Why only macro and not micro in type 2 diabetes? Time to change the goals of clinical trials in diabetes

Type 2 diabetes is a devastating disease causing several end-organ damages throughout the body. Vascular complications are the major disease burden responsible for the increased morbidity and mortality of diabetes. Therefore, the primary goal of diabetes treatment should be to safely prevent, delay, or slow down the progression of complications. While pharmaceutical companies race for commercializing new hypoglycaemic drugs, there are only few and sparse data showing that using one drug instead of the other one effectively impact vascular complications. At the end, several drugs for type 2 diabetes therapy are available but whether these drugs really match the primary goal of treatment, especially in primary prevention, is uncertain. That is despite the results of cardiovascular outcome trials published since 2013. In terms of macrovascular complications, only about 35% of the currently commercialized drugs approved for diabetes treatment have cardiovascular data from ad hoc randomized controlled trials and most of these trials were not powered to explore cardiovascular efficacy, but only safety. 2 What about the remaining 65%? In terms of evidence-based medicine, we are prescribing the majority of anti-diabetes drugs (and spending money) just to lower HbA1c, with a possible indirect effect on complications which has not really been proven beneficial. When we move to microvascular complications, the situation is even worse. Our knowledge about the impact of diabetes prescriptions on microvasculature is stuck at the evidences from trials evaluating intensive glycaemic control. All we have is information from subgroup or post-hoc analysis from some (even not all) cardiovascular outcome trials. In the best cases, microvascular outcomes, especially renal outcomes, have been considered as pre-specified secondary outcomes of the trials. We have no data from large randomized controlled trials specifically designed to show whether we may avoid blindness or neuropathy by using a specific anti-diabetes drug. In 2008 the Food and Drug Administration (FDA) issued a “Guidance for industry” calling for long-term safety trials evaluating cardiovascular risk of new antidiabetic therapies.