SGLT-2 Inhibitor and Myocardial Perfusion, Function and Metabolism in T2 DM Patients at High Cardiovascular Risk

Type2 Diabetes Mellitus Clinical Trial

— SIMPLE  

Official title:

Effects of SGLT-2 Inhibitor on Myocardial Perfusion, Function and Metabolism in Type 2 DM Patients at High Cardiovascular Risk: The SIMPle Randomized Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03151343
• Other study ID #: 2016-775
• Secondary ID: 2016-003743-10
• Status: Completed
• Phase: Phase 3
• Start date: March 29, 2017
• Est. completion date: May 22, 2020

Study information

• Verified date: August 2022
• Source: Herlev and Gentofte Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with type 2 diabetes (T2 DM) have a markedly increased risk of heart disease and it is estimated that, in the danish population, up 80% percent of patients with type 2 diabetes die from heart disease.

The sodium glucose cotransport-2 (SGLT-2) inhibitors were developed as an anti-diabetic therapy reducing blood glucose and weight by decreasing glucose reabsorption in the kidneys, leading to glucose excretion via the urine. However, in 2015 the EMPA-REG study showed that treatment with the SGLT-2 inhibitor empagliflozin significantly reduced the cardiovascular mortality and risk of admission under the diagnosis of heart failure in a population of patients with type 2 diabetes in addition to other risk factors for heart disease. The mechanism behind this surprising result is unknown and warrants further study.

The primary hypothesis of the present study is that treatment with empagliflozin improves the function and blood supply of the heart muscle cells in patients with type 2 diabetes and high risk of heart disease. The investigators will test this hypothesis by enrolling 92 participants with type 2 diabetes and other risk factors for heart disease, and treating them with either empagliflozin or a placebo. During the study period the investigators will monitor the effects of the treatment with various techniques such as heart scans using CT and ultrasound, measurements of the fluid pressures in the heart chambers, body composition measurements and a variety of relevant blood test.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: May 22, 2020
• Est. primary completion date: May 22, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• A diagnosis of type 2 diabetes mellitus at least 3 months prior to baseline visit

• For patients on background therapy: stable dose of anti-diabetics within 30 days prior to baseline

• HbA1c of =6.5% and =10% at screening for patients on background therapy or HbA1c of =6.5 % and = 9.0% at screening for drug-naïve patients.

• BMI = 45 kg/m2 at screening

• Age =18 years

• Negative pregnancy test (fertile women). Fertile women must use safe contraceptives (spiral, hormonal contraceptives) for the duration of the study

• Able to understand the written patient information and to give informed consent

• Patients must have high cardiovascular risk, defined as at least one of the following:

• Albuminuria ( albumin/creatinine ratio = 30 mg/g or plasma NT-proBNP = 70 pg/ml)

• Confirmed history of myocardial infarction (>2 months prior to baseline)

• Heart failure according to the Framingham Heart Failure Criteria

• Or patient discharged from hospital with a documented diagnosis of unstable angina within 12 months prior to baseline

• Evidence of coronary artery disease by CAG in 1 or more major coronary arteries

OR at least one of the following: a positive noninvasive stress test, or A positive stress echocardiography showing regional systolic wall motion abnormalities, or A positive scintigraphic test showing stress-induced ischemia,

• History of ischemic or haemorrhagic stroke (>2 months prior to informed consent)

• Presence of peripheral artery disease (symptomatic or not ) documented by either:

previous limb angioplasty, stenting or bypass surgery; or previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (> 50%) peripheral artery stenosis in at least one limb; or evidence from a non-invasive measurement of significant (>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb; or ankle brachial index of < 0.9

Exclusion Criteria:

• Allergic to the study medication

• Treatment with SGLT-2 inhibitor within 3 months prior to baseline

• Impaired kidney function, eGFR = 30 ml/min

• Severe liver insufficiency (Child-Pugh class C)

• ECG showing malign ventricular arrhythmia or prolonged QT-interval (>500ms)

• Untreated clinical significant heart valve disease

• Planned cardiac surgery or angioplasty within 3 months.

• Myocardial infarction (MI) = 30 days prior to baseline

• Percutaneous coronary intervention (PCI) = 4 weeks prior to baseline

• History of coronary artery bypass graft (CABG) = 8 weeks prior to enrollment

• Prior history of heart transplantation

• Unstable angina, known severe left main coronary artery stenosis, severe heart failure, uncontrolled arrhythmias, symptomatic hypotension or severe hypertension (systolic blood pressure < 90 or > 180 mmHg, respectively), sick sinus syndrome or > 1st degree atrioventricular block in the absence of a functioning pacemaker

• Requirement of emergent cardiac medical intervention or catheterization

• Treatment with theophylline, or theophylline containing medications

• History of known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma)

• Pregnancy or desire hereof or breastfeeding.

Additional exclusion criteria for hemodynamics substudy

• LVEF = 40 % evaluated at baseline echocardiography

• Inability to perform a VO2 max test

• Hypertrophic cardiomyopathy

• Left ventricular assist device

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type2 Diabetes Mellitus

Intervention

Drug:
• Empagliflozin
Empagliflozin tablet
• Placebo Oral Tablet
Sugar pill, visually identical to active comparator

Locations

Country	Name	City	State
Denmark	Herlev og Gentofte Hospital	Herlev

Sponsors (4)

Lead Sponsor	Collaborator
Caroline M Kistorp	Danish Heart Foundation, Herlev and Gentofte Hospital, Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (23)

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Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016 May;65(5):1190-5. doi: 10.2337/db15-1356. Epub 2016 Feb 9. — View Citation

Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016 Jul;39(7):1108-14. doi: 10.2337/dc16-0330. — View Citation

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. Erratum in: J Clin Invest. 2014 Apr 1;124(4):1868. — View Citation

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Hartog JW, Voors AA, Bakker SJ, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications. Eur J Heart Fail. 2007 Dec;9(12):1146-55. Review. — View Citation

Hasenfuß G, Hayward C, Burkhoff D, Silvestry FE, McKenzie S, Gustafsson F, Malek F, Van der Heyden J, Lang I, Petrie MC, Cleland JG, Leon M, Kaye DM; REDUCE LAP-HF study investigators. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet. 2016 Mar 26;387(10025):1298-304. doi: 10.1016/S0140-6736(16)00704-2. — View Citation

Jhund PS, Anand IS, Komajda M, Claggett BL, McKelvie RS, Zile MR, Carson PE, McMurray JJ. Changes in N-terminal pro-B-type natriuretic peptide levels and outcomes in heart failure with preserved ejection fraction: an analysis of the I-Preserve study. Eur J Heart Fail. 2015 Aug;17(8):809-17. doi: 10.1002/ejhf.274. Epub 2015 Apr 29. — View Citation

Jørgensen RM, Levitan J, Halevi Z, Puzanov N, Abildstrøm SZ, Messier MD, Huikuri HV, Haarbo J, Thomsen PE, Jons C; CARISMA investigators. Heart rate variability density analysis (Dyx) for identification of appropriate implantable cardioverter defibrillator recipients among elderly patients with acute myocardial infarction and left ventricular systolic dysfunction. Europace. 2015 Dec;17(12):1848-54. doi: 10.1093/europace/euu394. Epub 2015 Mar 8. — View Citation

Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Nakagawa T, Kusaka H, Kim-Mitsuyama S. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014 Oct 26;13:148. doi: 10.1186/s12933-014-0148-1. — View Citation

Mudaliar S, Alloju S, Henry RR. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016 Jul;39(7):1115-22. doi: 10.2337/dc16-0542. — View Citation

Naya M, Murthy VL, Foster CR, Gaber M, Klein J, Hainer J, Dorbala S, Blankstein R, Di Carli MF. Prognostic interplay of coronary artery calcification and underlying vascular dysfunction in patients with suspected coronary artery disease. J Am Coll Cardiol. 2013 May 21;61(20):2098-106. doi: 10.1016/j.jacc.2013.02.029. Epub 2013 Mar 21. — View Citation

Oelze M, Kröller-Schön S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinßius E, Agdauletova S, Gottschlich A, Steven S, Schulz E, Bottari SP, Mayoux E, Münzel T, Daiber A. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One. 2014 Nov 17;9(11):e112394. doi: 10.1371/journal.pone.0112394. eCollection 2014. — View Citation

Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014 Sep;2(9):691-700. doi: 10.1016/S2213-8587(14)70120-2. Epub 2014 Jun 16. Erratum in: Lancet Diabetes Endocrinol. 2015 Sept;3(9):e7. — View Citation

Ruwald AC, Bloch Thomsen PE, Gang U, Jørgensen RM, Huikuri HV, Jons C. New-onset atrial fibrillation predicts malignant arrhythmias in post-myocardial infarction patients--a Cardiac Arrhythmias and RIsk Stratification after acute Myocardial infarction (CARISMA) substudy. Am Heart J. 2013 Nov;166(5):855-63.e3. doi: 10.1016/j.ahj.2013.08.017. Epub 2013 Sep 26. — View Citation

Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia. 2016 Jul;59(7):1333-1339. doi: 10.1007/s00125-016-3956-x. Epub 2016 Apr 25. Review. Erratum in: Diabetologia. 2016 Jul;59(7):1573-4. — View Citation

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von Scholten BJ, Hasbak P, Christensen TE, Ghotbi AA, Kjaer A, Rossing P, Hansen TW. Cardiac (82)Rb PET/CT for fast and non-invasive assessment of microvascular function and structure in asymptomatic patients with type 2 diabetes. Diabetologia. 2016 Feb;59(2):371-8. doi: 10.1007/s00125-015-3799-x. Epub 2015 Nov 2. — View Citation

Willemsen S, Hartog JW, van Veldhuisen DJ, van der Meer P, Roze JF, Jaarsma T, Schalkwijk C, van der Horst IC, Hillege HL, Voors AA. The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction. Am Heart J. 2012 Nov;164(5):742-749.e3. doi: 10.1016/j.ahj.2012.07.027. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rb-82 PET	Between group difference in the change in myocardial flow reserve (MFR) by Rb-82 PET. Measured as change in global perfusion from rest to adenosine-induced stress.	13 weeks
Primary	Invasive hemodynamics	Substudy, performed on 38 participants from the main group. Using right heart catheterisation to measure between group difference in the change in pulmonary capillary weight pressure (PCWP) at 25 watts (supine bicycle ergometer)	13 weeks
Secondary	Echocardiography	Between group difference in the change in global left ventricular function assessed by echocardiography	13 weeks
Secondary	GFR	Between group difference in the change in renal function assessed by Cr-51 EDTA	13 weeks
Secondary	U-alb/crea	Between group difference in the change urinary albumin/creatinine ratio	13 weeks
Secondary	24 hour BP	Between group difference in the change in 24 hour BP	13 weeks
Secondary	Pulse wave analysis	Between group difference in the change in pulse wave analysis	13 weeks
Secondary	Insulin resistance	Between group difference in the changes in insulin resistance by Matsuda index	13 weeks
Secondary	Insulin resistance	Between group difference in the changes in insulin resistance by HOMA	13 weeks
Secondary	Biomarkers	Between group difference in the change in NT-proBNP, MR-proANP, MR-proADM, GAL-3, hsTNT, GDF-15, PIGF, sFlt-1, FFA, ADPN, leptin, TNF-a, IL-6, MCP-1, MAC-1, COLL-A1, FGF-21, beta-hydroxybutyrate, AGEs CML, sRAGE	13 weeks
Secondary	Questionnaires	Between group difference in the change in Health status, assessed by the EuroQol EQ-5D-5L questionnaire	13 weeks
Secondary	Questionnaires, continued	Between group difference in the change in Health status, assessed by the Minnesota Living with Heart Failure questionnaire	13 weeks
Secondary	DEXA	Between group difference in the change in body composition by DEXA scan	13 weeks
Secondary	Invasive hemodynamics - continued	Between group difference in the change in CO at rest, 25 watts and peak exercise	13 weeks
Secondary	Invasive hemodynamics - continued	Between group difference in the change in CVP at rest, 25 watts and peak exercise	13 weeks
Secondary	Invasive hemodynamics - continued	Between group difference in the change in PCWP at rest, 25 watts and peak exercise	13 weeks
Secondary	Invasive hemodynamics - continued	Between group difference in the change in PAP at rest, 25 watts and peak exercise	13 weeks
Secondary	Invasive hemodynamics - continued	Between group difference in the change in SvO2 at rest, 25 watts and peak exercise	13 weeks
Secondary	Adipose tissue	Between group difference in the changes in levels of adipocyte differentiation	13 weeks
Secondary	Adipose tissue	Between group difference in the changes in macrophage infiltration	13 weeks
Secondary	Adipose tissue	Between group difference in the changes in extracellular matrix fibrosis	13 weeks
Secondary	Daily activity	Between group difference in the change in daily activity levels measured by patient-worn accelerometers.	13 weeks