Glycemic control and the heart: it matters how you get there

The end cannot justify the means, for the simple and obvious reason that the means employed determine the nature of the ends produced. – Aldous Huxley On 4 March 2016, NovoNordisk released “top-line” results of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results–A Long Term Evaluation (LEADER) trial of 9340 adults with diabetes at high risk of cardiovascular (CV) events followed for 3.5–5 years; cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke all occurred less frequently among patients receiving liraglutide than among a comparator group, with significant reduction in the combined endpoint. The LEADER trial is the most recent of a nearly 50-year series of publications describing trials endeavoring to ascertain whether glycemic control strategies can effectively reduce CV endpoints. What have we learned? The first such trial performed in patients with diabetes (perhaps one of the first CV trials) was that of the University Group Diabetes Program, in which up to 8 years of follow-up of approximately 1000 patients randomized either to the sulfonylurea tolbutamide, the biguanide phenformin, insulin in a variable or a fixed dose, or placebo led to the conclusion that both oral agents led to increased CV mortality. In many ways, this trial was the impetus to the larger UK Prospective Diabetes Study of some 4000 newly diagnosed patients with diabetes randomized to insulin, to a sulfonylurea, to metformin, or to placebo, with a non-significant 16% reduction in CV outcomes at the time of the study completion, but significant 15% and 13% reductions in myocardial infarction and death, respectively, at the 10-year follow-up point of those patients originally treated with insulin or sulfonylureas, and 33% and 27% reductions, respectively, at follow-up of those patients originally treated with metformin. A decade later, three simultaneously reported trials found similar lack of evidence of CV benefit of intensive glycemic control, with the added finding of possible harm: the intensively treated group of patients with type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed a significant increase in CV mortality. Was it time to say that glycemic treatment leads to little CV benefit? Perhaps not. Close analysis of ACCORD suggested that at least part of the increase in mortality may be explained by the strong relationship between severe hypoglycemia and mortality, and, indeed, those participants in the intensive control intervention whose on-trial mean HbA1c was below 6.5% had lower mortality than the standard control group We now have three promising approaches to improving CV outcomes with glycemic control: liraglutide, pioglitazone, and empagliflozin. Last year we learned that the sodium–glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin is associated with a reduction in CV endpoints, in particular with reduction in CV mortality. Pioglitazone administration to insulin-resistant non-diabetic patients after stroke was just reported to be associated with a reduction in stroke and in myocardial infarction in the Insulin Resistance Intervention after Stroke (IRIS) trial, as further discussed in the accompanying Commentary by Professor Inzucchi, recalling the findings of the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) study among diabetic patients. Looking at another important manifestation of coronary atherosclerosis, a metaanalysis of seven randomized controlled trials involving 608 people following percutaneous coronary intervention showed that the use of either rosiglitazone or pioglitazone was associated with a more than 50 % reduction in the need for repeat target vessel revascularization; presaging the IRIS findings, this risk was similarly reduced among individuals with and without diabetes. Can it be that the use of treatment strategies associated with improvement in glycemia, but not intrinsically increasing the likelihood of hypoglycemia, are indeed the right approaches? Or, are non-glycemic effects important, differing from agent to agent: control of appetite and body weight with liraglutide, renal effects with empagliflozin, insulin sensitization with pioglitazone. Huxley’s musing, pertaining to completely different issues of ethics and tolerance, and of religion and nationalism, seems remarkably apt in helping us consider the treatment of diabetes.