Cardiac and Renal Effects of SGLT2 Inhibitors in Diabetes

Zelniker TA, Braunwald E.
Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol 2018;72:Jul 31:[Epub ahead of print].

The following are key points to remember from this state-of-the-art review about the cardiac and renal effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with diabetes:

  1. Individuals with type 2 diabetes mellitus (T2DM), a rapidly growing major global health problem, have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function.
  2. Patients with T2DM express a significantly higher number of SGLT2s in the proximal tubule than do healthy individuals. Consequently, glucose reabsorption from the glomerular filtrate is greatly increased in these patients. The inhibition of SGLT2 intentionally lowers this threshold, reduces reabsorption, and leads to more glucose excretion.
  3. Currently, four SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) have been approved by the Food and Drug Administration (FDA) for treatment of T2DM.
  4. The SGLT2 inhibitor-mediated natriuresis and glycosuria reduce plasma volume and lower cardiac preload, whereas afterload reductions may occur through lowering of arterial pressure and stiffness.
  5. After several large cardiovascular outcome trials with mostly neutral results, two studies of the SGLT2 inhibitors empagliflozin and canagliflozin reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death.
  6. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred.
  7. SGLT2 inhibitors should be used with caution or discontinued in the presence of hypovolemia to avoid worsening of renal function. Because SGLT2 inhibitors increase urinary glucose concentrations, they induce a favorable environment for bacterial and fungal growth and are therefore associated with an increase in genital and urinary tract infections that may be complicated by urosepsis and pyelonephritis.
  8. Diabetic ketoacidosis is a rare, but potentially serious complication for which the FDA had issued a formal warning for SGLT2 inhibitors. Diabetic ketoacidosis may occur in euglycemic patients with SGLT2 inhibitors, which might delay diagnosis and therapy.
  9. Based on available evidence, the American Diabetes Association has recommended that after lifestyle management and metformin, the use of empagliflozin, canagliflozin, or liraglutide should be considered to reduce major adverse cardiovascular events and, in the case of empagliflozin and the GLP-1 receptor agonist liraglutide, to reduce cardiovascular death in patients with T2DM with evident cardiovascular disease.
  10. Ongoing studies will further clarify the benefit of these drugs in patients with T2DM, including patients with diabetic nephropathy, for the prevention of cardiac and/or renal dysfunction and in type 1 DM, as well as in the management of HF in patients without diabetes.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure

Keywords: Diabetes Mellitus, Type 2, Diabetic Ketoacidosis, Diabetic Nephropathies, Glucagon-Like Peptides, Glucose, Heart Failure, Hypoglycemic Agents, Hypovolemia, Life Style, Metabolic Syndrome X, Metformin, Myocardial Infarction, Natriuresis, Primary Prevention, Renal Insufficiency, Sodium-Glucose Transport Proteins, Stroke, Urinary Tract Infections, Vascular Diseases

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