Examining Genetic Influence on Response to Beta-Blocker Medications in People With Type 2 Diabetes

Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00925119

Enrollment

Registered

2009-06-19

Start date

2009-12-31

Completion date

2014-05-31

Last updated

2019-09-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus, Type 2

Keywords

Diabetes, Atenolol, Genetic

Brief summary

Beta-blockers are medications used to treat cardiovascular disease (CVD) symptoms, including high blood pressure and chest pain. People with diabetes who receive beta-blockers may experience adverse health effects, but the exact cause of why this happens remains unknown. This study will examine the genetic factors that may influence how atenolol, a beta-blocker medication, affects fat breakdown, blood sugar levels, and heart function in people with type 2 diabetes.

Detailed description

People with diabetes who develop CVD have worse health outcomes than people without diabetes who develop CVD. Beta-blockers are medications used to treat high blood pressure, angina (i.e., chest pain), arrhythmias, and other CVD conditions. While beta-blockers are effective at treating these conditions, they may also have damaging effects on cholesterol or glucose levels, thereby possibly lessening their ability to prevent CVD events in people with diabetes. It is important to identify which patients may not benefit from receiving beta-blocker medications. Genetic factors may influence how people respond to beta-blocker medications. The purpose of this study is to evaluate the influence of genetic variation on beta-blocker-induced changes in insulin sensitivity, fat breakdown, and heart function in people with type 2 diabetes. This study will enroll people with type 2 diabetes. At a series of up to three baseline study visits, participants will have a blood collection, a glucose tolerance test, an echocardiogram to obtain images of the heart, and biopsies of muscle from the thigh and fat from the stomach. All participants will then receive atenolol once a day for 8 weeks. During Week 1, participants will receive a low dose of atenolol. They will then attend a study visit at the end of Week 1, and study researchers will examine how well participants are tolerating the medication. If the atenolol is well tolerated, the dose will be increased. Study researchers will call participants 1 week after any dosage changes to monitor for side effects. Blood collection will occur again at a study visit at Week 4. At Week 8, participants will then attend up to three study visits for repeat baseline testing. Participants will then be slowly tapered off of atenolol over a 1-week period.

Interventions

DRUGAtenolol

12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

21 Years to No maximum

Healthy volunteers

Inclusion criteria

* Type 2 diabetes * Pre-Diabetes

Exclusion criteria

* Insulin therapy * Treatment with any beta-blocker in the 30 days before study entry * Asthma * Chronic obstructive pulmonary disease (COPD) * Greater than first degree heart block * Heart rate less than 60 bpm * Systolic blood pressure less than 90 mm Hg * Raynaud's phenomenon * Known history of angina, heart attack, heart failure, coronary revascularization, or automatic implantable cardioverter defibrillators * Pregnant * Creatinine clearance less than 35 ml/min * Hematologic dysfunction (white blood cell \[WBC\] count less than 3000 or hematocrit less than 28%) * Allergy to amide anesthetics

Design outcomes

Primary

Measure	Time frame	Description
Change in Diastolic Function (Annular Tissue Velocity [Em])	8 weeks	—
Change in Free Fatty Acid Kinetics	Baseline and Week 8	Estimate of peripheral lipolysis using modeling of free fatty acid levels collected during an IV glucose tolerance test. The change in threshold for insulin action (post-atenolol minus pre-atenolol) is the primary variable from this modeling that we analyzed.

Secondary

Measure	Time frame	Description
Change in Glucose Effectiveness	Baseline and Week 8	Glucose effectiveness as measured by insulin-modified IV glucose tolerance test using the MINMOD model.
Change in Triglycerides	Baseline and Week 8	(Post atenolol triglycerides - Pre atenolol triglycerides)
Change in Insulin	Baseline and Week 8	fasting insulin (post - pre atenolol)
Change in HDL	Baseline and Week 8	—
Change in Insulin Sensitivity	Baseline and Week 8	As measured by the Homeostatic model assessment of insulin resistance (HOMA2-IR) (post atenolol - pre atenolol). he Homeostatic model assessment (HOMA) is a method for assessing insulin sensitivity from fasting glucose and insulin. A higher HOMA value indicates higher insulin resistance. The widely-used formulae available for HOMA1 provide only linear approximations of HOMA\_%B and HOMA\_IR, the inverse of HOMA\_%S. These are: HOMA1\_IR = \[FPI (uU/ml) x FPG (mmol/l) \]/22.5 HOMA1\_%B = (20 x FPI)/(FPG - 3.5) The results obtained for HOMA2 may differ considerably from HOMA1 computer-calculated values, especially for more extreme glucose and insulin values. For this reason, no attempt has been made to provide linear approximations of HOMA2 calculated values of HOMA\_%B, HOMA\_IR and HOMA\_%S. The software needed to calculate HOMA2 values is available on this website: https://www.dtu.ox.ac.uk/homacalculator/download.php, subject to the conditions specified on the downloads page.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Atenolol Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated	19
Total	19

Baseline characteristics

Characteristic	Atenolol
Age, Continuous	57 years STANDARD_DEVIATION 11
Sex: Female, Male Female	11 Participants
Sex: Female, Male Male	8 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	4 / 19
serious Total, serious adverse events	0 / 19

Outcome results

Primary

Change in Diastolic Function (Annular Tissue Velocity [Em])

Time frame: 8 weeks

Population: Data were not able to be collected from the echocardiography.

Primary

Change in Free Fatty Acid Kinetics

Estimate of peripheral lipolysis using modeling of free fatty acid levels collected during an IV glucose tolerance test. The change in threshold for insulin action (post-atenolol minus pre-atenolol) is the primary variable from this modeling that we analyzed.