Antihypertensive Medication Exposure as Risk for Impaired Glucose Tolerance: A PEAR Sub-Study

Beta-blockers and diuretics have a well-established role in treating hypertension and are frequently used first-line. However, it is increasingly evident that these medications have harmful metabolic effects. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR - NCT00246519) study was a greater than 700 participant, randomized, parallel assignment trial, aimed at determining the genetic factors that influence response to both a beta-blocker (atenolol) and a diuretic (hydrochlorothiazide \[HCTZ\]). The PEAR trial design includes evaluation at baseline, after monotherapy with either medication, and after combination therapy with both medications. This pilot, PEAR sub-study aims to characterize the ability of two diagnostics tests (fasting glucose versus glucose 2-hours after an OGTT) to detect prediabetes development prior to blood pressure medication use, after monotherapy (with atenolol or HCTZ) and after combination therapy (with atenolol and HCTZ).

• Oral glucose tolerance test (Other), also known as OGTT, Glucose tolerance diagnostic test, Glucose tolerance test, Glucola, Sugar beverage: For assessment of dysglycemia, 75 grams of glucose solution by mouth at 3 PEAR study visits for all enrolled participants: baseline, single drug therapy assessment, and dual drug therapy assessment.

Primary outcomes

• Number of Participants Diagnosed With Prediabetes or Normal Glucose, by 2 Measurements (Fasting Glucose Measurement and Glucose Measurement After a 2-hour Oral Glucose Tolerance Test [OGTT]), at Three Timepoints During Antihypertensive Treatment [Baseline, 9 weeks, and 18 weeks after initiation of PEAR intervention(s)]: A single cohort of patients was followed through participation in the parent study, PEAR, and had both fasting and 2-hour OGTT labs evaluated at three time points. At each of these time points the two methods for evaluating prediabetes were compared. Consistent with the definition for prediabetes recommended by the American Diabetes Association, a fasting glucose above 99mg/dL or 2-hour oral glucose tolerance test glucose above 139mg/dL was considered prediabetic for this study.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* participation in PEAR:

  * an average seated home DBP > 85 mmHg and home SBP < 180 mmHg.
  * subjects must also have an average seated (> 5 minutes) clinic DBP between 90 mmHg and 110 mmHg and SBP < 180 mmHg.

Exclusion Criteria:

* secondary forms of HTN,
* patients currently treated with three or more antihypertensive drugs, isolated systolic HTN,
* other diseases requiring treatment with BP lowering medications,
* heart rate < 55 beats/min,
* known cardiovascular disease (including history of angina pectoris, heart failure, presence of a cardiac pacemaker, history of myocardial infarction or revascularization procedure, or cerebrovascular disease, including stroke and TIA),
* diabetes mellitus (Type 1 or 2),
* renal insufficiency (serum creatinine > 1.5 in men or 1.4 in women),
* primary renal disease,
* pregnancy or lactation,
* liver enzymes > 2.5 upper limits of normal,
* current treatment with NSAIDS,
* COX2-inhibitors,
* oral contraceptives or estrogen.

Participant flow

Outcome results

• Number of Participants Diagnosed With Prediabetes or Normal Glucose, by 2 Measurements (Fasting Glucose Measurement and Glucose Measurement After a 2-hour Oral Glucose Tolerance Test [OGTT]), at Three Timepoints During Antihypertensive Treatment (Primary), Number, participants: 2-hour Glucose 6; Fasting Glucose 8 (p 0.41)

Adverse events

Limitations and caveats: This was a pilot study to evaluate two glucose phenotypes in a small sample from a larger trial. As such, our sample size was small. Further, if participants were withdrawn from the parent trial, they were also withdrawn from the sub-study.

• Julie A Johnson, PharmD, Principal investigator, University of Florida

NIH grants: U01GM074492