Sodium–glucose cotransporter 2 inhibition: cardioprotection by treating diabetes—a translational viewpoint explaining its potential salutary effects

Abstract

Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general reduction of hyperglycaemia is considered a therapeutic goal, hypoglycaemic therapies do not necessarily reduce cardiovascular mortality and may even aggravate cardiovascular risk factors, such as body weight. A new class of antidiabetic drugs acts by inhibition of the sodium-glucose cotransporter 2 (SGLT2), which (partially) prevents reabsorption of glucose from the renal filtrate. The induction of glucose excretion via the urine (glycosuria) was turned into an effective strategy to reduce blood glucose. Ancillary advantages are the caloric and volumetric loss and thereby the reduction of body weight and blood pressure. Additionally, SGLT2 inhibition has been suggested to exert direct cardioprotective effects by the reduction of cardiac fibrosis, inflammation, and oxidative stress. This article summarizes the functional consequences of SGLT2 inhibition on the diabetic and hyperglycaemic organism. We especially focused on the effects on the kidney and the cardiovascular system as described in experimental studies. The interesting observations in experimental studies may extend to clinical medicine, as a recent trial reported a decrease in heart failure outcomes in patients at high cardiovascular risk. In conclusion, SGLT2 inhibition represents a novel treatment, which might be a promising target not only to (further) reduce blood glucose but also to target other cardiovascular risk factors. More research and long-term follow-ups will reveal the specific influence of SGLT2 inhibition on the circulatory system and cardiovascular outcomes.

European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients with heart failure

“…SGLT‐2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin) have a unique glucose‐lowering effect via inhibiting glucose reabsorption in the proximal renal tubule . Due to the favourable outcomes in recent trials, SGLT‐2 inhibitors are assumed to have cardioprotective properties, via several mechanisms, as reviewed . Beneficial effects of SGLT‐2 inhibition on CV outcomes have been shown in the recent landmark CVOTs with empagliflozin, canagliflozin and dapagliflozin ( Table ), while ertugliflozin is being assessed in an ongoing VERTIS trial (NCT01986881).…”

“…52 Due to the favourable outcomes in recent trials, SGLT-2 inhibitors are assumed to have cardioprotective properties, via several mechanisms, as reviewed. 22,[53][54][55] Beneficial effects of SGLT-2 inhibition on CV outcomes have been shown in the recent landmark CVOTs with empagliflozin, canagliflozin and dapagliflozin ( Table 3), while ertugliflozin is being assessed in an ongoing VERTIS trial (NCT01986881). Notably, SGLT-2 inhibitors are the first class of glucose-lowering medications that have demonstrated a positive effect on risk reduction for HF hospitalisation (Figure 2).…”

Sodium Glucose Cotransporter-2 Inhibition in Heart Failure

“…There are limited data evaluating whether SGLT2 inhibitors modify cardiac structure and function. In animals, SGLT2 inhibition reduces cardiac fibrosis, inflammation, and oxidative stress 85 . In several rodent models of T2D, SGLT2 inhibition improves diastolic function and left ventricular hypertrophy while simultaneously reducing myocardial fibrosis and expression of profibrotic/prohypertrophic proteins 86–88 .…”

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

“…The proposed mechanisms include improved cardiac energy metabolism by increased utilization of circulating ketone bodies (Mudaliar et al. ), attenuation of oxidative stress in the myocardium (de Leeuw and de Boer ) and vessels (Oelze et al. ), reduction in ventricular afterload by blood pressure lowering (Cherney et al.…”