SGLT2 inhibitor therapy in patients with type-2 diabetes mellitus: is acute kidney injury a concern?
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REVIEW
SGLT2 inhibitor therapy in patients with type‑2 diabetes mellitus: is acute kidney injury a concern? Megan Leila Baker1 · Mark Anthony Perazella2,3 Received: 9 September 2019 / Accepted: 11 February 2020 © Italian Society of Nephrology 2020
Abstract Sodium-glucose co-transporter-2 (SGLT2) inhibitor drugs are effective for treatment of type-2 diabetes mellitus. These medications target the SGLT2 transporter in the proximal convoluted tubule to prevent reabsorption of filtered glucose, resulting in glucosuria. Other clinically meaningful benefits beyond glycemic control include reductions in blood pressure, weight, and albuminuria. Three large clinical trials and subsequent meta-analyses studying SGLT2 inhibitors demonstrated significant cardiovascular benefits including reductions in heart failure hospitalizations, as well as reduced risk of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. In addition, these agents produced kidney benefits including significant reductions in worsening estimated glomerular filtration rate, progression to end-stage kidney disease, and progression of chronic kidney disease in patients with type-2 diabetes mellitus and albuminuric chronic kidney disease. However, despite these beneficial cardiovascular and kidney effects, numerous reports of acute kidney injury, including need for dialysis and death, have been reported to the FDA adverse events reporting system raising concern among providers and a warning announcement from the FDA. This review will examine the clinical effects of the SGLT2 inhibitor drugs, mechanisms behind both kidney protection and harm, and clinical recommendations for their use. Keywords SGLT2 inhibitors · Acute kidney injury · Tubuloglomerular feedback · Chronic kidney disease · Albuminuria · Cardiovascular
Introduction Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) are a new class of oral anti-diabetic medications with a unique site of action for the group, within the kidney. Located in the proximal convoluted tubule (PCT), their target transporter reabsorbs filtered glucose to prevent its excretion in urine. Blockade of SGLT2 results in insulin-independent but glomerular filtration-dependent improvement in all glycemic parameters through reductions in plasma glucose via glucosuria. These agents have other clinically meaningful * Mark Anthony Perazella [email protected] 1
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
2
Section of Nephrology, Department of Medicine, Yale University School of Medicine, BB114, 330 Cedar Street, New Haven, CT 06520, USA
3
Department of Medicine, Veterans Affairs Medical Center, West Haven, CT, USA
benefits beyond glycemic control including reductions in blood pressure, weight, and albuminuria [1–3]. Currently there are three agents available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Four large clinical trials on SGLT2-Is in patients with type-2 diabet
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