Effects of Empagliflozin on Cardiac Microvasculature and Insulin Sensitivity in Subjects With Type 2 Diabetes

Summary

The aim is to test in T2DM patients, whether, compared to placebo, 12 weeks of SGLT-2 inhibitor improves post-absorptive, post-insulin infusion or postprandial insulin action to enhance Cardiac Muscle vascular function and whether changes correlate with improved GV or postprandial hyperglycemia

Timeline

Start

2020-02-01

Primary completion

2023-10-30

Completion

2023-11-30

Publications

• Background Nishimura R, Tanaka Y, Koiwai K, Inoue K, Hach T, Salsali A, Lund SS, Broedl UC. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol. 2015 Jan 30;14:11. doi: 10.1186/s12933-014-0169-9.
• Background Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018 Feb;41(2):356-363. doi: 10.2337/dc17-1096. Epub 2017 Dec 4.
• Background Zhao L, Chai W, Fu Z, Dong Z, Aylor KW, Barrett EJ, Cao W, Liu Z. Globular adiponectin enhances muscle insulin action via microvascular recruitment and increased insulin delivery. Circ Res. 2013 Apr 26;112(9):1263-71. doi: 10.1161/CIRCRESAHA.111.300388. Epub 2013 Mar 4.
• Background Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011 Feb;96(2):438-46. doi: 10.1210/jc.2010-1174. Epub 2010 Nov 3.
• Background Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro A. Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation. 2005 Jul 12;112(2):179-84. doi: 10.1161/CIRCULATIONAHA.104.495127. Epub 2005 Jul 5.
• Background Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011 Jul;34(7):1634-8. doi: 10.2337/dc10-2345. Epub 2011 May 26.
• Background Kovatchev BP, Clarke WL, Breton M, Brayman K, McCall A. Quantifying temporal glucose variability in diabetes via continuous glucose monitoring: mathematical methods and clinical application. Diabetes Technol Ther. 2005 Dec;7(6):849-62. doi: 10.1089/dia.2005.7.849.
• Background Kovatchev BP. Metrics for glycaemic control - from HbA1c to continuous glucose monitoring. Nat Rev Endocrinol. 2017 Jul;13(7):425-436. doi: 10.1038/nrendo.2017.3. Epub 2017 Mar 17.
• Background Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1094. doi: 10.1056/NEJMc1600827. No abstract available.
• Background Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Nov 23;377(21):2099. doi: 10.1056/NEJMc1712572. No abstract available.
• Background Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.
• Background Kolka CM, Rattigan S, Richards SM, Barrett EJ, Clark MG. Endothelial Na+-D-glucose cotransporter: no role in insulin-mediated glucose uptake. Horm Metab Res. 2005 Nov;37(11):657-61. doi: 10.1055/s-2005-870574.
• Background Chai W, Wang W, Liu J, Barrett EJ, Carey RM, Cao W, Liu Z. Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use. Hypertension. 2010 Feb;55(2):523-30. doi: 10.1161/HYPERTENSIONAHA.109.145409. Epub 2009 Dec 7.
• Background Wang N, Ko SH, Chai W, Li G, Barrett EJ, Tao L, Cao W, Liu Z. Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFalpha. Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E195-201. doi: 10.1152/ajpendo.00414.2010. Epub 2010 Oct 26.
• Background Fu Z, Zhao L, Aylor KW, Carey RM, Barrett EJ, Liu Z. Angiotensin-(1-7) recruits muscle microvasculature and enhances insulin's metabolic action via mas receptor. Hypertension. 2014 Jun;63(6):1219-27. doi: 10.1161/HYPERTENSIONAHA.113.03025. Epub 2014 Apr 7.
• Background Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes Metab. 2010 Apr;12(4):288-98. doi: 10.1111/j.1463-1326.2009.01160.x.

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Indications