Does Sugar Control Arrest Complications in Type 2 Diabetes? Examining the Rigour in Statistical Methods and Causal Inference in Clinical Trials.

Abstract

BACKGROUND: In contrast to type 1 diabetes mellitus (T1DM), in type 2 (T2DM) the success of intensive glucose normalisation in arresting diabetic complications is marginal and inconsistent across multiple clinical trials. However, glucose regulation still largely remains the main target of treatment for T2DM in clinical practice. OBJECTIVES: We examine the possible causes of inconsistency across studies, the scientific rigour behind the design, conduct and inferences of 6 large institutional clinical trials targeting glucose normalisation and following up for diabetic complications and mortality. STUDY DESIGN: We enumerate the possible flaws in the design, statistical treatment of the results and possible logical traps in making inferences. Further, we evaluate whether the flaws can mislead the conclusions. We also suggest a more sound statistical treatment of the data and interpret results of the trials together in a coherent way. RESULTS: The clinical trials for intensive glucose control suffer from a number of common problems that have not been addressed. The most important being the failure to correct for multiple outcomes. This is recognised by some reviewers but no correction is attempted. The second is the interdependence of the outcomes, owing to which statistics based on the assumption of independence can be misleading. Simulations show that the apparent inconsistency or heterogeneity between trial results can be explained by the violation of assumed independence alone. Further, the problems with placebo control, failure to recognise alternative possibilities, inability to segregate clinical significance from statistical significance and misleading reporting formats point to conformity bias and publication bias. CONCLUSIONS: We find no support for the prevalent belief that glucose normalisation has any benefit in terms of reducing the frequency of any of the complications or mortality. It is time to reconsider the glucocentric line of treatment of T2DM. Rethinking some of the fundamental beliefs about the pathophysiology of diabetic complications and facilitating novel alternative lines of research is the need of the field.