Comparative Effects of Empagliflozin Versus Glimepiride After 26-weeks of Treatment Add on Metformin on Myocardial Metabolic Rate of Glucose Estimated Through 18FDG-PET in Patients With Type 2 Diabetes

Diabetes mellitus type 2 (T2DM) is the most common metabolic disease and its prevalence is rapidly increasing. T2DM is a chronic disease that affects over 451 million people in the world and this number is expected to increase over the years and it is estimated that in 2045 there will be in the world over 693 million patients with T2DM. Diabetes is an independent risk factor for ischemic heart disease (CAD), stroke and peripheral artery disease and cardiovascular diseases are the main cause of mortality and morbidity in patients with diabetes. It is estimated that subjects with T2DM have a risk of cardiovascular events same as those of non-diabetic subjects with a previous cardiovascular event and several epidemiological studies have reported that the incidence of fatal and nonfatal coronary events in patients with T2DM is 1.5 to 3-4 times higher than non-diabetics of the same age.

Many studies showed that, in diabetic subjects, improved plasma glucose is associated with a reduction in microvascular complications. Instead, is not completely shown that a reduction of plasma glucose result in a reduction of cardiovascular events. In fact, although it was noted that, in subjects with T2DM, good control glyco-metabolic is associated with modest cardiovascular benefits in the long term, however, the intensive treatment hypoglycemic agent or the use of antidiabetic drugs is often associated with adverse events cardiovascular.

Recently, it was approved for the treatment of T2DM a new class of drugs, inhibitors of sodium glucose cotransporter type 2 (SGLT-2), that work by blocking the renal glucose reabsorption, causing glycosuria. SGLT-2 inhibitors have a good safety profile, are effective in reducing HbA1c regardless of the duration of diabetes and the degree of beta-cell dysfunction and insulin resistance and exhibit a low risk of hypoglycemia. In addition, the loss of glucose renal induced by SGLT2 inhibitors is associated with modest weight loss and reduction in blood pressure. Pre clinical studies showed that SGLT2 inhibitors, through a reduction in glucose toxicity, determine an improvement in insulin resistance liver and muscle and a restoration of first and second phase insulin secretion. The improvement of β-cell function and insulin sensitivity, assessed by indexes derived from OGTT, was obtained in subjects with T2DM, even after a single dose of empagliflozin, selective SGLT2 inhibitor. There are few data on the changes in insulin sensitivity, assessed by hyperinsulinemic euglycemic clamp, and insulin secretion, estimated by intravenous glucose test tolerance (IVGTT), induced by SGLT2 inhibitor. It was shown that, in subjects with T2DM at high cardiovascular risk, treatment with empagliflozin in addition to standard therapy was associated with a significant reduction of the composite cardiovascular endpoint, consisting of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, compared to placebo. In addition, treatment with empagliflozin in addition to standard therapy determined in a significant reduction in cardiovascular mortality, mortality from all causes and hospitalization for heart failure compared to placebo. It is not completely known the mechanism through which treatment with empagliflozin is associated to an improvement of cardiovascular outcomes. Growing evidences suggest that empagliflozin performs positive cardiovascular effects through a reduction in blood pressure, an improvement in arterial stiffness, a reduction in body weight and visceral adiposity. Recently, it was shown that in nondiabetic porcine model with heart failure, the treatment with empagliflozin was associated with a switch of myocardial fuel utilization from glucose uptake toward uptake of ketone bodies and free fatty acid, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.

Myocardial positron emission tomography (PET) with 18F-Fluorodeoxyglucose (18F-FDG), a widely used glucose analogue, in combination with the euglycemic-hyperinsulinemic clamp is considered the gold standard to measure myocardial metabolic rate of glucose under standardized experimental conditions. In this study we hypothesize that empagliflozin may determine beneficial cardiovascular effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes with no history of coronary heart disease, compared to treatment with glimepiride, both add on metformin.

Study design