Clinical trial NCT03485092: Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects
Official title: Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus (or Pre-diabetes) and Heart Failure (SUGAR-DM-HF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Diabetes Mellitus
Keywords: heart failure
diabetes mellitus
empagliflozin
Randomised, placebo controlled trial
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
First posted: 2018-04-02
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, placebo controlled trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Left Ventricular End Systolic Volume Index (LVESVI)
timeFrame: 36 weeks
measure: left ventricular global longitudinal strain (GLS)
timeFrame: 36 weeks
Secondary outcomes:
measure: Left ventricular end diastolic volume index (LVEDVI)
timeFrame: 36 weeks
measure: Left ventricular ejection fraction (LVEF)
timeFrame: 36 weeks
measure: Left ventricular mass index (LVMI)
timeFrame: 36 weeks
measure: Left ventricular global function index (LVGFI)
timeFrame: 36 weeks
measure: Left atrial volume index (LAVI)
timeFrame: 36 weeks
measure: Microvascular perfusion
timeFrame: 36 weeks
measure: Extracellular volume fraction
timeFrame: 36 weeks
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
timeFrame: 36 weeks
measure: 6 minute walk distance (Exercise Capacity)
timeFrame: 36 weeks
measure: Pulmonary congestion
timeFrame: 36 weeks
measure: Biomarker profile -glycated haemaglobin (HbA1c)
timeFrame: 36 weeks
measure: Biomarker profile - creatine
timeFrame: 36 weeks
measure: Biomarker profile - estimated glomerular filtration rate (eGFR)
timeFrame: 36 weeks
measure: Biomarker profile - liver function tests (LFTs)
timeFrame: 36 weeks
measure: Biomarker profile - uric acid
timeFrame: 36 weeks
measure: Intensification of diuretic therapy
timeFrame: 36 weeks
Other outcomes:
measure: Left ventricular global longitudinal strain (GLS)
timeFrame: 36 weeks
measure: Left ventricular global circumferential strain (GCS)
timeFrame: 36 weeks
measure: Left ventricular global radial strain (GRS)
timeFrame: 36 weeks
measure: total renal blood flow measured by magnetic resonance imaging
timeFrame: 36 weeks
measure: Renal fibrosis
timeFrame: 36 weeks
measure: Bioelectrical impedance analysis
timeFrame: 36 weeks
measure: 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
timeFrame: 36 weeks
measure: Clinical composite analysed using Win-ratio approach
timeFrame: 36 weeks
measure: Left ventricular diastolic function
timeFrame: 36 weeks
measure: DNA and epigenetics
timeFrame: 36 weeks
Locations:
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
state: Scotland
Study officials:
affiliation: Glasgow University and NHS GGC
name: Naveed Sattar, PhD
role: STUDY_CHAIR
References:
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.
citation: 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.
citation: 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.