Clinical trial NCT01021865: Effects of Hyperglycemia on Myocardial Perfusion in Humans With and Without Type 2 Diabetes
Official title: Effects of Hyperglycemia on Myocardial Perfusion in Humans With and Without Type 2 Diabetes: Modulation by Glucagon-Like-Peptide-1
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Coronary Artery Disease
Diabetes Mellitus Type 2
Keywords: GLP-1
Myocardial contrast echocardiography
Myocardial perfusion
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: University of Nebraska
name: Astellas Pharma US, Inc.
name: Lantheus Medical Imaging
First posted: 2009-11-30
Enrollment: 33
Sex: ALL
Minimum age (years): 40
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 25 subjects with type 2 diabetes and 25non-diabetic subjects matched for age, gender and degree of obesity will be studied.

The diabetic subjects will be between 40 and 60 years of age and will have a body mass index of \< or =35 kg/m2. Diabetic subjects treated according to ADA guidelines will be eligible for study including a blood pressure \< 140/90, LDL cholesterol \< 130 mg/dl, HDL cholesterol \>40 mg/dl and triglycerides \<200 mg/dl.

All nondiabetic subjects will not have a history of diabetes in their first degree family members. None of the subjects will have any overt evidence of cardiac, renal, pulmonary or hepatic disorder nor will they be engaging in regular vigorous physical activities. All subjects will undergo a resting ECG and a treadmill ECG test to ensure that they do not have active or occult coronary artery disease unless such testing had been completed within six months of enrollment and reported as normal.

Brief summary: The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion at rest and during vasodilator stress (to ascertain coronary flow reserve) while subjects are under controlled pancreatic clamp conditions during euglycemia (glucose \~100 mg/dl) and hyperglycemia (glucose \~250 mg/dl) in the presence and absence of concomitant GLP-1 infusion. The investigators believe that the translational significance of their studies is immense, impacting upon both acute and chronic cardiovascular disease manifestations. The effect of glycemic control on cardiovascular outcomes, morbidity and mortality remains an area of active investigation, fueled by the recent conflicting results of several large clinical trials (ACCORD, United Kingdom Prospective Diabetes Study (UKPDS), ADVANCE, VADT). If the investigators find that hyperglycemia is associated with altered myocardial perfusion, the mechanistic implications in the prevention and management of acute and chronic cardiovascular diseases in DM will be groundbreaking. Furthermore, if GLP-1 augments myocardial perfusion (as it does in the peripheral vasculature), the therapeutic benefits for prevention of cardiovascular events in this predisposed population are clear.


Eligibility criteria: Inclusion Criteria:

* Males and females
* Age 40-60 years
* BMI\< or = 35 kg/m2
* Diabetic subjects with HbA1c concentrations of \< or = 8%.
* Diabetic subjects will be either on diet and lifestyle therapy alone, or monotherapy with metformin or sulphonylureas (except glyburide).
* All diabetic subjects should be on stable dose oral agent therapy for 3 months prior to enrollment.

Exclusion Criteria:

* Subjects with cerebrovascular or peripheral vascular disease.
* Subjects with suspected or overt autonomic neuropathy.
* Diabetic subject on thiazolidinediones, insulin, GLP-1 based therapies (exenatide or sitagliptin), alpha-glucosidase inhibitors, glyburide or combination antidiabetic drug therapies.
* Diabetics with microalbuminuria.

Primary outcomes:
measure: To determine whether hyperglycemia alters myocardial perfusion in subjects with type 2 diabetes
timeFrame: Nov 2009-2011
Secondary outcomes:
measure: To determine whether GLP-1 modulates myocardial perfusion in subjects with type 2 diabetes.
timeFrame: Nov 2009-2011
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Ananda Basu, MBBS, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Sharon L Mulvagh, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abdelmoneim SS, Hagen ME, Mendrick E, Pattan V, Wong B, Norby B, Roberson T, Szydel T, Basu R, Basu A, Mulvagh SL. Acute hyperglycemia reduces myocardial blood flow reserve and the magnitude of reduction is associated with insulin resistance: a study in nondiabetic humans using contrast echocardiography. Heart Vessels. 2013 Nov;28(6):757-68. doi: 10.1007/s00380-012-0305-y. Epub 2012 Nov 23.