title: Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.
abstract: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
authors.affiliation: From Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.); Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, ON, Canada (B.A.P.); Department of Medicine, Division of Cardiology, St. Michael's Hospital, University of Toronto, ON, Canada (D.H.F.); Ted Rogers Centre for Heart Research and Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada (M.H.); Department of Medicine, Division of Nephrology, Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.); Department of Physiology, University of Toronto, ON, Canada (D.Z.I.C.); and Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.).
authors.forename: Hiddo J L
authors.initials: HJ
authors.lastname: Heerspink
authors.affiliation: From Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.); Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, ON, Canada (B.A.P.); Department of Medicine, Division of Cardiology, St. Michael's Hospital, University of Toronto, ON, Canada (D.H.F.); Ted Rogers Centre for Heart Research and Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada (M.H.); Department of Medicine, Division of Nephrology, Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.); Department of Physiology, University of Toronto, ON, Canada (D.Z.I.C.); and Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.).
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Perkins
authors.affiliation: From Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.); Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, ON, Canada (B.A.P.); Department of Medicine, Division of Cardiology, St. Michael's Hospital, University of Toronto, ON, Canada (D.H.F.); Ted Rogers Centre for Heart Research and Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada (M.H.); Department of Medicine, Division of Nephrology, Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.); Department of Physiology, University of Toronto, ON, Canada (D.Z.I.C.); and Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.).
authors.forename: David H
authors.initials: DH
authors.lastname: Fitchett
authors.affiliation: From Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.); Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, ON, Canada (B.A.P.); Department of Medicine, Division of Cardiology, St. Michael's Hospital, University of Toronto, ON, Canada (D.H.F.); Ted Rogers Centre for Heart Research and Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada (M.H.); Department of Medicine, Division of Nephrology, Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.); Department of Physiology, University of Toronto, ON, Canada (D.Z.I.C.); and Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.).
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.affiliation: From Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.); Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, ON, Canada (B.A.P.); Department of Medicine, Division of Cardiology, St. Michael's Hospital, University of Toronto, ON, Canada (D.H.F.); Ted Rogers Centre for Heart Research and Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada (M.H.); Department of Medicine, Division of Nephrology, Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.); Department of Physiology, University of Toronto, ON, Canada (D.Z.I.C.); and Banting and Best Diabetes Centre, University of Toronto, ON, Canada (D.Z.I.C.). david.cherney@uhn.ca.
authors.forename: David Z I
authors.initials: DZ
authors.lastname: Cherney
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002986:Clinical Trials as Topic / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: cardiovascular diseases; heart failure; sodium-glucose transporter 2