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Type2 Diabetes MellitusPhase 3SIMPLENCT03151343

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

A Phase 3 study testing Empagliflozin in people with Type2 Diabetes Mellitus, run by Caroline M Kistorp at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Type2 Diabetes Mellitus
What is being tested?
Empagliflozin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
92 participants
Where
1 siteDenmark
Study dates
29 Mar 2017to 22 May 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

Denmark1 site

  • Herlev og Gentofte Hospital

    Herlev, 2730

Other trials in Denmark

About this study

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

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.

Being tested
Empagliflozin, Placebo Oral Tablet

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EmpagliflozinDrug

    Also called Jardiance

    Empagliflozin tablet

  • Placebo Oral TabletDrug

    Sugar pill, visually identical to active comparator

Study groups in NCT03151343
Study groupRoleWhat they receive
EmpagliflozinExperimentalEmpagliflozin, coated tablets, 25mg, once daily, for 13 weeks
Receives: Drug: Empagliflozin
PlaceboPlacebo comparatorPlacebo, coated tablets, once daily, for 13 weeks
Receives: Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 13 weeks

  2. 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)

    Measured: 13 weeks

Secondary outcomes (20)

  1. Echocardiography

    Between group difference in the change in global left ventricular function assessed by echocardiography

    Measured: 13 weeks

  2. GFR

    Between group difference in the change in renal function assessed by Cr-51 EDTA

    Measured: 13 weeks

  3. U-alb/crea

    Between group difference in the change urinary albumin/creatinine ratio

    Measured: 13 weeks

  4. 24 hour BP

    Between group difference in the change in 24 hour BP

    Measured: 13 weeks

  5. Pulse wave analysis

    Between group difference in the change in pulse wave analysis

    Measured: 13 weeks

  6. Insulin resistance

    Between group difference in the changes in insulin resistance by Matsuda index

    Measured: 13 weeks

  7. Insulin resistance

    Between group difference in the changes in insulin resistance by HOMA

    Measured: 13 weeks

  8. 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-α, IL-6, MCP-1, MAC-1, COLL-A1, FGF-21, beta-hydroxybutyrate, AGEs CML, sRAGE

    Measured: 13 weeks

  9. Questionnaires

    Between group difference in the change in Health status, assessed by the EuroQol EQ-5D-5L questionnaire

    Measured: 13 weeks

  10. Questionnaires, continued

    Between group difference in the change in Health status, assessed by the Minnesota Living with Heart Failure questionnaire

    Measured: 13 weeks

  11. DEXA

    Between group difference in the change in body composition by DEXA scan

    Measured: 13 weeks

  12. Invasive hemodynamics - continued

    Between group difference in the change in CO at rest, 25 watts and peak exercise

    Measured: 13 weeks

  13. Invasive hemodynamics - continued

    Between group difference in the change in CVP at rest, 25 watts and peak exercise

    Measured: 13 weeks

  14. Invasive hemodynamics - continued

    Between group difference in the change in PCWP at rest, 25 watts and peak exercise

    Measured: 13 weeks

  15. Invasive hemodynamics - continued

    Between group difference in the change in PAP at rest, 25 watts and peak exercise

    Measured: 13 weeks

  16. Invasive hemodynamics - continued

    Between group difference in the change in SvO2 at rest, 25 watts and peak exercise

    Measured: 13 weeks

  17. Adipose tissue

    Between group difference in the changes in levels of adipocyte differentiation

    Measured: 13 weeks

  18. Adipose tissue

    Between group difference in the changes in macrophage infiltration

    Measured: 13 weeks

  19. Adipose tissue

    Between group difference in the changes in extracellular matrix fibrosis

    Measured: 13 weeks

  20. Daily activity

    Between group difference in the change in daily activity levels measured by patient-worn accelerometers.

    Measured: 13 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 May 2017
  2. Study start29 Mar 2017
  3. Primary completion22 May 2020
  4. Study completion22 May 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Participants will be treated with either empagliflozin or placebo
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
92 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03151343
Sponsor's protocol ID
2016-775
Other IDs
2016-003743-10, 2016
Acronym
SIMPLE
Status last verified
Aug 2022
First submitted
12 Mar 2017
Last updated
18 Aug 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: Any sharing of data must be approved by the regional ethics committee, and at the time of protocol writing there was no justification for data sharing outside of the current project

Publications

  • Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015 Mar;12(2):78-89. doi: 10.1177/1479164114561992. Epub 2015 Jan 23.

    PubMed 25616707

  • 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.

    PubMed 26378978

  • 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.

    PubMed 25344694

  • deKemp RA, Yoshinaga K, Beanlands RS. Will 3-dimensional PET-CT enable the routine quantification of myocardial blood flow? J Nucl Cardiol. 2007 May-Jun;14(3):380-97. doi: 10.1016/j.nuclcard.2007.04.006.

    PubMed 17556173

  • 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.

    PubMed 23524053

  • Dorbala S, Di Carli MF, Beanlands RS, Merhige ME, Williams BA, Veledar E, Chow BJ, Min JK, Pencina MJ, Berman DS, Shaw LJ. Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry. J Am Coll Cardiol. 2013 Jan 15;61(2):176-84. doi: 10.1016/j.jacc.2012.09.043. Epub 2012 Dec 5.

    PubMed 23219297

  • 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.

    PubMed 27112340

  • 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.

    PubMed 27025436

  • Ersboll M, Valeur N, Mogensen UM, Andersen M, Greibe R, Moller JE, Hassager C, Sogaard P, Kober L. Global left ventricular longitudinal strain is closely associated with increased neurohormonal activation after acute myocardial infarction in patients with both reduced and preserved ejection fraction: a two-dimensional speckle tracking study. Eur J Heart Fail. 2012 Oct;14(10):1121-9. doi: 10.1093/eurjhf/hfs107. Epub 2012 Jun 28.

    PubMed 22753861

  • 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.

    PubMed 25921853

  • Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 2004 Nov;18(14):1692-700. doi: 10.1096/fj.04-2263com.

    PubMed 15522914

  • 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.

    PubMed 24463454

  • 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.

    PubMed 26861783

  • 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.

    PubMed 27289124

  • 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.

    PubMed 27289126

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Empagliflozin in people with Type2 Diabetes Mellitus, run by Caroline M Kistorp at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rb-82 PET (time frame: 13 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03151343, which also lists 26 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Aug 2022.

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