require careful design to avoid period and carryover effects. We did see a period effect with a reduction in HbA1c in the second period, but in line with our statistical analysis plan we adjusted for this in our analysis, and this was not a sustained reduction over the year, which would indicate a more general decline in glycaemic control. We did not see a carryover effect for HbA1c, our primary outcome, but there was carryover with weight limiting the interpretability of the effect sizes for the associations seen with weight. In addition, the crossover design only enabled an assessment of short-term outcomes, meaning that we did not evaluate durability of HbA1c reduction, cardiovascular outcomes or development of diabetes complications. However, our previous work using parallel group trial data and observational data suggest that differences in response associated with strata are maintained over time, with early HbA1c response representative of long-term effectsIt should be recognised that we have only studied patients treated with metformin (with or without a sulphonylurea) at baseline and that the glycaemia and tolerability related outcomes we have studied are not the only factors considered by clinicians and patients when choosing a glucose lowering therapy for a patient with type 2 diabetes. In patients with established atherosclerotic cardiovascular disease (or those at elevated risk), or chronic kidney disease or heart failure, SGLT2-inhibitors are the recommended drugs in international guidelines, and GLP1-RAs are recommended for those with atherosclerotic cardiovascular diseaseWe have shown, in a randomised crossover study, that clinically relevant differences in glycaemic responses to therapy in type 2 diabetes can be seen when stratifying a patient population based on BMI and eGFR, leading to benefits in those who tolerate these therapies that would not be observed if considering overall glycaemic response to the three drugs in the population as a whole. This study represents a prospective demonstration of a potential stratified approach to type 2 diabetes treatment.