Effects of empagliFlozin on myocardIal metabOlic Rate of glucosE Estimated Through 18FDG PET (FIORE Study)

Summary

Diabetes is an independent risk factor for ischemic heart disease (CAD) and heart failure, and cardiovascular diseases are the main cause of mortality and morbidity in patients with diabetes. Recent studies on cardiovascular outcomes have shown that type 2 sodium glucose co-transporter (SGLT-2i) inhibitors are not only effective in improving glycometabolic control, but are also able to reduce major CV events (MACE) and hospitalization for heart failure. However, it is still unclear whether the beneficial CV effects of treatment with SGLT2i are due to indirect mechanisms such as reduction in blood pressure, improvement of vascular stiffness, reduction in body weight and visceral adiposity, reduction in uricemia or whether they have effects direct on the heart. Recently, it was shown that in nondiabetic porcine model with heart failure, the treatment with empagliflozin was associated with a switch of myocardial fuel utilization from glucose uptake toward uptake of ketone bodies and free fatty acid, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling. It is not known whether empagliflozin treatment is able to modify the heart's energy metabolism even in humans. In this study we hypothesize that empagliflozin may determine beneficial CV effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes. This is a single-center, prospective, controlled, randomized, open-label, two parallel group and switch, active-comparator study that evaluates the comparative effects of 26 weeks of treatment with empagliflozin versus glimepiride add on metformin on myocardial metabolic rate of glucose estimated through 18F-FGD-PET scan in patients with type 2 diabetes without a history of coronary heart disease. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.

Timeline

Start

2016-04

Primary completion

2021-10

Completion

2021-10

Publications

• Background Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 Apr;138:271-281. doi: 10.1016/j.diabres.2018.02.023. Epub 2018 Feb 26.
• Background Vaccaro O, Eberly LE, Neaton JD, Yang L, Riccardi G, Stamler J; Multiple Risk Factor Intervention Trial Research Group. Impact of diabetes and previous myocardial infarction on long-term survival: 25-year mortality follow-up of primary screenees of the Multiple Risk Factor Intervention Trial. Arch Intern Med. 2004 Jul 12;164(13):1438-43. doi: 10.1001/archinte.164.13.1438.
• Background Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34. doi: 10.1056/NEJM199807233390404.
• Background Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation. 1979 Jan;59(1):8-13. doi: 10.1161/01.cir.59.1.8.
• Background Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
• Background Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53.
• Background Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16;373(3):232-42. doi: 10.1056/NEJMoa1501352. Epub 2015 Jun 8.
• Background Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015 May;3(5):356-66. doi: 10.1016/S2213-8587(15)00044-3. Epub 2015 Mar 17.
• Background Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care. 2015 Jan;38 Suppl:S4. doi: 10.2337/dc15-S003. No abstract available.
• Background Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011 Aug;32(4):515-31. doi: 10.1210/er.2010-0029. Epub 2011 May 23.
• Background Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27.
• Background Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
• Background Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015 Dec;17(12):1180-93. doi: 10.1111/dom.12572. Epub 2015 Oct 9.
• Background Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ; EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015 Mar;38(3):420-8. doi: 10.2337/dc14-1096. Epub 2014 Sep 30.
• Background Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl UC; EMPA-REG MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014 Jul;37(7):1815-23. doi: 10.2337/dc13-3055. Epub 2014 Jun 14.
• Background Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J Am Coll Cardiol. 2019 Apr 23;73(15):1931-1944. doi: 10.1016/j.jacc.2019.01.056.
• Background Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002 Oct;51(10):3020-4. doi: 10.2337/diabetes.51.10.3020.
• Background Nishikawa J, Ohtake T, Yokoyama I, Watanabe T, Momose T, Sasaki Y. Simple method to quantify myocardial glucose metabolism from MB ratio in myocardial FDG PET. Ann Nucl Med. 1996 Aug;10(3):323-8. doi: 10.1007/BF03164739.
• Background Gerber BL, Ordoubadi FF, Wijns W, Vanoverschelde JL, Knuuti MJ, Janier M, Melon P, Blanksma PK, Bol A, Bax JJ, Melin JA, Camici PG. Positron emission tomography using(18)F-fluoro-deoxyglucose and euglycaemic hyperinsulinaemic glucose clamp: optimal criteria for the prediction of recovery of post-ischaemic left ventricular dysfunction. Results from the European Community Concerted Action Multicenter study on use of(18)F-fluoro-deoxyglucose Positron Emission Tomography for the Detection of Myocardial Viability. Eur Heart J. 2001 Sep;22(18):1691-701. doi: 10.1053/euhj.2000.2585.
• Background Marini MA, Succurro E, Frontoni S, Mastroianni S, Arturi F, Sciacqua A, Lauro R, Hribal ML, Perticone F, Sesti G. Insulin sensitivity, beta-cell function, and incretin effect in individuals with elevated 1-hour postload plasma glucose levels. Diabetes Care. 2012 Apr;35(4):868-72. doi: 10.2337/dc11-2181. Epub 2012 Feb 22.
• Background Morbelli S, Marini C, Adami GF, Kudomi N, Camerini G, Iozzo P, Massollo M, Capitanio S, Bodrato S, Verardi MT, Papadia F, Cordera R, Knuuti J, Scopinaro N, Sambuceti G. Tissue specificity in fasting glucose utilization in slightly obese diabetic patients submitted to bariatric surgery. Obesity (Silver Spring). 2013 Mar;21(3):E175-81. doi: 10.1002/oby.20003.
• Background Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS; American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002 Jan 29;105(4):539-42. doi: 10.1161/hc0402.102975. No abstract available.

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