The New Era for Reno-Cardiovascular Treatment in Type 2 Diabetes

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the developed world. Until 2016, the only treatment that was clearly demonstrated to delay the DKD was the renin-angiotensin system blockade, either by angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, this strategy only partially covered the DKD progression. Thus, new strategies for reno-cardiovascular protection in type 2 diabetic patients are urgently needed. In the last few years, hypoglycaemic drugs, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, demonstrated a cardioprotective effect, mainly in terms of decreasing hospitalization for heart failure and cardiovascular death in type 2 diabetic patients. In addition, these drugs also demonstrated a clear renoprotective effect by delaying DKD progression and decreasing albuminuria. Another hypoglycaemic drug class, dipeptidyl peptidase 4 inhibitors, has been approved for its use in patients with advanced chronic kidney disease, avoiding, in part, the need for insulinization in this group of DKD patients. Studies in diabetic and non-diabetic experimental models suggest that these drugs may exert their reno-cardiovascular protective effect by glucose and non-glucose dependent mechanisms. This review focuses on newly demonstrated strategies that have shown reno-cardiovascular benefits in type 2 diabetes and that may change diabetes management algorithms.

Keywords: diabetes; diabetic kidney disease; dipeptidyl peptidase 4 inhibitors; glucagon-like peptide-1 receptor agonists; reno-cardiovascular protection; sodium-glucose co-transporter 2 inhibitors.

Figure 1

Mechanisms of glucose reabsorption and intraglomerular pressure control in healthy individuals and in diabetic patients. (A) In healthy individuals, approximately 90% of glucose is reabsorbed by SGLT2 that is located at the apical membrane of the proximal tubular cells and transported back to the blood stream by the basolateral glucose transporter 2 (GLUT2) transporter. Na⁺ is reabsorbed by the apical transporters SGLT2 (with glucose) and the Na⁺/H⁺ exchanger isoform 3 (NHE3) and returned to the circulation via several basolateral Na⁺ transporters: sodium bicarbonate transporters, Na⁺ channels, and the Na⁺/K⁺ ATPase. Tubular glucose and Na⁺ reabsorption mechanisms contribute to glucose homeostasis and glomerular tone control thanks to the tubuloglomerular feedback controlled by the macula densa. (B) In diabetic patients, glucose and Na⁺ reabsorption mechanisms are increased secondary to the hyperfiltration. This fact contributes importantly to the hyperglycaemia and raises the intraglomerular pressure. (C) Both SGLT2i and GLP-1RAs produce natriuresis that leads to a decrease of the glomerular pressure. In the case of SGLT2 inhibitors, the natriuretic effect is due to the direct blockade of SGLT2 and the collateral inhibition of NHE3, which has an SGLT2 dependent activity. Regarding GLP-1RAs, these drugs impair only NHE3 activity by an unknown mechanism. Moreover, SGLT2 inhibition contributes to blood glucose level control. ℥: Basolateral Na⁺ transporters.