The Effect of Liraglutide on Left Ventricular Function in Chronic Heart Failure Patients With and Without Type 2 Diabetes Mellitus
Condition: Hyperglycemia; Chronic Heart Failure
MeSH terms: Heart Failure; Hyperglycemia
Study type: Interventional

Summary: 
      Type 2 diabetes (T2D) is a major risk factor of chronic heart failure (CHF). Glycemic control
      in patients with the combination of T2D and CHF is complicated and the currently available
      treatments have proven to be inadequate in clinical trials.

      Objectives To investigate the effect of Liraglutide compared to placebo on left ventricular
      ejection fraction (LVEF) in CHF patients with and without T2D.

      Multicenter, randomized, double blind study of 240 patients with documented systolic CHF (50%
      with T2DM) will be randomised. The effect of Liraglutide on left ventricular systolic and
      diastolic function will be evaluated by advanced echocardiography

      Primary outcome parameter is change in LVEF from visit 1 to week 24.
    

Detailed description: 
      Background The number of patients with diabetes in Denmark has doubled in the preceding
      10-years period and has now increased to 271.000 individuals (5% of the population). T2D is a
      major risk factor of CHF and CHF per se is associated with insulin resistance, thus T2D and
      CHF often co-exists, and is associated with markedly impaired prognosis. Glycemic control in
      patients with the combination of T2D and CHF is complicated and the currently available
      treatments have proven to be inadequate in clinical trials. Therefore, new treatment
      modalities of hyperglycaemia in CHF are warranted.

      Glucagon-like peptide 1 (GLP-1) is a naturally existing hormone, which is secreted from the
      incretine system. A beneficial effect of GLP-1 on cardiac function has recently been
      suggested in small clinical studies, demonstrating improved left ventricular ejection
      fraction (LVEF) in both diabetic and non-diabetic patients. Liraglutide (Victoza®) is a
      GLP-1-analogue developed for the treatment of T2D. However, the impact of Liraglutide on
      cardiac function is currently under investigation.

      Objectives Primary objective: To investigate the effect of Liraglutide 1.8 mg once daily
      compared to placebo on LVEF in CHF patients with and without T2D after 24 weeks of treatment.

      Secondary objectives: To investigate the effect of Liraglutide 1.8 mg once daily compared to
      placebo on left ventricular diastolic function, on plasma levels of NT-proBNP, on symptoms of
      heart failure and quality of life over 24 weeks of treatment.

      Design Multicenter, randomized, double blind study evaluating the impact of 24 weeks
      treatment of Liraglutide versus placebo on cardiac function in CHF patients with and without
      T2D.

      Population A total of 240 patients with documented systolic CHF (50% with T2DM) will be
      randomised. The effect of Liraglutide on left ventricular systolic and diastolic function
      will be evaluated by advanced echocardiography using 2D, 3D, and tissue Doppler imaging.

      Primary outcome parameter is change in LVEF from visit 1 to week 24

      Perspectives Irrespective of the outcome, the study will contribute with essential
      information regarding treatment of CHF. Potentially Liraglutide can improve heart function
      substantially, thus changing the prognosis of CHF-patients worldwide.

      Detailed statistical analyses plan

      Outcomes Primary objective To investigate the effect of liraglutide uptitrated to a maximum
      of 1.8 mg once daily compared with placebo for 24 weeks on the difference in left ventricular
      ejection fraction (LVEF) from baseline to follow-up in chronic heart failure patients (CHF)
      patients with and without type 2 diabetes (T2D).

      Secondary objectives To investigate the effect of liraglutide compared with placebo in terms
      of change from baseline to follow-up of

        1. Left ventricular contractile function measured by I. Global longitudinal strain by
           speckle tracking II. Mitral plane systolic annular max velocity by TDI (s', average of
           six points)

        2. Left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV)

        3. Grade of diastolic function

        4. Functional capacity measured by a 6-minute walk test (6MWT)

        5. Plasma NT-proBNP levels

        6. Blood pressure

        7. Quality of life evaluated by the MLHF questionnaire

        8. Hospitalisations due to cardiovascular disease

        9. All-cause mortality (will be confirmed by the Central Personal Register)

      The investigators who were blinded to liraglutide versus placebo assessed all the outcomes.

      Investigators will analyse data as treatment group A and B, and only when all primary
      analyses have been performed and approved then data can be unblinded. The managing committee
      has contributed to the preparation of the analysis plan and did also approve it.

      Sample size Primary objective The primary outcome parameter is change in LVEF from visit 1 to
      week 24. A total of 241 patients were randomised to allow for approximately 20% of the
      randomised patients with major protocol deviations or withdrawal. With 90% power and with a
      two-sided significance level of 0.05, the sample size analysis estimated the study to detect
      a difference of 2.5% in LVEF in absolute values. The power analysis was based on a standard
      deviation of 6% in delta EF (absolute units). An absolute difference of 2.5% in change from
      baseline between the two treatment groups was based on clinical relevance as determined from
      studies of the impact of ACE inhibitors and betablockers on LVEF. These key outcome
      ACE-inhibitor and key betablocker trials showed a relative risk reduction in outcome of
      approximately 25 - 30% during treatment.

      Stratification The randomisations were performed using two stratification variables: Gender
      (female/male) and diabetes (yes/no).

      Data management Data were collected real time in a custom-made web based electronic case
      record form (eCRF) hosted by an external data management unit at Aarhus University. In
      compliance with GCP, a study manual on collection of endpoints and procedures were developed,
      and quality assurance of relevant instruments collected in sponsors trial master file.

      Data on other adverse events assessed by the investigator as clinically significant,
      including abnormal laboratory values, were collected and recorded on standardised forms at
      each contact. These data were reported to the relevant authorities in accordance with current
      legislation and ICH-GCP guidelines. An unblinded data monitoring committee, consisting of
      independent cardiologists and endocrinologists, were established to evaluate events during
      study conduct.

      Statistical analysis Data will be analysed according to the intention-to-treat principle.
      Sites were encouraged to obtain a final measure of the primary endpoint as soon as possible
      after a patient terminated study medication prematurely. Multiple imputation methods will be
      applied to handle missing data on the primary endpoint.

      A per protocol analysis will also be performed. The per protocol population will consist of
      all patients who completed the study with a documented valid baseline, 24 week assessment of
      the primary objective and no major protocol deviations.

      Data will be analysed as the difference from baseline to follow-up. Normally distributed
      variables will be presented as mean ± standard deviation (SD), whereas non-normally
      distributed variables will be presented as median [range]. Comparisons between groups will be
      performed by an unpaired Student's t-test or ANOVA when data are normally distributed.
      Mann-Whitney U test or Kruskal-Wallis one-way analysis will be used for non-normally
      distributed data. Subgroup analyses will be made with respect to: presence of diabetes, cause
      of heart failure (ischemic/non-ischemic), body mass index, NYHA-class, LVEF above/below mean,
      atrial fibrillation. Linear regression will be used to study correlation between outcome
      parameters and baseline patient characteristics. Categorical variables are presented as
      number and percentage; Chi-square-test is used to compare groups of categorical variables.
      P-values <0.05 are considered statistically significant. All calculations will be performed
      using a commercially available program (SPSS for Windows and Mac, version 22.0).

      Population and handling of missing data Most statistical methods fail to handle any case that
      has a missing value, which may introduce bias or affect the representativeness of the
      results. Imputation preserves all cases by replacing missing data with a probable value based
      on other available information in the data set. Once all missing values have been imputed,
      the data set can then be analysed using standard techniques for complete data. Imputation
      methods will be applied to handle missing data on the primary endpoint.

      Characteristics of patients at baseline A description of baseline characteristics by
      intervention group will be presented. Discrete variables will be summarised by frequencies
      and percentages. Percentages will be calculated according to the total number of patients in
      the particular group.

      Continuous variables will be summarised using standard measures of central tendency and
      dispersion using either mean ± SD for data with normal distribution or median and
      interquartile range for non-normally distributed data.

      Outline of figures and tables The first figure will be a consort flow chart of respectively
      GLP-1 versus placebo. The first tables will describe the baseline characteristics. Follow-up
      data will be described in tables.
    

Intervention name(s): liraglutide; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1.8 mg sc QOD; 1 U sc QOD
Other intervention name(s): Victoza
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: CHF, Diabetes; Liraglutid, Ecco