Kidney and cardiovascular protection with SGLT2 inhibitors: lessons from cardiovascular outcome trials and CREDENCE
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REVIEW
Kidney and cardiovascular protection with SGLT2 inhibitors: lessons from cardiovascular outcome trials and CREDENCE D. V. O’Hara1,2 · B. L. Neuen1,2 · M. J. Jardine1,3 Received: 18 March 2020 / Accepted: 15 July 2020 © Italian Society of Nephrology 2020
Abstract The burden of diabetic kidney disease is rising rapidly worldwide, and new therapies are of vital importance to reduce the risk of kidney failure and major cardiovascular events. Of the newer glucose-lowering agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown exciting potential in preventing these adverse events. The results of several large cardiovascular outcome trials, a single dedicated kidney outcome trial and a dedicated heart failure trial, demonstrate substantial clinical benefits for several different SGLT2 inhibitors. Emerging evidence raises the possibility that these benefits may extend to those with non-diabetic chronic kidney disease. This review summarises the current evidence for SGLT2 inhibitor benefits and harms, and examines which patients are most likely to gain from these therapies. Keywords SGLT2 inhibitors · Type 2 diabetes · Chronic kidney disease · Clinical outcomes
Background Chronic kidney disease (CKD) is a global problem, affecting approximately 10% of adults, and leading to the deaths of 1.2 million people in 2017 [1]. CKD due to diabetes contributes most substantially to this burden of disease, accounting for 30.7% of the disability-adjusted life years lost to CKD [1]. With a rising prevalence over time, [2] and significant negative impacts on life expectancy and quality of life, [3] diabetic kidney disease poses a major challenge to global health care systems. Until recently, there has been a paucity of therapies for targeted treatment of diabetic kidney disease. The inhibition of the renin-angiotensin system (RAS) is the foundation of therapy, with kidney benefits for captopril, irbesartan and losartan demonstrated over 18 years ago [4–6]. Intensive glycemic control is also important, after it was demonstrated in observational follow-up of the ADVANCE trial participants that targeting a HbA1c of < 6.5% could reduce * D. V. O’Hara [email protected] 1
The George Institute for Global Health, UNSW, Sydney, Australia
2
Royal North Shore Hospital, Sydney, Australia
3
Concord Repatriation General Hospital, Sydney, Australia
progression to end-stage kidney disease (ESKD) by nearly one half, (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.34–0.85), but the risk of hypoglycaemia limits this approach [7]. Despite the use of current therapies, the residual risk of kidney failure and cardiovascular events remains high [7]. Early clinical trials of SGLT2 inhibitors sparked hope for new advances in this field. These agents were found to have robust effects in improving glycaemic control, as well as having benefits for weight loss, diuresis, and blood pressure reduction [8–10]. There was also a reduction in albuminuria, and this drew attention to possible kidney protective e
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