COMMON
QUESTIONS AND ANSWERS IN THE MANAGEMENT OF HYPERTENSION Debbie L. Cohen, MD and Raymond R. Townsend, MD, Section Editors
Sweet & Low: New Treatment for Diabetes That May Reduce Blood Pressure The sodium glucose co-transporter-2 (SGLT2) inhibitors are a new class of agents for the treatment of type 2 diabetes mellitus.1 SGLT2 inhibitors are based on the structure of phlorizin, which was originally isolated from apple tree bark. Among the 6 sodium glucose transporters, SGLT is a low-affinity, high-capacity transporter expressed exclusively in the S1 and S2 segments of the renal proximal tubule, where 90% of glucose reabsorption occurs.2 The concept that SGLT2 inhibitors would reduce glucose transport was derived from observations of patients with renal glycosuria caused by mutations in the SLGT2 gene.3 These patients are generally asymptomatic aside from increased renal glucose excretion. Interestingly, patients with type 2 diabetes show upregulation of SGLT2 with greatly increased renal cell glucose uptake.4,5 Therefore, in type 2 diabetics there is the opportunity to increase renal glucose excretion by inhibiting SLGT2. SGLT2 inhibitors work independently of insulin, and could be used in combination with exogenous insulin as an adjunct for therapy in patients with type 1 diabetes. SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule resulting in glycosuria without harming renal function. SLGT2 inhibitors also decrease plasma glucose levels and reverse glucotoxicity resulting from insulin resistance.6 Studies have shown these drugs to be relatively safe with no major side effects including no major hypoglycemic events.7–9 Mild or moderate hypoglycemia has only been observed when superimposed on the background of insulin therapy. SGLT2 inhibitors have also been shown in preclinical studies to increase insulin sensitivity.10,11 Chronic treatment with an SGLT2 inhibitor sergliflozin has been shown to decrease triglyceride levels and improve fatty liver.12 These drugs have also been associated with loss of calories and mild weight loss.13 SGLT2 inhibitors have also been shown to have a beneficial effect on lowering BP. SGLT2 inhibitors have a sodium-dependent co-transport system with concurrent mild diuretic effects, which could lead to sodium loss and decrease blood pressure. There are some studies that have specifically assessed blood pressure changes in type 2 diabetics with the use of SGLT2 inhibitors. One study administered remogliflozin etabonate for 12 days to patients with type 2 diabetes and resulted in a decrease in systolic blood pressure of 6 to 9 mm Hg, depending on the dosage used.14 Another study using dapagliflozin vs Address for correspondence: Debbie L. Cohen, MD, Renal Hypertension Division, University of Pennsylvania, 1 Founders Building, 3400 Spruce St., Philadelphia, PA 19104 E-mail:
[email protected]
placebo in type 2 diabetics showed a more modest decrease in systolic blood pressure of 4.61.8 vs 0.91.8 mm Hg with placebo, and a decrease in diastolic blood pressure of 2.81.1 vs 0.71.0 with placebo.7 There are now a growing number of SGLT2 inhibitors being developed with multiple preclinical and clinical studies being conducted. One agent, canagliflozin, was favorably evaluated by an FDA advisory panel in January 2013. Dapagliflozin was approved in the European Union in 2012. SGLT2 inhibitors represent an exciting new class of drugs with the potential to impact cardiovascular disease risk through improved glycemic control with possible additional benefits of weight loss, improved triglycerides, and lowering of blood pressure. Sweet! References 1. Chen LH, Leung PS. Inhibition of the sodium glucose co-transporter2: its beneficial action and potential combination therapy for type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Jan 17. doi: 10.1111/ dom.12064. [Epub ahead of print]. 2. Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol. 2001;280:F10–F18. 3. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14:2873–2882. 4. Freitas HS, Anhe GF, Melo KF, et al. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008;149: 717–724. 5. Vestri S, Okamoto MM, de Freitas HS, et al. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol. 2001;182:105–112. 6. Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo R, ed. Current Therapy in Diabetes Mellitus. St. Louis, MO: MosbyYear Book; 1998. 7. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–2224. 8. Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85:520–526. 9. Komoroski B, Vachharajani N, Feng Y, et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009;85:513–519. 10. Macdonald FR, Peel JE, Jones HB, et al. The novel sodium glucose transporter 2 inhibitor dapagliflozin sustains pancreatic function and preserves islet morphology in obese, diabetic rats. Diabetes Obes Metab. 2010;12:1004–1012. 11. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57:1723–1729. 12. Katsuno K, Fujimori Y, Ishikawa-Takemura Y, Isaji M. Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A(y) mice. Eur J Pharmacol. 2009;3:98–104. 13. Hermansen K, Mortensen LS. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf. 2007;30:1127–1142. 14. Dobbins RL, O’Connor-Semmes R, Kapur A, et al. Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients. Diabetes Obes Metab. 2012;14:15–22.
DOI: 10.1111/jch.12092 Official Journal of the American Society of Hypertension, Inc.
The Journal of Clinical Hypertension
Vol 15 | No 5 | May 2013
305
