Liraglutide and Heart Failure in Type 2 Diabetes
Condition: Congestive Heart Failure; Type 2 Diabetes Mellitus
MeSH terms: Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with insulinotropic
      properties. Apart from the glycemic actions, cardiovascular effects by GLP-1 have recently
      been reviewed. Receptors for GLP-1 are expressed in the rodent and human heart and acute
      activation of GLP-1 signalling has been shown to influence e.g. heart rate and blood
      pressure. In a knock-out mouse model, GLP-1R-/- mice exhibited a defective cardiovascular
      contractile response together with left ventricular hypertrophy. GLP-1 improves severe left
      ventricular heart failure in humans suffering from a myocardial infarction. Hence, it has
      been demonstrated that GLP-1 exerts direct functional effects through both GLP-1 receptor
      dependent and independent pathways in the heart.

      Native GLP-1 is an extremely short acting peptide, with a half-time breakdown of 1-2 minutes,
      a feature that makes it unsuitable as a drug treatment for type 2 diabetes. To this end,
      several long-acting GLP-1 analogues, drugs for treating type 2 diabetes, have been tested for
      this purpose. The analogue liraglutide exerts its effects via the native GLP-1 receptor,
      localized not only on the pancreatic β-cells, but also in the human heart. Interestingly,
      liraglutide has been demonstrated to have beneficial effect on heart function in mice. Taken
      together, recent data shows that GLP-1 and its stable analogue liraglutide exert beneficial
      cardiovascular effects.

      The purpose of this study is to determine whether the glucagon-like peptide-1 (GLP-1)
      analogue liraglutide improves heart function (measured as left ventricle longitudinal
      function and/or functional reserve during rest and/or after exercise) after 18 weeks of
      liraglutide + metformin, compared with glimepiride + metformin, using tissue Doppler
      echocardiography.
    

Detailed description: 
      The subjects will attend a screening visit (Visit 1) in order to assess their eligibility. If
      found eligible, the subjects will return at Visit 2 within approximately 4 weeks, after Visit
      1, with an up-titration with metformin 1 g BID or the maximal tolerated dosage of metformin
      (Run-in period).

      At Visit 2 patients will be tested for;

        -  Heart function at rest and during an exercise ECG Stress Test with tissue Doppler
           echocardiography

        -  24-hour blood pressure

        -  Anthropometric assessment

        -  Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).

        -  Quality of life (SF 36)

        -  Blood test (venipuncture)

      Subsequently thereafter, subjects will during visit 2 be randomized to receive either
      liraglutide 1.8 mg s.c. (initial dose of 0.6 mg with an up-titration of 0.6 mg every week,
      final dose 1.8 mg QD) or glimepiride 4 mg p.o (initial dose of 2 mg, with an up-titration of
      1 mg every week, final dose 4 mg QD).

      At Visit 2, subjects will be supplied with a glucose meter (Abbot Contour) and instruction on
      use of the device including regular calibration according to the manufacturer's instruction.
      Subjects will be instructed on how to record the results of the self measured plasma glucose
      (SMPG) values in the meter. Subjects will then ask to monitor a 7 point profile glucose curve
      consecutively in three days before visit 3, at visit 4 and at the end of treatment (visit 5).
      SMBG values will be transferred via a computerized system (Diasend®).

      Visit 3. Telephone visit. Self-reporting glucose measurements.

      Visit 4. Telephone visit. Self-reporting glucose measurements.

      At week 18 (Visit 5), subjects will be re-tested for:

        -  Heart function at rest and during an exercise ECG Stress Test with tissue Doppler
           echocardiography

        -  24-hour blood pressure

        -  Anthropometric assessment

        -  Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).

        -  Quality of life (SF 36)

        -  Blood test (venipuncture)
    

Intervention name(s): liraglutide; glimepiride; Metformin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 1.8 mg s.c. (QD); 4 mg p.o. (QD); 500 mg p.o. (BID)
Intervention MeSH terms: Metformin; Liraglutide; Glimepiride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Congestive Heart Failure; Type 2 Diabetes Mellitus; GLP-1; Liraglutide