Insulin Treatment in Diabetic Older People With Heart Failure.

Study Overview
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Brief Summary
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Cardiac failure (HF) and type 2 diabetes mellitus (T2DM) are two clinical conditions with a significant impact on public health worldwide. In the elderly population the prevalence of T2DM is constantly increasing as well as its incidence in all Western countries including Italy. The combination of HF and T2DM is frequent and leads to an increased risk of death and of non-fatal adverse cardiovascular (CV) events which justifies the frailty of this population. Although diabetic patients (pts) with HF respond to recommended treatments for HF, the effective and safe control of blood glucose levels is still an outstanding clinical problem, since glucose lowering drugs may increase the risk of CV adverse events. Insulin, used in about 30% of diabetic patients with HF, causes adverse effects such as fluid and sodium retention and unwanted effects of hypoglycemia. Even if insulin remains a milestone in glucose lowering therapy of T2DM, its risk/benefit ratio is still controversial, more so when given to old patients with HF. The issue has gained relevance since new antidiabetic agents, as the sodium glucose co-transporter 2 (SGLT- 2) inhibitors and glucagon-like peptide (GLP-1) analogues, with a safer CV profile have been made available. While the transferability of the CV benefits attributed to the new drugs needs to be assessed in clinical practice, the present study explore the benefit/risk profile of insulin in HF. Objectives: to assess comparatively in patients with heart failure and T2DM the benefit/risk profile over 1-year follow-up of two antidiabetic strategies, standard care with vs without insulin in terms of humoral and clinical endpoints including body weight change, all-cause mortality and burden of care components (hospitalizations for CV events and episodes of severe hypoglycemia).

Detailed Description
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The project will consist in a controlled, randomized, open-label (PROBE design) multicenter, pilot study. Central randomization stratified by center, performed online, will allow a comparison of two groups of patients one receiving standard care including insulin, the other standard care without insulin. Patients considered not eligible for randomization will be included in a registry. The first objective of this exploratory randomized study is to assess in patients with heart failure and T2DM if a standard anti-diabetic strategy which includes insulin has a different safety and efficacy profile than one without insulin. The number of patients to be included in this exploratory pilot study will be insufficient to prove or disprove a statistically significant beneficial effect of the two antidiabetic strategies on clinical events. Special care will be paid to the biologic consistency of the different endpoints, primary and secondary, even if none of them will individually yield statistically significant differences.

Official Title
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Management of the Patient With Heart Failure and Diabetes: May Insulin be a Problem? A Pilot Randomized Clinical Study (Insulin-HF)

Conditions
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Heart Failure, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women aged ≥70 years; at discharge after admission to hospital for worsening of HF or ambulatory patients with chronic HF; New York Heart Association (NYHA) class II or III with any level of left ventricular ejection fraction; plasma natriuretic peptide (BNP) ≥200 pg/mL or N-terminal pro-BNP ≥900 pg/mL (NT pro-BNP) prior history or newly diagnosed T2DM; candidate by the responsible physician to insulin therapy; signed informed consent. Exclusion Criteria: significant renal insufficiency (GFR <30 mL/min/1.73 m2) or severe liver disease (liver function test abnormalities (alanine or aspartate aminotransferase ≥ 3 × upper limit of normal [ULN]); levels of hemoglobin <10 g/dl; HbA1c ≤5% or ≥11%; unstable diabetes: type of diabetes presentation in patients with an anamnesis of frequent episodes of hypoglycemia, hyperglycemic hyperosmolar state, ketoacidosis or lactic acidosis; planned CV surgery or angioplasty in 3 months; any non-cardiac disease that shortens life expectancy to<1 year (e.g.most cancers); inability to comply with study protocol; participation to another interventional clinical study.

Ages Eligible for Study
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Minimum Age: 70 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The primary endpoint, glucose variability, will be computed from 3 daily glucose profiles performed before the baseline, 1, 6, 12 mo follow-up and at end study visit and calculated as the average of the three daily standard deviations. Blood glucose values will be reported by the patient in an ad hoc form and the responsible physician will input this data in the e-CRF. An intensive ambulatory self-monitoring of weekly body weight and possible changes in diuretic treatment is required. At 1, 6, 12 mo of follow up and/or at end of study visit: patients will be examined, the information about clinical events will be collected. natriuretic peptide plasma concentration, HbA1c and urinary albumin excretion will be measured Echocardiographic evaluation will be done at baseline, 1 and 12 mo after randomization. Central randomization in a 1:1 ratio will be performed by a web-based system.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: non insulin<br>standard care + antidiabetic therapy non insulin | |
| Experimental: Insulin<br>standard care including insulin | Drug: Insulin<br>* Insulin as well as oral anti-diabetic drugs will be prescribed by the responsible physician and/or the diabetologist from each participating site, in conformity with the current guidelines, and the therapeutic target chosen according to patient characteristics. The choice of anti-diabetic medications should be guided by medical needs of each patient and taking into consideration their general safety profile.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood glucose variability | Mean change from baseline to 12 months in glucose variability. Glucose variability is estimated as standard deviation (SD) of serial glycemic values, and is based on 3 daily glucose profiles (each with at least 5 self-measurements of blood glucose). | baseline to 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with episodes of hypoglycemia. | Hypoglycemic episodes: an event accompanied or not accompanied by typical symptoms but with a measured plasma glucose concentration ≤70 mg/dl (3.9 mmol/l). | baseline, 1, 6, 12 months. | 
| Change in body weight. | Weight will be measured in Kg. An increase in body weight ≥2 kg gain in one week will be considered a marker of fluid congestion. | baseline, 1, 6, 12 months. | 
| Change in plasma concentration of a natriuretic peptide | BNP or NT-proBNP concentrations will be measured as ng/L of plasma. | baseline, 1, 6, 12 months. | 
| Changes in urinary albumin excretion | Urinary albumin concentration will be expressed as the urinary albumin-to-creatinine ratio (UACR), measured in milligrams per grams of creatinine, with a limit of detection of 1.5 mg/g. | baseline, 1, 6, 12 months. | 
| Change in New York Heart Association (NYHA) class | Any change in NYHA class. The New York Heart Association (NYHA) Functional Classification places patients in one of four categories (I through IV) based on heart failure symptoms and functional limitations. Higher NYHA classes indicate a greater heart failure severity and poorer outcome. | baseline, 1, 6, 12 months. | 
| All-cause hospitalizations | Number of patients admitted to hospital for any cause. | baseline to 12 months | 
| Hospitalizations for worsening of HF. | Number of patients admitted to hospital for worsening of HF. | baseline to 12 months | 
| All-cause mortality | Number of patients who died for cardiovascular and non-cardiovascular causes. | baseline to 12 months | 
| Number of patients with episodes of ketoacidosis as evaluation of safety. | Ketoacidosis is defined as the presence of at least two of the following factors: a) elevated plasma glucose (>250 mg/dL), b) ketones in serum or urine and c) acidosis (serum bicarbonate <18 mEq/L and/or pH <7.30). | baseline to 12 months | 
| Number of patients with episodes of lactic acidosis as evaluation of safety. | Lactic acidosis is characterized by persistently increased blood lactate levels (usually >5 mmol/L) in association with metabolic acidosis. | baseline to 12 months | 
| Changes in left ventricular ejection fraction (LVEF). | LVEF will be calculated from left ventricular volume in diastole and systole estimated by echocardiography. LVEF will be measured as percentage. A decrease in LVEF will be taken as a marker of worsening of cardiac function. | baseline, 1, 6, 12 months. | 
| Changes in E/e'. | E/e' ratio will be calculated from echo-Doppler recordings. As a ratio it will not have a unit of measure. | baseline, 1, 6, 12 months. | 
| Changes in Hemoglobin A1c (HbA1c). | HbA1c will be measured as percentage of total hemoglobin concentration. | baseline, 1, 6, 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Type 2 diabetes mellitus, Insulin, Older adults