Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus (or Pre-diabetes) and Heart Failure (SUGAR-DM-HF)
Overview
- Phase
- Phase 4
- Intervention
- Empagliflozin 10 MG
- Conditions
- Heart Failure
- Sponsor
- NHS Greater Glasgow and Clyde
- Enrollment
- 105
- Locations
- 1
- Primary Endpoint
- Left Ventricular End Systolic Volume Index (LVESVI)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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.
Investigators
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
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
Arms & Interventions
Empagliflozin
Empagliflozin 10mg tablets for oral self-administration once daily
Intervention: Empagliflozin 10 MG
Placebo Oral Tablet
placebo tablets for oral self-administration once daily
Intervention: Placebo Oral Tablet
Outcomes
Primary Outcomes
Left Ventricular End Systolic Volume Index (LVESVI)
Time Frame: 36 weeks
Cardiac structure measured by left ventricular end-systolic volume index measured by cardiac magnetic resonance imaging as mL/m2
left ventricular global longitudinal strain (GLS)
Time Frame: 36 weeks
Cardiac structure measured by left ventricular global longitudinal strain measured by cardiac magnetic resonance imaging GLS%
Secondary Outcomes
- Intensification of diuretic therapy(36 weeks)
- Microvascular perfusion(36 weeks)
- Left atrial volume index (LAVI)(36 weeks)
- Extracellular volume fraction(36 weeks)
- 6 minute walk distance (Exercise Capacity)(36 weeks)
- Biomarker profile - uric acid(36 weeks)
- Left ventricular mass index (LVMI)(36 weeks)
- Left ventricular global function index (LVGFI)(36 weeks)
- Pulmonary congestion(36 weeks)
- Biomarker profile -glycated haemaglobin (HbA1c)(36 weeks)
- Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)(36 weeks)
- Biomarker profile - creatine(36 weeks)
- Biomarker profile - liver function tests (LFTs)(36 weeks)
- Left ventricular end diastolic volume index (LVEDVI)(36 weeks)
- Left ventricular ejection fraction (LVEF)(36 weeks)
- Biomarker profile - estimated glomerular filtration rate (eGFR)(36 weeks)