Empagliflozin Reduces Myocardial Glucose Metabolic Rate for Type 2 Diabetes Patients Without Coronary Artery Disease

Treatment with empagliflozin (Jardiance) in patients with type 2 diabetes (T2D) without coronary artery disease leads to a significant reduction in the myocardial glucose metabolic rate, according to a study recently published in Diabetes, Obesity, and Metabolism.

Evidence from cardiovascular outcome trials (CVOTs) suggests that treatment with sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduces major cardiovascular (CV) events in patients with T2D and established atherosclerotic CV disease and decreases the risk of hospitalization for heart failure (HF) and CV mortality. It has been suggested that these beneficial effects in subjects with HF may be a result of improved cardiac energetics and efficiency.

However, no head-to-head trial had previously compared the effect of SGLT2is on the myocardial glucose metabolic rate in patients with T2D, according to the authors of the current study.

The researchers sought to determine whether treatment with empagliflozin was able to affect the myocardial glucose metabolic rate, as assessed by cardiac dynamic 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) combined with euglycaemic-hyperinsulinaemic clamp compared with glimepiride in patients with T2D.

To further investigate the cardioprotective mechanism of SGLT2is, they performed a 26-week, randomized, open-label, crossover, active comparator study to determine the effects of empagliflozin 10 mg versus glimepiride 2 mg daily on the myocardial glucose metabolic rate assessed by cardiac dynamic 18F-FDG-PET combined with euglycaemic-hyperinsulinaemic clamp in 23 patients with T2D.

The study was conducted at the Department of Medical and Surgical Sciences of the University Magna Graecia of Catanzaro, Italy. Eligible patients were randomized 1:1 to receive empagliflozin 10 mg or glimepiride 2 mg daily for 26 weeks. After the first 26 weeks, patients crossed over to the opposite treatment for an additional 26 weeks.

Researchers measured cardiac geometry and myocardial mechano-energetic efficiency, as well as systolic and diastolic function by echocardiography between groups.

The results indicated that, compared with glimepiride, treatment with empagliflozin resulted in a greater reduction in the myocardial glucose metabolic rate from baseline to 26 weeks (adjusted difference −6.07 [−8.59, −3.55] μmol/min/100 g; P < .0001). Treatment with empagliflozin reduced the myocardial glucose metabolic rate by 45.1%, whereas treatment with glimepiride increased the myocardial glucose metabolic rate by 33.9%.

Empagliflozin treatment was found to increase insulin-stimulated whole-body glucose disposal by 58%. Glimepiride was observed to reduce insulin-stimulated whole-body glucose disposal.

Compared with glimepiride, empagliflozin also led to significant reductions in left atrial diameter, left ventricular end-systolic and end-diastolic volumes, N-terminal pro b-type natriuretic peptide levels, blood pressure, heart rate, stroke work, and myocardial oxygen consumption estimated by the rate pressure produced, and increases in ejection fraction, myocardial mechano-energetic efficiency, red blood cells, and hematocrit and hemoglobin levels.

Overall, the findings provided evidence that empagliflozin treatment in patients with T2D without coronary artery disease leads to a significant reduction in the insulin-stimulated myocardial glucose metabolic rate, according to the study authors. Treatment with empagliflozin generally improves cardiac geometry, myocardial mechano-energetic efficiency, and cardiac function.

The study had some limitations. Due to the design, the sample size was small and follow-up was brief.

As participants with comparatively early T2D in monotherapy treatment with metformin were recruited to investigate the cardiac effects of SGLT2i treatment as second-line therapy, the results may not be generalizable to patients with more advanced disease. Additionally, researchers only recruited Caucasian subjects in a homogenous geographical region in the south of Italy, meaning the results may not extend to other ethnic groups.

Despite these and other limitations, the authors highlight multiple strengths. The study used the gold standard methods to assess myocardial and whole-body metabolism by cardiac 18F-FDG-PET combined with the euglycemic-hyperinsulinemic clamp technique, which allows evaluation of myocardial glucose uptake under uniform experimental conditions of euglycemia and physiological hyperinsulinemia, thus removing the confounding factor of different circulating glucose and insulin levels.

The use of a single study center reduced variability in imaging results. The crossover design also allowed patients to serve as their own control. The active-controlled design allowed researchers to examine the effects of empagliflozin on primary and secondary endpoints without the confounding effect of differences in glucose control between treatment groups.

Reference

Succurro E, Vizza P, Papa A, et al. Effects of 26 weeks of treatment with empagliflozin versus glimepiride on the myocardial glucose metabolic rate in patients with type 2 diabetes: The randomized, open-label, crossover, active-comparator FIORE trial [published online July 15, 2022]. Diabetes Obes Metab. https://doi.org/10.1111/dom.14816. Accessed August 18, 2022.