Discussion
This meta-regression of 174 RCTs including 86,940 participants revealed a small increase in the variability of HbAWhat is the reason for this unexpected result of rather small treatment heterogeneity that might limit the enthusiasm for precision medicine, at least with regard to the effects of glucose-lowering drugs on glycaemic control? The key point is that we should not view the existing outcome variability in clinical trials or clinical practice as proof that a treated person responds differently to different treatments. What we observe in real life are the effects of treatments As stated before, heterogeneity of the treatment effect can best be assessed in studies that repeatedly look at the same person receiving at least two different treatments. Even standard crossover trials with each single treatment given only once are of no help here. Instead, we would need repeated-crossover or Of course, individual treatment paths with individuals having a treatment more than once can also be collected from observational studies. This would come with the additional advantage of larger external validity, because populations from observational studies are in general more representative than those from clinical trials. However, the challenges of non-randomised data are also well known. Treatment switches would not be randomised but depend on the current glycaemic state of the person, thus potentially confounding the treatment effect and, more importantly, treatment effect heterogeneity.Our results suggest an intensified search for new, multiomics predictors, e.g. genomics, phenomics or metabolomics for differential treatment response. At least with respect to genomic predictors, such efforts have not yet been very successful [Beyond the actual empirical analysis, we proposed a general procedure to assess the potential of the precision medicine approach in diabetology. Extending previous analyses in other medical disciplines where only treatment heterogeneity (our first prerequisite) was examined, we argue, following Wilkinson et al [We have to acknowledge some limitations of our approach. Foremost, treatment heterogeneity can also exist even though outcome variabilities are similar in the verum and placebo arms; a fictitious example is given in ESM Fig. Finally, a low variability of the clinical outcome in verum arms is not necessarily a disadvantage. Glucose-lowering treatment might have a stabilising quality, eventually shifting HbAClosely related to this, a further reason for this stabilisation of HbAIn conclusion, the overall small differences in HbA