SGLT2i for evidence-based cardiorenal protection in diabetic and non-diabetic chronic kidney disease: a comprehensive review by EURECA-m and ERBP working groups of ERA

Abstract

Chronic kidney disease (CKD) is a major public health issue affecting an estimated 850 million people globally. The leading causes of CKD is diabetes and hypertension, which together account for >50% of patients with end-stage kidney disease. Progressive CKD leads to the requirement for kidney replacement therapy with transplantation or dialysis. In addition, CKD, is a risk factor for premature cardiovascular disease, particularly from structural heart disease and heart failure (HF). Until 2015, the mainstay of treatment to slow progression of both diabetic and many non-diabetic kidney diseases was blood pressure control and renin-angiotensin system inhibition; however, neither angiotensin-converting enzyme inhibitors (ACEIs) nor angiotensin receptor blockers (ARBs) reduced cardiovascular events and mortality in major trials in CKD. The emergence of cardiovascular and renal benefits observed with sodium-glucose cotransporter-2 inhibitors (SGLT2i) from clinical trials of their use as anti-hyperglycaemic agents has led to a revolution in cardiorenal protection for patients with diabetes. Subsequent clinical trials, notably DAPA-HF, EMPEROR, CREDENCE, DAPA-CKD and EMPA-KIDNEY have demonstrated their benefits in reducing risk of HF and progression to kidney failure in patients with HF and/or CKD. The cardiorenal benefits-on a relative scale-appear similar in patients with or without diabetes. Specialty societies' guidelines are continually adapting as trial data emerges to support increasingly wide use of SGLT2i. This consensus paper from EURECA-m and ERBP highlights the latest evidence and summarizes the guidelines for use of SGLT2i for cardiorenal protection focusing on benefits observed relevant to people with CKD.

Keywords: cardiorenal syndrome; cardiovascular; chronic renal failure; diabetic kidney disease; heart failure.

Figure 1:

Effect of sodium-glucose cotransporter-2 inhibition on kidney disease outcomes from meta-analysis of large placebo-controlled randomized controlled trials. Figure adopted from [45]. eGFR: estimated glomerular filtration rate; SGLT2i: sodium-glucose cotransporter-2 inhibitor; RR: relative risk; NA: not available.

Figure 2:

Proposed algorithm for selection of SGLT2i based on large clinical trial evidence/indication and threshold of eGFR for initiation based on patient's main complaint (A) and clinical indication (B). Note that current prescribing licences for agents may not apply in all regions. CKD: chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or urine albumin-creatinine ratio (uACR) >30 mg/g; HF: heart failure; pEF: preserved ejection fraction; rEF: reduced ejection fraction; DM: Type 2 diabetes mellitus: eGFR values expressed in ml/min/1.73 m², w/: with; wo: without, RCT: randomized controlled trials; KRT: kidney replacement therapy, SGLT2i: sodium-glucose cotransporter-2 inhibitor; ASCVD: atherosclerotic cardiovascular disease.

Figure 3:

Broad schematic to support clinical use of SGLT2i in as foundational therapy for CKD considering need for specific treatment in both cardiometabolic and glomerular disease. CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate (eGFR); FSGS: focal segmental glomerulosclerosis; DM: type 2 diabetes mellitus; SGLT2i: sodium-glucose cotransporter-2 inhibitor; uACR: urine albumin-creatinine ratio; ASCVD: atherosclerotic cardiovascular disease; RASi renin-angiotensin system inhibition.