Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial.

Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101552874 Publication Model: Electronic Cited Medium: Internet ISSN: 2044-6055 (Electronic) Linking ISSN: 20446055 NLM ISO Abbreviation: BMJ Open Subsets: MEDLINE

Original Publication: [London] : BMJ Publishing Group Ltd, 2011-

Cardiovascular Diseases* ; Diabetes Mellitus, Type 2*/complications ; Diabetes Mellitus, Type 2*/drug therapy ; Hyperglycemia* ; Hyperinsulinism* ; Sodium-Glucose Transporter 2 Inhibitors*/therapeutic use; Benzhydryl Compounds/therapeutic use ; Cross-Over Studies ; Fatty Acids, Nonesterified ; Glucose ; Glucosides ; Humans ; Hypoglycemic Agents/therapeutic use ; Insulin/therapeutic use ; Randomized Controlled Trials as Topic ; Stroke Volume ; Ventricular Function, Left

Introduction: Type 2 diabetes (T2D) is characterised by elevated plasma glucose, free fatty acid (FFA) and insulin concentrations, and this metabolic profile is linked to diabetic cardiomyopathy, a diastolic dysfunction at first and increased cardiovascular disease (CVD) risk. Shifting cardiac metabolism towards glucose utilisation has been suggested to improve cardiovascular function and CVD risk, but insulin treatment increases overall glucose oxidation and lowers lipid oxidation, without reducing CVD risk, whereas SGLT2 inhibitors (SGLT2i) increase FFA, ketone body concentrations and lipid oxidation, while decreasing insulin concentrations and CVD risk. The aim of the present study is to elucidate the importance of different metabolic profiles obtained during treatment with a SGLT2i versus insulin for myocardial function in patients with T2D.
Methods and Analyses: Randomised, crossover study, where 20 patients with T2D and body mass index>28 kg/m ² receive 25 mg empagliflozin daily or NPH insulin two times per day first for 5 weeks followed by a 3-week washout before crossing over to the remaining treatment. Insulin treatment is titrated to achieve similar glycaemic control as with empagliflozin. In those randomised to insulin first, glycaemia during an initial empagliflozin run-in period prior to randomisation serves as target glucose. Metabolic and cardiac evaluation is performed before and at the end of each treatment period.The primary endpoint is change (treatment-washout) in left ventricular peak filling rate, as assessed by cardiac MRI with and without acute lowering of plasma FFAs with acipimox. Secondary and explorative endpoints are changes in left atrial passive emptying fraction, left ventricular ejection fraction, central blood volume and metabolic parameters.
Ethics and Dissemination: This study is approved by the Danish Medicines Agency (ref. nr.: 2017061587), the Danish Data Protection Agency (ref. nr.: AHH-2017-093) and the Capital Region Ethics Committee (ref. nr.: H-17018846). The trial will be conducted in accordance with ICH-GCP guidelines and the Declaration of Helsinki and all participants will provide oral and written informed consent. Our results, regardless of outcome, will be published in relevant scientific journals and we also will seek to disseminate results through presentations at scientific meetings.
Trial Registration Number: EudraCT: 2017-002101.
Competing Interests: Competing interests: SM and NBJ have received research grants from Boehringer Ingelheim and JJH serves on advisory boards for Novo Nordisk.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiovasc Res. 1997 Feb;33(2):243-57. (PMID: 9074687)
J Clin Endocrinol Metab. 1994 Mar;78(3):717-21. (PMID: 8126147)
Cardiovasc Res. 1997 Apr;34(1):25-33. (PMID: 9217869)
Circulation. 2019 Apr 30;139(18):2129-2141. (PMID: 30884964)
J Am Coll Cardiol. 2019 Apr 23;73(15):1931-1944. (PMID: 30999996)
J Clin Invest. 2014 Feb;124(2):509-14. (PMID: 24463448)
Lancet Diabetes Endocrinol. 2015 Nov;3(11):827. (PMID: 26476884)
Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. (PMID: 10702749)
Eur Heart J Cardiovasc Imaging. 2012 Nov;13(11):954-60. (PMID: 22634739)
Am J Physiol Heart Circ Physiol. 2012 Dec 15;303(12):H1469-73. (PMID: 23086990)
Curr Diab Rep. 2020 Nov 23;20(12):74. (PMID: 33230620)
BMJ. 2011 Nov 24;343:d6898. (PMID: 22115901)
Ann Intern Med. 2004 Sep 21;141(6):421-31. (PMID: 15381515)
Diabetes. 2015 Mar;64(3):673-86. (PMID: 25713189)
J Am Coll Cardiol. 2009 Oct 13;54(16):1524-32. (PMID: 19815124)
Diabetes. 2021 Mar;70(3):800-808. (PMID: 33334875)
Diabetes Obes Metab. 2015 Dec;17(12):1180-93. (PMID: 26343814)
Diabetes Care. 2000 Aug;23(8):1097-102. (PMID: 10937504)
Diabetes Care. 2016 Jul;39(7):1108-14. (PMID: 27289126)
Arch Intern Med. 2000 Apr 24;160(8):1160-8. (PMID: 10789610)
Drug Des Devel Ther. 2020 Nov 06;14:4775-4788. (PMID: 33192053)
Metabolism. 2018 Aug;85:32-37. (PMID: 29452178)
Diabetologia. 2019 Jul;62(7):1154-1166. (PMID: 31001673)
J Clin Invest. 2014 Feb;124(2):499-508. (PMID: 24463454)
Eur Heart J Cardiovasc Imaging. 2019 Jun 1;20(6):687-693. (PMID: 30428010)
Eur Heart J. 2005 Apr;26(7):650-61. (PMID: 15728645)
Acta Diabetol. 2011 Sep;48(3):173-81. (PMID: 20198391)
Springerplus. 2016 Jul 25;5(1):1163. (PMID: 27512622)
J Diabetes Complications. 2016 May-Jun;30(4):753. (PMID: 26970674)
JAMA. 2003 Jan 8;289(2):194-202. (PMID: 12517230)
Diabetes Care. 2017 Jun;40(6):771-776. (PMID: 28325783)
N Engl J Med. 2012 Jul 26;367(4):319-28. (PMID: 22686416)
N Engl J Med. 2008 Jun 12;358(24):2545-59. (PMID: 18539917)
Cardiovasc Diabetol. 2021 Feb 2;20(1):32. (PMID: 33530982)
N Engl J Med. 2015 Nov 26;373(22):2117-28. (PMID: 26378978)
FASEB J. 2012 Aug;26(8):3118-26. (PMID: 22611083)
Diabetes. 2015 Oct;64(10):e37. (PMID: 26405279)
Diabetes Obes Metab. 2018 Feb;20 Suppl 1:34-46. (PMID: 29364584)
Diabetologia. 2017 Mar;60(3):568-573. (PMID: 27752710)
N Engl J Med. 2009 Mar 26;360(13):1283-97. (PMID: 19318384)
Diabetes. 2009 Apr;58(4):773-95. (PMID: 19336687)
Diabetes Obes Metab. 2021 Jul;23(7):1505-1517. (PMID: 33625777)
Medicine (Baltimore). 2019 Dec;98(49):e18245. (PMID: 31804352)
J Am Coll Cardiol. 2003 Jul 16;42(2):328-35. (PMID: 12875772)
JAMA. 2005 Jan 26;293(4):437-46. (PMID: 15671428)
Cardiovasc Diabetol. 2014 Jun 19;13:102. (PMID: 24943000)
N Engl J Med. 2019 Nov 21;381(21):1995-2008. (PMID: 31535829)
N Engl J Med. 2009 Jan 8;360(2):129-39. (PMID: 19092145)
Cardiovasc Diabetol. 2021 Jan 7;20(1):6. (PMID: 33413355)
Am J Cardiol. 2002 Jul 1;90(1):29-34. (PMID: 12088775)
Circulation. 2006 Nov 14;114(20):2130-7. (PMID: 17088453)
J Am Coll Cardiol. 1995 Jul;26(1):57-65. (PMID: 7797776)
Curr Opin Pharmacol. 2020 Oct;54:82-90. (PMID: 32980777)
Diabetologia. 1999 Aug;42(8):926-31. (PMID: 10491751)
Card Fail Rev. 2018 Aug;4(2):99-103. (PMID: 30206484)
Am J Cardiol. 2004 Apr 1;93(7):870-5. (PMID: 15050491)
J Diabetes Complications. 2016 Jan-Feb;30(1):1-2. (PMID: 26541076)
FASEB J. 2013 Oct;27(10):3966-78. (PMID: 23825227)
Am J Physiol Heart Circ Physiol. 2013 Dec;305(12):H1693-7. (PMID: 24097426)
Nutr Metab Cardiovasc Dis. 2016 May;26(5):387-92. (PMID: 27118107)
Am J Med. 1955 Mar;18(3):385-96. (PMID: 14349963)
Diabetes Care. 2017 Jan;40(1):117-124. (PMID: 27797930)
N Engl J Med. 2008 Jun 12;358(24):2560-72. (PMID: 18539916)
ESC Heart Fail. 2020 Sep 18;:. (PMID: 32946200)

Keywords: coronary heart disease; diabetes & endocrinology; diabetic nephropathy & vascular disease; ischaemic heart disease; myocardial infarction

0 (Benzhydryl Compounds)
0 (Fatty Acids, Nonesterified)
0 (Glucosides)
0 (Hypoglycemic Agents)
0 (Insulin)
0 (Sodium-Glucose Transporter 2 Inhibitors)
HDC1R2M35U (empagliflozin)
IY9XDZ35W2 (Glucose)

Date Created: 20220811 Date Completed: 20220815 Latest Revision: 20220831

20221213

PMC9379482

10.1136/bmjopen-2021-054100

35953245