Clinical trial NCT03665350: Insulin Treatment in Diabetic Older People With Heart Failure.
Official title: Management of the Patient With Heart Failure and Diabetes: May Insulin be a Problem? A Pilot Randomized Clinical Study (Insulin-HF)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Heart Failure
Diabetes Mellitus, Type 2
Keywords: Heart Failure
Type 2 diabetes mellitus
Insulin
Older adults
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
First posted: 2018-09-11
Enrollment: 10
Sex: ALL
Minimum age (years): 70
Maximum age (years): 100
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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:

1. patients will be examined,
2. the information about clinical events will be collected.
3. 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. men and women aged ≥70 years;
2. at discharge after admission to hospital for worsening of HF or ambulatory patients with chronic HF;
3. New York Heart Association (NYHA) class II or III
4. with any level of left ventricular ejection fraction;
5. plasma natriuretic peptide (BNP) ≥200 pg/mL or N-terminal pro-BNP ≥900 pg/mL (NT pro-BNP)
6. prior history or newly diagnosed T2DM;
7. candidate by the responsible physician to insulin therapy;
8. signed informed consent.

Exclusion Criteria:

1. 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 \[ULN\]);
2. levels of hemoglobin \<10 g/dl;
3. HbA1c ≤5% or ≥11%;
4. unstable diabetes: type of diabetes presentation in patients with an anamnesis of frequent episodes of hypoglycemia, hyperglycemic hyperosmolar state, ketoacidosis or lactic acidosis;
5. planned CV surgery or angioplasty in 3 months;
6. any non-cardiac disease that shortens life expectancy to\<1 year (e.g.most cancers);
7. inability to comply with study protocol;
8. participation to another interventional clinical study.

Primary outcomes:
measure: Change in blood glucose variability
timeFrame: baseline to 12 months.
Secondary outcomes:
measure: Number of patients with episodes of hypoglycemia.
timeFrame: baseline, 1, 6, 12 months.
measure: Change in body weight.
timeFrame: baseline, 1, 6, 12 months.
measure: Change in plasma concentration of a natriuretic peptide
timeFrame: baseline, 1, 6, 12 months.
measure: Changes in urinary albumin excretion
timeFrame: baseline, 1, 6, 12 months.
measure: Change in New York Heart Association (NYHA) class
timeFrame: baseline, 1, 6, 12 months.
measure: All-cause hospitalizations
timeFrame: baseline to 12 months
measure: Hospitalizations for worsening of HF.
timeFrame: baseline to 12 months
measure: All-cause mortality
timeFrame: baseline to 12 months
measure: Number of patients with episodes of ketoacidosis as evaluation of safety.
timeFrame: baseline to 12 months
measure: Number of patients with episodes of lactic acidosis as evaluation of safety.
timeFrame: baseline to 12 months
measure: Changes in left ventricular ejection fraction (LVEF).
timeFrame: baseline, 1, 6, 12 months.
measure: Changes in E/e'.
timeFrame: baseline, 1, 6, 12 months.
measure: Changes in Hemoglobin A1c (HbA1c).
timeFrame: baseline, 1, 6, 12 months.
Other outcomes:
Locations:
city: Seriate
country: Italy
facility: Ospedale Bolognini di Seriate
state: BG
city: Treviglio
country: Italy
facility: Ospedale Treviglio
state: BG
city: Passirana
country: Italy
facility: Ospedale di Passirana
state: MI
Study officials:
affiliation: Istituto Di Ricerche Farmacologiche Mario Negri
name: Lidia Staszewsky, MD
role: PRINCIPAL_INVESTIGATOR
References:
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