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Presenters at the Cardiovascular Outcome Trials (CVOT) in Type 2 Diabetes Mellitus: Controversies to Consensus session at the 2016 American Heart Association (AHA) Scientific Sessions in New Orleans expect recent CVOT data to lead to increased use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, despite uncertainty surrounding the mechanism of the drugs’ observed cardiovascular (CV) benefit. Dr George Bakris and Dr Sundar Mudaliar, who presented data on Jardiance’s (empagliflozin; Boehringer Ingelheim/Eli Lilly) EMPA-REG OUTCOME CVOT, were clearly impressed with the results of the SGLT-2 inhibitor’s trial, in which Jardiance demonstrated a 38% reduction in the risk of CV death. Both presenters agreed that use of SGLT-2 inhibitors would dramatically increase as a result of this observed CV benefit, and they anticipate that the drug class will be used both more often and earlier in the treatment of type 2 diabetes.


However, the mechanism by which Jardiance produces this CV benefit has not yet been determined. During the session, Dr Bakris and Dr Mudaliar debated two possible mechanisms of action by which SGLT-2 inhibitors could reduce the risk of CV events in diabetes patients: beneficial changes in myocardial function versus improved myocardial and renal fuel energetics and efficiency. Both of these proposed mechanisms would primarily drive a reduction in heart failure, which matches the CV benefit observed in the EMPA-REG OUTCOME trial.


Dr Bakris postulated that the reduction in heart failure observed in patients receiving Jardiance was most likely a result of the reduction in weight, blood pressure, and sodium levels in these patients, which eased stress on the heart and could improve myocardial function. He argued that the moderate reduction in blood pressure (weighted mean difference of -4.0/1.6 mmHg) was actually a significant reduction given that these patients were already receiving blood pressure-lowering agents. Dr Mudaliar, on the other hand, hypothesized that the reduction in CV events in this patient group was most likely due to improvements in myocardial and renal fuel energetics and efficiency. Some studies have shown that the hearts of diabetic patients have increased fat oxidation and decreased glucose oxidation, which results in fewer molecules of adenosine triphosphate, or ATP, generated per atom of oxygen (phosphate/oxygen ratio [P/O ratio]) and potentially increases myocardial hypoxia. Dr Mudaliar hypothesized that treatment with SGLT-2 inhibitors reduces fat oxidation while increasing B-hydroxybutyrate and ketone oxidation (which have similar P/O ratios to glucose). This would decrease the incidence and progression of heart failure by increasing cardiac work efficiency.


Regardless of the exact mechanism of action, the results of the EMPA-REG OUTCOME trial will certainly boost the profile of the SGLT-2 inhibitors within the cardiology community. Physicians attending the AHA Scientific Sessions expressed similar sentiments to Dr Bakris and Dr Mudaliar with regard to the drug class, and several cardiologists expect to take a more active role in diabetes management by recommending use of SGLT-2 inhibitors to primary care physicians and endocrinologists who are managing diabetes treatment. These cardiologists believe it will be important to coordinate CV and diabetes management, as physicians gain a greater understanding of the connection between the two conditions.

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