Discussion
obesity, T2D, myocardial infarction, weight gain, 4.7mmol/mol greater reduction, diabetes
OBESITY, MYOCARDIAL INFARCTION, ADVERSE EVENTS, DISEASE, INSULIN RESISTANCE, TYPE 2 DIABETES, DIABETES
This multicentre, two-way, randomised crossover trial showed that the glucose-lowering response to pioglitazone relative to vildagliptin was not different between people of Māori or Pacific ethnicity and other New Zealand ethnicities. However, there was a significant interaction in relative glucose-lowering by OHTG status, with 4.7mmol/mol greater reduction in HbA1c by pioglitazone relative to vildagliptin among those with OHTG. Those without OHTG had similar glucose lowering to each medication. Importantly, both treatments generated similar treatment satisfaction scores although there was greater weight gain and greater improvement in lipids and liver enzymes after pioglitazone than vildagliptin. No severe adverse events were directly related to these treatments.While people of Māori or Pacific ethnicity had higher prevalence of OHTG, such ethnicity grouping did not predict altered glucose lowering response to pioglitazone versus vildagliptin. Within Māori and Pacific populations, there is genetic heterogeneity in risk and aetiology of T2D. A genetic variant (In contrast to rosiglitazone, which is no longer used due to its associated increased risk of myocardial infarction and overall mortality (The lack of interaction of reduction in liver enzymes or lipids after pioglitazone with baseline OHTG is interesting. One explanation is that the glucose lowering action of pioglitazone is mediated by ligand binding to nuclear receptor PPARG which are most abundant in adipocytes and hence greater in people with obesity (Comparative medication glucose response data from this crossover study design provides evidence-based understanding of how patients would respond if they were to switch from one medication to another. While this is something that happens frequently in diabetes care, there is very limited clinical data about how patients’ glycaemic control changes when this happens or which medication they prefer. In addition, several consensus reports describe that when making treatment decisions for patients with type 2 diabetes it is important to consider not only the efficacy and safety of each medication, but also patient preference. This open-label cross-over study provides the added value of patient preference outcomes between pioglitazone and vildagliptin in the real-world setting. The protocol for a three-way crossover study including a DPP4 inhibitor, thiazolidinedione and a SGLT2 inhibitor has been described, which will provide further information on stratification of glucose response to three diabetes medications by routine clinical features ascertained at baseline (A key limitation of this trial was the low follow up rate resulting in only 203 participants with valid HbA1c data after both treatments. Some of this related to difficulties encountered during the pandemic in obtaining a timely HbA1c result at the end of each study medication treatment phase and in conducting in person assessments. This is unlikely to have introduced any retention bias as each person contributed their own comparative data for both medications. Furthermore, the analysis was conducted with and without imputation on the primary analysis population, to test the robustness of the findings. Secondly, the open-label nature of the trial was selected for lower cost and complexity, which may have introduced observer and participant bias, but increased external validity. Thirdly, the crossover trial design might have led to the inappropriate estimation of the risk of weight gain with each medication, although the sensitivity analysis showed no significant carryover effect. The crossover design was selected as the best method to test differential glucose-lowering responses using HbA1c as the primary outcome measure between two diabetes medications in different patient subgroups (It is well recognised that overall glucose lowering effects of pioglitazone are typically greater than vildagliptin. The important finding of this study is that a superior glucose-lowering response to pioglitazone versus vildagliptin is observed mainly in those with OHTG. Whilst OHTG is more prevalent in those of Māori and Pacific ethnicity, the glucose-lowering response was not significantly different by such ethnicity group in a multi-ethnic New Zealand population. This has several clinical implications. Firstly, these findings suggest that ethnicity is not a sufficient proxy for stratified medicine for pioglitazone and vildagliptin in T2D. Rather, clinical markers of insulin resistance that are routinely available in clinical practice such as BMI and triglyceride levels are able to predict whether superior glucose lowering response to pioglitazone relative to vildagliptin is expected. The recent progress in better defining novel T2D subtypes based on underpinning disease mechanisms such as age at diabetes diagnosis, GAD antibodies, C-peptide and genetic factors need to be explored for their utility in predicting other stratified glucose lowering responses (