Abstract
It is common knowledge in the United Kingdom that you can wait an age for your bus to arrive and then all of a sudden two will turn up at once. This is such a common occurrence in daily life, that this knowledge is commonly used as a metaphor for other events unrelated to the British omnibus. ‘It’s like waiting for a bus’ indicates that an event you have been waiting for suddenly and unexpectedly occurs twice in quick succession. This clearly brings us to the sudden unexpected appearance of two positive cardiovascular outcome trials in subjects with diabetes after decades of waiting by the bus stop. In a recent editorial, 1 I wrote about the stunning results obtained from the EMPA-REG trial of empagliflozin in high-risk type 2 diabetes subjects, which were presented at the European Association for the Study of Diabetes (EASD) in 2015 and simultaneously published in the New England Journal. 2 Since that time, the results have become even more stunning with significant improvements in renal outcomes reported 3 and a plausible theory as to the mechanism of benefit to boot. 4
Then, dramatically, after 20 years of waiting for a positive outcome study, a second, the LEADER trial was reported positive at the American Diabetes Association meeting in New Orleans in June 2016. This double-blind, placebo-controlled study investigated the effects of once daily liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on cardiovascular outcomes in 9340 type 2 diabetes patients followed up for a median time of 3.8 years. 5 The primary composite outcome in this study comprised death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke and the results demonstrated both non-inferiority (p < 0.001) and superiority (p < 0.01) of liraglutide to placebo.
Many have asked the question as to the mechanisms underlying these findings, after all, trials of sulphonylureas, thiazolidinediones and dipeptidyl peptidase 4 (DPP-4) inhibitors have demonstrated equivocal findings that have been mired in controversy. Some have focused on the rates of divergence of the treatment and placebo arms in EMPA-REG and Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER), suggesting that the profile in EMPA-REG indicates a haemodynamic effect, while LEADER perhaps suggests a more traditional effect on risk.
Either way, these results need confirming and raise important questions about how we can use these drugs alone and perhaps in combination to ameliorate cardiovascular outcomes. The use of sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as empagliflozin, has been reported to be associated with elevated levels of beta-hydroxybutyrate and rarely with frank ketoacidosis. Interestingly, it has been proposed that higher levels of beta-hydroxybutyrate, which diabetologists traditionally worry about, may underpin the cardiac and reno-protective effects through producing a more efficient substrate for adenosine triphosphate (ATP) generation in the heart and kidney. 4 Initially, this proposal needs further investigation, perhaps in murine models of heart failure and renal dysfunction before progressing to human studies. However, this hypothesis, if correct, produces a potential conundrum in combination therapy, as drugs which affect the generation of beta-hydroxybutyrate, such as liraglutide, may actually negate the cardio-renal protection described in EMPA-REG.
Like waiting for a bus, we have unexpectedly seen two major trials of therapeutics in diabetes yielding positive outcomes coming along at much the same time after years of disappointing or controversial outcomes. These results continue to challenge our understanding of cardiovascular disease in diabetes and, indeed, the very basis of the management of diabetes itself. There is a feeling that we may get to the core of the metabolic basis of some of the vascular complications of diabetes, as diabetologists, and we await the next instalment of this story with great interest.