Glucagon-like Peptide-1 and Coronary Microvascular Dysfunction in Women With Angina Pectoris and no Coronary Stenosis
Condition: Microvascular Angina
MeSH terms: Angina Pectoris; Microvascular Angina
Study type: Interventional
Phase: Phase 4

Summary: 
      The aim of the present study is to evaluate the effect of treatment with Liraglutide on the
      coronary microvasculature and angina symptoms, in overweight patients with microvascular
      dysfunction and angina pectoris but no coronary artery stenosis.
    

Detailed description: 
      Background:

      Patients with symptoms and signs of ischemia are referred to coronary angiography (CAG) or CT
      angiography (CT-CAG). A significant proportion of these patients and especially women appear
      to have no obstructive coronary stenosis. Patients with angina-like symptoms and no
      macrovascular coronary stenosis have previously been considered without increased risk of
      major cardiovascular events, but novel data indicate that this assumption may not be true.

      Abnormal coronary flow and metabolic response to stress have been reported, which is
      consistent with a possible microvascular ethology for the symptoms. Both endothelium- and
      non-endothelium dependent impaired coronary reactivity may contribute. The endothelium
      dependent component has been linked to risk factors and pro-inflammatory processes promoting
      atherosclerosis. The non-endothelium dependent mechanisms may involve vascular smooth muscle
      cells, undergoing alterations in phenotype in response to physiological and
      pathophysiological stimuli like hypertension and diabetes.

      Both invasive and non-invasive diagnostic methods are available for the assessment of
      coronary microvascular dysfunction. In the absence of a flow limiting stenosis upstream,
      indirect measurement is possible by using transthoracic Doppler stress echocardiography
      (TTDSE). TTDSE provides assessment of coronary blood flow velocity in one of the major
      coronary vessels that can be used to determine coronary flow velocity reserve (CFR) after
      hyperemia. This method does primarily assess the non-endothelium dependent component of
      coronary microvascular dysfunction.

      Despite reassurance that no stenosis on major coronary vessels is found, many patients
      continue to have chest pain resulting in emergency visits, hospitalizations and repeat
      cardiac catheterizations with adverse effect on quality of life, employment and health care
      costs.

      Treatment options for patients with angina symptoms are lacking when no macrovascular
      coronary stenosis is found. Standard anti-angina treatments are usually tried, but do not
      relieve symptoms in many of these patients.

      Preclinical studies with Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor (GLP-1R) agonists
      demonstrate cardioprotective effects. However, the underlying mechanisms are often not well
      defined. Many studies do not distinguish between direct versus indirect actions of GLP-1R
      agonists, nor take into account the potential actions of the cleavage product, GLP-1. GLP-1R
      is found in atrial cardiomyocytes in animal models and in the sinoatrial node in humans.
      Furthermore endothelial cells and vascular smooth muscle cells seem to be targets for GLP-1
      action. In animal models GLP-1 promotes myocardial glucose uptake independent of insulin,
      increases contractility and coronary flow and improves outcome and survival after myocardial
      infarction in vivo. Limited data exists on the cardioprotective effect of GLP-1 in humans. A
      few studies have evaluated the effect of GLP-1 in patients presenting acute myocardial
      infarction or stenosis of major coronary vessels, whereas no data exists on the effect in
      patients with stable coronary artery disease. Two randomized studies have investigated the
      effect of GLP-1 infusion in ST-elevation acute myocardial infarction, and found reduced
      infarct size at three months follow-up. Several small pilot studies in patients with coronary
      heart disease have found that GLP-1 infusion or dipeptidyl peptidase-4 inhibitor improves
      left ventricular ejection fraction. None of the human trials have involved prolonged
      treatment with GLP-1.

      Data from previous work suggest that GLP-1 and weight loss may have beneficial effects on
      microvascular circulation and cardiovascular risk factors. In a small cross-over study of 20
      patients with type2 diabetes but no angina, 10 weeks of GLP1-R agonist treatment
      (Liraglutide, 1,2 mg/day) led to a small but insignificant improvement in coronary
      microcirculation, concomitant with a significant decrease in body weight and blood pressure
      and improvement in glycemic control. Another study included overweight patients with ischemic
      heart disease and found, that a mean weight loss of 10.6% achieved through a low energy diet
      improved microvascular function (CFR) and coronary risk factors such as blood pressure, lipid
      profile, and glycemic control (non-diabetics) as well as symptoms. Thus data on any
      cardioprotective effect of long-term treatment with GLP-1 in humans is sparse, and it may be
      speculated that any beneficial effect may be due to the weight lowering effect.

      Objective The aim of the present study is to evaluate the effect of treatment with
      Liraglutide on the coronary microvasculature and angina symptoms, in overweight patients with
      microvascular dysfunction (CFR≤2,5) and angina pectoris but no coronary artery stenosis.

      Hypothesis Liraglutide improves microvascular function and alleviates symptoms in women with
      angina pectoris and microvascular coronary dysfunction, but no obstructive stenosis of major
      coronary vessels.

      Design An open label trial consisting of a four-weeks control period without intervention,
      followed by Liraglutide 3 mg once daily for 12 weeks + 2 weeks of weight maintenance diet.
      Study participants will serve as their own controls during the first four weeks not receiving
      treatment. Outcome parameters will be measured at baseline and at 4 and 18 weeks. The first
      two measurements (baseline and four weeks measurements) will in this way serve as
      documentation of the variance of repeated measurements. Blinding of participants and
      investigators will not be possible due to the study setup, but investigators will be blinded
      to pre- and posttreatment measurements when analysing results at the end of the study.
      Furthermore investigator will be blinded to previous CFR measurements during data collection.

      Study drug Liraglutide s a once daily human GLP-1 analogue with 97% linear amino-acid
      sequence homology to human GLP-1. Liraglutide works by stimulating the release of insulin
      only when glucose levels become too high and by inhibiting appetite. It lowers blood glucose
      with the unique advantage that glucose lowering ceases when blood glucose gets into the
      normal range. Liraglutide is approved in the EU and US for the treatment of type 2 diabetes
      mellitus at doses up to 1,8 mg administered subcutaneously once daily. Recently the US Food
      and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved
      Liraglutide as obesity treatment. The indication is as an adjunct to lifestyle modifications
      for chronic weight management in individuals with a body mass index (BMI) of ≥30 kg/m2, or
      BMI≥27 kg/m2 with at least one weight-related comorbidity such as dysglycaemia (pre-diabetes
      or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea. The
      max dose for obesity treatment is 3.0 mg daily.

      When prescribed with the aim of weight loss, Liraglutide is administrated subcutaneously and
      titrated up to the maximally recommended dosage for obesity. By treating participants on the
      indication overweight interference with other antihyperglycemic medications is avoided.
      Treatment is initiated with 0.6 mg once daily for one week and increased weekly until the
      recommended max dose of 3 mg. If it is not possible to reach maximal dosage due to adverse
      effects, the participants will stay at the highest dose tolerated. Participants will be
      excluded if they do not tolerate a treatment dose of at least 1.2 mg Liraglutide per day,
      since a lower dosage is unlikely to result in a weight loss of at least 5% .Treatment
      duration will be 12 weeks and the last two weeks will consist of a weight maintenance diet
      before outcome measurements are done. On this dosage and duration a weight loss of at least
      5% is expected. Participants will be advised to reduce calorie intake and increase physical
      activity. Control of compliance will be made at visits by telephone calls (structured open
      questions interviews) Furthermore participants will note every time the medication is taken
      in a diary.

      Participants Study participants will be recruited from an ongoing multicenter study of women
      with symptoms and signs of angina pectoris, 'Improving diagnosis and treatment of women with
      angina pectoris and microvascular disease (iPower)'. Before inclusion in the iPower study,
      participants have undergone CAG or CT-CAG with no significant stenosis of major coronary
      vessels. As part of the iPower study the coronary flow reserve is measured by transthoracic
      doppler stress echocardiography with dipyridamole induces stress.

      Diagnostic methods Fasting blood samples will be collected. Some of the blood samples will be
      stored in a biobank. Blood samples will be stored until the end of the study (last patient,
      last visit) plus five years, and the blood samples will be destroyed thereafter.

      Angina symptoms will be assess by the Seattle Angina Questionnaire (SAQ) which is a 19-item
      health-related quality-of-life measure for patients with coronary artery disease.

      A score change of 10 points is clinically perceptible to patients and is considered a
      clinically relevant difference, while a substantial change is considered to be a change of 20
      points.

      Echocardiographic measurements of CFR, systolic and diastolic function including strain will
      be done both at rest and during dipyridamole induced stress. CFR is calculated as the ratio
      between coronary flow velocity during hyperemia and rest. Coronary microvascular dysfunction
      is defined as CFR<2.5.

      Endothelial function will be measured by flow mediated dilation (FMD). Peripheral endothelial
      function correlates well with coronary endothelial function.

      A whole body dual X-ray absorptiometry (DEXA) scan will be performed at baseline and after 18
      weeks to estimate body composition.

      Statistics There are two main outcomes: Microvascular function assessed by CFR and symptom
      burden assessed by SAQ.

      CFR is a continuous response variable. A difference in repeated measurements within each
      subject is found to be normally distributed with a standard deviation 0.35. If the mean
      change in CFR post treatment is 0.23, the investigators will need to study 27 subjects to be
      able to reject the null hypothesis that there will be no change in the mean CFR with
      probability (power) 0.9. The Type I error probability associated with this test of the null
      hypothesis is 0.05. At least 33 participants will be included in anticipation of around 20%
      drop-out.

      SAQ has four subscales each with a score from 1-100. According to previous studies a change
      in SAQ score of 10 points is perceptible by the patients and therefore clinically meaningful.
      The investigators have not found data on within-study subject variation on SAQ. However,
      previous trials have obtained changes in SAQ of 10-20 points after an intervention. Based on
      these findings the investigators expect to see a change in SAQ score of at least 10 point. By
      estimating a SD of 15, it is calculated that 26 study subjects is sufficient to attain a
      statistical power of >90% to detect a significant difference of 10 points post treatment in
      any SAQ item.

      For the remaining secondary outcomes, if the response is normally distributed, the
      investigators will be able to detect a true difference in the mean response of participants
      of 0.66 x the SD of the within group change with a probability (power) 0.9. The Type I error
      probability associated with this test of the null hypothesis, that the population mean is
      unchanged after the intervention, is 0.05.

      Monitoring:

      The study will be monitored by the unit for Good Clinical Practice (GCP-unit) at the
      University of Copenhagen. Quality checks of data, data registry procedures and source data
      verification will be performed by the GCP-unit.
    

Intervention name(s): Liraglutide
Intervention type(s): Drug
Intervention description(s): Liraglutide up to 3 mg daily injected subcutaneously (minimum 1.2 mg daily) for 12 weeks.
Weight maintenance diet for 2 weeks
Other intervention name(s): Victoza
Intervention MeSH terms: Liraglutide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment