The Pleiotropic Effects of Sodium–Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit

Abstract

Type 2 diabetes (T2D) is associated with an increased risk of macro-and microvascular complications, including cardiovascular disease (CVD), heart failure (HF), and chronic kidney disease (CKD). Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are the only class to target the pathophysiologic increase in renal glucose reabsorption in patients with T2D. In CV outcomes trials of SGLT-2is in patients with T2D and established CVD or varying levels of CV risk, empagliflozin, canagliflozin, and dapagliflozin were associated with significant improvements in the risk of composite CV and renal outcomes compared with placebo that extended beyond their glycemic effects. Real-world observational studies have also reported improvements in CV outcomes with SGLT-2is compared with other glucose-lowering therapy in routine clinical practice. This review describes the pleiotropic effects of SGLT-2is and discusses the potential mechanisms for these effects as well as how they potentially provide benefits beyond glycemic control in patients with T2D. These favorable nonglycemic effects indicate that SGLT-2is may be of particular benefit in patients with diabetic complications, such as CVD, HF, or CKD. Ongoing large randomized trials in specific patient populations, including those with CVD, HF, or CKD (with or without T2D), may help to confirm the benefits of SGLT-2is in these patients and further elucidate the potential mechanisms of their pleiotropic effects. Funding: AstraZeneca.

<p>Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice</p>

“…Our findings corroborate with the results proposed by multiple clinical trials. 19,20 Effects of SGLT-2i on the BG, BP, HR…”

Coagulatory Defects in Type-1 and Type-2 Diabetes

“…They also lower postprandial dyslipidaemia [207]. SGLT2 inhibitors are mostly beneficial in decreasing heart failure as they enhance cardiac cell metabolism, reduce cardiac fibrosis, inhibit Na + /H + exchange in myocardial cells, modulate adipokine and cytokine production, improve ventricular loading conditions and decrease blood pressure [208,209].…”

Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

“…For example, Cana reduces systolic and diastolic blood pressure, fatal and non-fatal cardiovascular events, and hospitalization for heart failure (19). The potent cardioprotective effects of Cana and other SGLT2i are not observed to the same degree in patients treated with other, comparably potent, glucose-lowering agents, suggesting that pleiotropic effects of SGLT2i may be involved (20). Since most UM-HET3 mice die of neoplastic disease, the effects of Cana on cancer may be particularly relevant for its ability to extend mouse lifespan.…”

“…In T2DM patients with kidney disease, Cana greatly reduced the risk of progression to kidney failure, as well as the risk of cardiovascular events. Cana, like other SGLT2 inhibitors, reduces fasting blood glucose, HbA1c levels, and body weight, while modestly increasing blood ketone levels (20). Like acarbose, Cana suppresses the post-prandial glucose surge (21,22).…”