Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects (SUGAR-DM-HF)

Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus (or Pre-diabetes) and Heart Failure (SUGAR-DM-HF)

The investigators hypothesise that empagliflozin 10mg daily will have haemodynamic, cardiac, and renal benefits compared to placebo over 36 weeks in heart failure patients with type 2 diabetes (or pre-diabetes), leading to measurable improvements in clinical measures of cardiac structure and function (LVESVI, and LV strain) as well as renal blood flow.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Diabetes Mellitus
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Placebo Oral Tablet

Detailed Description

The results of the EMPA-REG OUTCOME trial on CVD outcomes and heart failure hospitalisation suggests that empagliflozin works quickly to lessen CVD mortality and reduce heart failure hospitalisations in patients with diabetes and existing cardiovascular disease. The lack of effect on non-fatal MI and stroke would suggest limited impact on atherothrombotic mechanisms. It is important to understand the mechanisms by which empagliflozin is acting in more detail, in order that the drug can be more widely targeted at patient groups that might benefit most; particularly patients with heart failure and diabetes (or pre-diabetes) (as discussed in the rationale).

The investigators have hypothesised, in a detailed published review, that the benefit derives from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of heart failure hospitalisation (HFH) and sudden cardiac death.

The investigators have therefore designed the present trial to perform a comprehensive clinical trial to interrogate in detail the effects of empagliflozin on specific pathways (inclusive of cardiac and renal effects) in patients with type 2 diabetes (or pre-diabetes) and heart failure.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Queen Elizabeth University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent
• Male or female, aged ≥18 years age

• Type 2 DM (diet-controlled or on stable treatment) or prediabetes

  • Stable treatment defined as no change in oral therapy agents or doses for diabetes mellitus and (where applicable) <10% change in average total daily insulin dose over last 6 weeks
  • HbA1c ≤97 mmol/mol (11%) (routine available data from medical records, recorded in the last year)
  • Prediabetes defined as HbA1c 39-47 mmol/mol (5.7-6.4%) at the time of screening (specifically for the prediabetes group, HbA1c will be repeated at the time of screening if there are no recent results within the last 3 months, in order to confirm the diagnosis of prediabetes)

• Heart failure (as defined by the presence of typical signs and symptoms of heart failure with documented reduced ejection fraction (ref SIGN and ESC guidelines))

  • NYHA class II-IV
  • LVEF ≤40%
  • On stable doses of ACEI, ARB or ARNI for 4 weeks prior to randomisation unless contraindicated or not tolerated. They should also be taking a beta-blocker at a stable dose for 4 weeks unless contraindicated or not tolerated

• Women of childbearing potential (WOCBP) must be currently adhering to, or be willing to use, highly effective birth control methods for study treatment duration including:

  • Combined hormonal contraception (oestrogen and progestogen containing medication) either orally, intravaginally, or transdermally
  • Progesterone only hormonal contraception either orally, injected, or implanted
  • Intrauterine device (IUD)
  • Intrauterine hormone release system (IUS)
  • Bilateral fallopian tube occlusion
  • Vasectomised partner
  • Complete sexual abstinence where this is their preferred and usual lifestyle

WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. Post-menopausal is defined as:

o Women who have had amenorrhea for ≥12 consecutive months (without another medical cause)

Exclusion Criteria:

• Type 1 DM
• History of hospital admission with a diagnosis of diabetic ketoacidosis (DKA)
• Insulin use within 1 year of diagnosis of diabetes
• History of acute or chronic pancreatitis
• eGFR <30 ml/min/1.73m2 (derived using CKD EPI)
• Persistent/permanent atrial fibrillation/flutter (conditions which significantly impede MRI image interpretability)
• Acute coronary syndrome, stroke or surgery within 1 month (small type 2 MI in the context of acute HF does not apply)
• BMI >52 kg/m2
• Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening
• Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
• Any condition outside the cardiovascular and renal disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator's clinical judgement
• Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma, adjuvant hormonal therapy for breast cancer and hormone therapy for prostate cancer)
• Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia)
• Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
• Any uncontrolled endocrine disorder except Type 2 DM
• Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
• Known hypersensitivity to the empagliflozin or excipients
• Known hypersensitivity to gadolinium
• Inability to give informed consent
• SGLT2 inhibitor use (current or previous)
• Devices or any other contraindication to MRI scans
• Currently pregnant, planning pregnancy, or currently breastfeeding
• History of previous lower limb amputation
• Current participation in another interventional medical study or within the last 90 days
• Anyone who, in the investigators' opinion, is not suitable to participate in the trial for other reasons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Empagliflozin; Empagliflozin 10mg tablets for oral self-administration once daily	Drug: Empagliflozin 10 MG; Empagliflozin 10mg tablets for oral self administration once a day
PLACEBO_COMPARATOR: Placebo Oral Tablet; placebo tablets for oral self-administration once daily	Drug: Placebo Oral Tablet; placebo tablets for oral self administration once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular End Systolic Volume Index (LVESVI)	Cardiac structure measured by left ventricular end-systolic volume index measured by cardiac magnetic resonance imaging as mL/m2	36 weeks
left ventricular global longitudinal strain (GLS)	Cardiac structure measured by left ventricular global longitudinal strain measured by cardiac magnetic resonance imaging GLS%	36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular end diastolic volume index (LVEDVI)	Left ventricular end diastolic volume index (LVEDVI) measured by Cardiac MR in ml/m2	36 weeks
Left ventricular ejection fraction (LVEF)	Left ventricular ejection fraction (LVEF) measured by Cardiac MR in percentage	36 weeks
Left ventricular mass index (LVMI)	Left ventricular mass index (LVMI) measured by cardiac MR in grams/m2	36 weeks
Left ventricular global function index (LVGFI)	Left ventricular global function index (LVGFI) measured by cardiac MR in percentage	36 weeks
Left atrial volume index (LAVI)	Left atrial volume index (LAVI) measured by cardiac MR in ml/m2	36 weeks
Microvascular perfusion	Microvascular perfusion measured by Gadolinium enhanced Cardiac magnetic resonance imaging measured as ml/min/g	36 weeks
Extracellular volume fraction	Extracellular volume fraction measured by Gadolinium enhanced Cardiac magnetic resonance imaging measured as %	36 weeks
Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)	Kansas City Cardiomyopathy Questionnaire Total Symptom score (TSS) measured by mean overall difference and responder analysis (higher score = better outcome)	36 weeks
6 minute walk distance (Exercise Capacity)	Exercise capacity measured by six minute walk test measured in m	36 weeks
Pulmonary congestion	Pulmonary congestion as B-lines measured using lung ultrasound	36 weeks
Biomarker profile -glycated haemaglobin (HbA1c)	biomarker profile of HbA1c (mmol/mol)	36 weeks
Biomarker profile - creatine	biomarker profile of creatine (umol/L)	36 weeks
Biomarker profile - estimated glomerular filtration rate (eGFR)	biomarker profile of eGFR (ml/min/m2)	36 weeks
Biomarker profile - liver function tests (LFTs)	biomarker profile of LFTs (U/L)	36 weeks
Biomarker profile - uric acid	biomarker profile of uric acid (umol/L)	36 weeks
Intensification of diuretic therapy	Intensification of diuretic therapy through addition and/or increase dose of diuretic medication	36 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular global longitudinal strain (GLS)	Left ventricular global longitudinal strain (GLS) measured by CMR tagging measured in percentage	36 weeks
Left ventricular global circumferential strain (GCS)	Left ventricular global circumferential strain (GCS) measured in CMR featured-tracking and tagging in percentage	36 weeks
Left ventricular global radial strain (GRS)	Left ventricular global radial strain (GRS)measured in CMR featured-tracking and tagging in percentage	36 weeks
total renal blood flow measured by magnetic resonance imaging	total renal blood flow measure using cardiac magnetic resonance imaging measured as ml/min/100g	36 weeks
Renal fibrosis	Renal fibrosis measured by T1 mapping in MRI in miiliseconds	36 weeks
Bioelectrical impedance analysis	Bioelectrical impedance analysis in percentage	36 weeks
Clinical composite outcome of death, hospitalisation with worsening heart failure, ED visit for worsening heart failure, outpatient worsening of heart failure accompanied by increase in HF therapy	Clinical composite outcome of death, hospitalisation with worsening heart failure, ED visit for worsening heart failure, outpatient worsening of heart failure accompanied by increase in HF therapy	36 weeks
Clinical composite analysed using Win-ratio approach	Clinical composite (analysed using Win-ratio approach) outcome of death, hospitalisation with worsening heart failure, ED visit for worsening heart failure, outpatient worsening of heart failure accompanied by increase in HF therapy, KCCQ-TSS >5-point decrease, or no decrease, >30% in NT-proBNP from baseline	36 weeks
Left ventricular diastolic function	Left ventricular diastolic function measured by echocardiogram	36 weeks
DNA and epigenetics	DNA and epigenetic analysis	36 weeks

Collaborators and Investigators

• Sponsor: NHS Greater Glasgow and Clyde
• Collaborators: University of Glasgow
• Investigators: Study Chair: Naveed Sattar, PhD, Glasgow University and NHS GGC

Publications and helpful links

General Publications

• Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.
• 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.
• Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, Berry C, Chong V, Coyle L, Docherty KF, Dreisbach JG, Labinjoh C, Lang NN, Lennie V, McConnachie A, Murphy CL, Petrie CJ, Petrie JR, Speirits IA, Sourbron S, Welsh P, Woodward R, Radjenovic A, Mark PB, McMurray JJV, Jhund PS, Petrie MC, Sattar N. Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation. 2021 Feb 9;143(6):516-525. doi: 10.1161/CIRCULATIONAHA.120.052186. Epub 2020 Nov 13.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 16, 2018
• Primary Completion (ACTUAL): March 28, 2020
• Study Completion (ACTUAL): March 28, 2020

Study Registration Dates

• First Submitted: March 19, 2018
• First Submitted That Met QC Criteria: March 26, 2018
• First Posted (ACTUAL): April 2, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 18, 2020
• Last Update Submitted That Met QC Criteria: September 16, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: heart failure; diabetes mellitus; empagliflozin; Randomised, placebo controlled trial
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: GN15CA580

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No