Is Glucagon-like Peptide-1 Insufficiency a Residual Risk in Coronary Artery Disease?
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Observational

Summary: 
      In this study, the investigators hypothesized that significant proportion of patients with
      coronary artery disease (CAD) has reduced capacity of glucagon-like peptide-1 (GLP-1)
      secretion, which is detectable as blunted response of plasma active GLP-1 level to oral
      glucose loading and that reduced GLP-1 secretory function is associated with increased
      severity of coronary artery stenosis but not with classic risk factors for CAD. To test this
      hypothesis, the investigators will analyze correlation between GLP-1 secretory capacity and
      severity of coronary artery stenosis determined by Gensini Score (GS), an established score
      system for coronary artery stenoses. Additionally, the investigators will analyze
      relationship between level of "total" GLP-1 and severity of coronary artery stenosis to
      determine how it is different from the active GLP-1 - coronary stenosis relationship.
    

Detailed description: 
      Recently, the investigators found that a significant proportion of subjects in a general
      population shows attenuated secretion of active GLP-1 in response to oral glucose loading and
      that the insufficient secretion of GLP-1 was independently associated with elevation of blood
      pressure (BP) (Yoshihara et al. PLoS One 2013;8:e67578). In that study, it was also found
      that the amount of GLP-1 secreted after glucose loading was not correlated with any of
      conventional serum lipid parameters (i.e., triglyceride, LDL-cholesterol and HDL-cholesterol)
      or plasma insulin level. These findings suggest that insufficiency of GLP-1 secretion may
      promote atherosclerosis and formation of coronary plaques. Furthermore, lack of correlation
      between response of active GLP-1 secretion and serum lipids or plasma insulin indicates that
      insufficient secretion of active GLP-1 may be a hidden risk factor of atherosclerotic
      vascular disease. Based on those results in a previous study, the investigators designed the
      present study.

      The present study is a single-centered (Sapporo Medical University Hospital), observational
      study enrolling patients who will be admitted to our institute for coronary angiogram.
      Written informed consent will be obtained from patients on admission. Patients will receive
      demographic measurements, blood sampling for routine serum biochemistry and detailed analyses
      of serum lipids (such as apolipoproteins, remnant-like lipoprotein particle and
      oxidized-LDL-cholesterol) after overnight fast and oral glucose tolerance test (OGTT). In
      OGTT, blood will be sampled for assay of glucose, insulin, active GLP-1 and total GLP-1
      before, 30 min, 60 min, and 120 min after oral 75 g-glucose loading. Capacity of GLP-1
      secretion will be determined as area under the curve of plasma GLP-1 level (AUC-GLP-1). All
      study subjects will undergo coronary angiogram and severity of coronary artery stenosis will
      be quantified by Gensini score (GS). Relationship between GS, AUC-active-GLP-1 or
      AUC-total-GLP-1, blood pressure, serum lipid parameters, and indices of insulin resistance
      (homeostasis model assessment as an index of insulin resistance and Matsuda-Defronzo index)
      will be examined by use of univariate and multivariate regression analyses to determine
      whether AUC-active-GLP-1 or AUC-total-GLP-1 is an independent determinant of coronary artery
      stenosis. This study will be conducted as one of projects in BOREAS registry, a
      non-interventional, multicenter registry of cardiovascular and/or renal diseases conducted by
      our institute and affiliated hospitals.

      The time frame for which the outcome measures is assessed: Informed consent on Hospital day
      1, Demographic examinations and blood and urine tests on Hospital day 1 and day 2, OGTT on
      Hospital day 2 or day 3, Coronary angiogram and scoring coronary stenoses on Hospital day 3
      or a later day within 14 days after admission (patients who could not undergo angiogram
      within 14 days after admission by incidental causes will be excluded), Acquisition of data
      necessary for analyses on Day 9-17 (Data set of each patients, including remnant-like protein
      particle, ApoA1, ApoB, and ApoE, will be mostly completed within approximately 9-17 days
      after admission. Samples for determination of GLP-1 will be stored at -80 C until assay).
    

Intervention name(s): Determination of plasma GLP-1 level
Intervention type(s): Other
Intervention description(s): Determination of GLP-1 level in samples of oral glucose tolerance tests
Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Non-diabetic patients with suspected or diagnosed CAD who are hospitalized for coronary
        angiogram will be enrolled in this study. The patients are expected to be similar to those
        who have visited our institute recently; approximately 28% of patients with CAD are
        diabetics, and one third of them are medically untreated at the time of their first visit.
        In recent years, 500-600 patients have undergone coronary angiography per year in this
        institute, and approximately 50% of them were without history of percutaneous coronary
        interventions (PCI) or coronary bypass surgery. Hence, approximately 180-210 patients per
        year will be candidates for the present project.
      
Keywords: GLP-1