The SGLT2 inhibitor empagliflozin (Jardiance) shifted myocardial metabolism from glucose to other more energy-efficient metabolites in a pig model, researchers said, suggesting a mechanism for its cardiac benefits beyond glucose lowering.
Among non-diabetic pigs with an induced MI, those that were randomized to empagliflozin had better myocardial energy production and lower uptake of glucose. Consumption of more ketone bodies, free fatty acids, and branched-chain amino acids was demonstrated by greater uptake of these three metabolites (and enhanced activity in the enzymes that metabolize them) compared with control animals at 2 months.
With greater utilization of the non-glucose fuel, empagliflozin increased myocardial ATP production and improved myocardial work efficiency, as Juan Badimon, PhD, of Mount Sinai School of Medicine in New York City, and colleagues reported in the April 23 issue of the Journal of the American College of Cardiology.
In turn, the improved myocardial energetics resulted in enhanced left ventricular (LV) systolic function and an easing of adverse LV remodeling at the anatomical, metabolic, and neurohormonal levels, the investigators found. “Therefore, it seems reasonable to conclude that the benefits of empagliflozin are, at least in part, mediated via a mechanism independent of its glucose-lowering activity.”
Empagliflozin was unexpectedly shown in the EMPA-REG OUTCOME trial to reduce both cardiovascular mortality and heart failure hospitalizations in patients with type 2 diabetes.
Glucose- and blood pressure-lowering alone couldn’t explain these outcomes, as differences in glycemic control were minimal between groups and there were no reductions in MI or stroke with SGLT2 inhibition, the study authors said. Moreover, “it takes years to show the benefits of controlling glycemia/ blood pressure, while the curves in [EMPA-REG OUTCOME] separated in the first months.”
Since the trial’s release in 2015, the class effect of reduced heart failure hospitalization by SGLT2 inhibition has been confirmed in the CANVAS and DECLARE-TIMI 58 trials of diabetes patients taking canagliflozin (Invokana) and dapagliflozin (Farxiga), respectively, noted Michael Lehrke, MD, of the University Hospital Aachen in Germany.
“The current study supports a cardiac origin of these metabolic changes, strengthens the fuel hypothesis as a relevant mechanism of cardioprotection by SGLT2 inhibition, and suggests maladaptive contributing of glucocentric metabolism in heart failure,” he wrote in an accompanying editorial.
“The heart acts as an omnivore under healthy conditions, metabolizing glucose, fatty acids, ketone bodies, as well as branched chain amino acids. Manifestation of heart failure however restricts substrate flexibility and favors glucose oxidation, which has been attributed to the reactivation of a fetal [gene] program. This runs in parallel with a reduced capacity of the insufficient heart to metabolize fatty acids, branched chain amino acids, and ketone bodies,” Lehrke explained.
The 14 female pigs in the study were randomized to daily empagliflozin or placebo for 2 months. Myocardial metabolite consumption was assessed from blood samples of coronary artery and coronary sinus.
Control and experimental groups shared a similar extent of initial induced ischemic myocardial injury.
Badimon and colleagues cited their small sample as a limitation of the study, along with the potential effect of menstrual cycle in the female pigs.
“[T]he current study cannot determine whether improved LV function of empagliflozin-treated animals is the consequence of metabolic adaptation or, vice versa, metabolic adaptation occurs secondarily to improved LV function,” added Lehrke.
“Further, it currently remains unknown how urinary glucose excretion — which mimics a fasting response with increased ketone body production — results in the observed adaptation of the substrate using machinery in the heart,” the editorialist continued.
Nevertheless, the findings in this study fuel “high hopes” for ongoing heart failure studies using SGLT2 inhibitors, Lehrke said.
In 2016, empagliflozin became the first diabetes drug to win an indication in cardiovascular prevention from the FDA, followed by canagliflozin 2 years later.
The study was funded by a grant from Boehringer Ingelheim.
Badimon disclosed no relevant conflicts of interest.
Lehrke reported serving as an advisor to Merck, Boehringer Ingelheim, Novo Nordisk, Amgen, Sanofi, and AstraZeneca; receiving speaker honoraria from Merck, Boehringer Ingelheim, Novo Nordisk, Amgen, Sanofi, Bayer, Lilly, and AstraZeneca; and getting research support from Boehringer Ingelheim, Novo Nordisk, and Merck.