Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk

Abstract

Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin–angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium–glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.

Effects of sodium‐glucose cotransporter type 2 inhibitors on cardiovascular, renal, and safety outcomes in patients with cardiovascular disease: a meta‐analysis of randomized controlled trials

“…Initially, the inhibitory effects of SGLT-2i can lead to tubule-glomerular negative feedback by enhancing natriuresis and sodium delivery to dense plaques, thereby reducing diabetic glomerular hyperfiltration caused by hyperglycaemia. SGLT-2i are thought to reduce chronic renal damage caused by hyperglycaemia [ 36 ]. The significant increase in haematocrit concentrations in patients receiving SGLT-2i appears to be associated with increased production of erythropoietin, which may also increase oxygen delivery to the kidneys and reduce renal hypoxia.…”

Polypharmacology of clinical sodium glucose co‐transport protein 2 inhibitors and relationship to suspected adverse drug reactions

“… 6 Thus, SGLT2i have both cardioprotective and nephroprotective features. 7 , 8 , 10 This has been supported by the following EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), DAPA‐HF (Dapaglifozin and Prevention of Adverse Outcomes in Heart Failure), and CANVAS (the CANagliflozin cardioVascular Assessment Study) trials. 5 , 6 , 11 , 12 , 13 , 14 , 15 Collectively, the results of the landmark trials demonstrated that SGLT2i correspond to a reduction in all cardiovascular mortality risks, reduced heart failure‐associated hospitalization, and decline in CKD progression in diabetic patients.…”

“…Another indirect action of SGLT2 inhibition is natriuresis; this further reduces blood pressure and slows down the progression of chronic kidney disease (CKD) 6 . Thus, SGLT2i have both cardioprotective and nephroprotective features 7,8,10 . This has been supported by the following EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), DAPA‐HF (Dapaglifozin and Prevention of Adverse Outcomes in Heart Failure), and CANVAS (the CANagliflozin cardioVascular Assessment Study) trials 5,6,11–15 .…”

Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide

“…Up to 30% of the burden of CKD is a result of diabetes [ 3 ] and the progression to end stage renal failure in patients with diabetic kidney disease (DKD) is only slowed by current clinical therapies which attempt to target hyperglycemia and hypertension [ 4 ]. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that are approved and indicated for type 2 diabetes and have shown promising renoprotective effects independent of their glucose lowering actions [ 5 ]. However, their use in type 1 diabetes is limited, mainly due to complications such as diabetic ketoacidosis as the main safety concern [ 6 ].…”