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Study Objective To determine the effects of low-dose pioglitazone on plasma adipocyte-derived cytokines, high-sensitivity C-reactive protein (hs-CRP), and components of the metabolic syndrome in adults with the metabolic syndrome without diabetes mellitus. Design Prospective, randomized, double-blind, placebo-controlled study. Setting University of Colorado Clinical and Translational Research Center. Patients Thirty-two men and women, aged 30-60 years, without diabetes who had a clinical diagnosis of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute criteria. Intervention Patients were randomly assigned to receive oral pioglitazone 7.5 mg daily or matching placebo for 8 weeks. Measurements and Main Results The primary end point was the change in plasma high-molecular-weight (HMW) adiponectin level from baseline to week 8. Other end points were changes in plasma total adiponectin, omentin, and hs-CRP levels, and changes in components of the metabolic syndrome (e.g., insulin sensitivity) from baseline to week 8. Pioglitazone was associated with a significant increase in plasma HMW adiponectin from baseline to week 8 compared with placebo (+47% vs −10%, p<0.001). Insulin sensitivity increased significantly from baseline to week 8 in the pioglitazone group (+88%, p=0.02) but not in the placebo group (+15%, p=0.14). Change in HMW adiponectin was significantly correlated with the change in insulin sensitivity in the pioglitazone group ( r = 0.784, p=0.003). No significant differences in mean percentage changes in plasma total adiponectin, omentin, and hs-CRP levels were observed between the pioglitazone and placebo groups. Likewise, changes in body weight, insulin sensitivity, glucose, lipids, and blood pressure did not differ significantly between the groups. Conclusion Low-dose pioglitazone favorably modulates plasma HMW adiponectin, which was associated with an improvement in insulin sensitivity, in patients with the metabolic syndrome without diabetes. [ABSTRACT FROM AUTHOR]

Study Objective To develop and validate a predictive model for glucose change and risk for new-onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide ( HCTZ). Design Randomized multicenter clinical trial. Patients A total of 735 white or African-American men and women with uncomplicated hypertension. Measurements and Main Results Pharmacogenomic Evaluation of Antihypertensive Responses ( PEAR) is a randomized clinical trial to assess the genetic and nongenetic predictors of blood pressure response and adverse metabolic effects following treatment with atenolol or HCTZ. To develop and validate predictive models for glucose change, PEAR participants were randomly divided into a derivation cohort of 367 and a validation cohort of 368. Linear and logistic regression modeling were used to build models of drug-associated glucose change and impaired fasting glucose ( IFG), respectively, in the derivation cohorts. These models were then evaluated in the validation cohorts. For glucose change after atenolol or HCTZ treatment, baseline glucose was a significant (p<0.0001) predictor, explaining 13% of the variability in glucose change after atenolol and 12% of the variability in glucose change after HCTZ. Baseline glucose was also the strongest and most consistent predictor (p<0.0001) for development of IFG after atenolol or HCTZ monotherapy. The area under the receiver operating curve was 0.77 for IFG after atenolol and 0.71 after HCTZ treatment, respectively. Conclusion Baseline glucose is the primary predictor of atenolol or HCTZ-associated glucose increase and development of IFG after treatment with either drug. [ABSTRACT FROM AUTHOR]

Study Objective To assess the relationship of the 33 single nucleotide polymorphisms ( SNPs) previously associated with fasting glucose in Caucasians in genome-wide association studies ( GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes. Design Randomized, multicenter clinical trial. Patients A total of 456 Caucasian men and women with uncomplicated hypertension. Measurements and Main Results The Pharmacogenomic Evaluation of Antihypertensives Responses study evaluated blood pressure and glucose response in uncomplicated hypertensive patients randomized to either atenolol or hydrochlorothiazide ( HCTZ) monotherapy, followed by combination therapy with both agents. Association of these SNPs with atenolol- or HCTZ-induced glucose response was evaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index, baseline glucose, baseline insulin, and principal component for ancestry. The SNP rs340874 in the 5′ region of PROX1 gene was significantly associated with atenolol-induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately 9 weeks of atenolol monotherapy (β = +2.39 mg/dl per C allele), consistent with the direction of effect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose. Conclusion These data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may also be a pharmacogenetic risk factor for antihypertensive-induced hyperglycemia. β-blockers and thiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes. [ABSTRACT FROM AUTHOR]

Study Objective To estimate the cost-effectiveness of genotype-guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype. Design Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction ( TRITON- TIMI) 38. Patients Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention ( PCI), consisting of three arms: those receiving genotype-guided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype. Measurements and Main Results All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 ( CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio (ICER) for each event avoided in the genotype-guided therapy arm versus the other two arms. Genotype-guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel ( ICER −$6760 [95% confidence interval ( CI) −$6720 to −$6790]) or prasugrel ( ICER −$11,710 [95% CI −$11,480 to −$11,950]) for all patients without regard to genotype. Genotype-guided therapy that included generic clopidogrel was dominant to prasugrel for all patients ( ICER −$27,160 [95% CI −$27,890 to −$26,420]). Cost savings were not evident when genotype-guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients ( ICER $2300 [95% CI $2290 to $2320]). [Correction added after online publication 12-Mar-2012: In the previous sentence −$2300 has been corrected as $2300.]. Conclusion Genotype-guided antiplatelet therapy selection may be more cost-effective and may provide more clinical value due to fewer adverse outcomes. [ABSTRACT FROM AUTHOR]

Study Objective. To determine whether the effects of spironolactone on potassium homeostasis vary by race by comparing serum potassium concentrations and potassium supplement use in African-American and Caucasian patients receiving spironolactone for heart failure. Design. Retrospective medical record review. Setting. Two heart failure centers. Patients. Fifty African-American and 67 Caucasian patients with heart failure who were receiving a stable dosage of spironolactone in addition to standard heart failure therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. Measurements and Main Results. Medical records of eligible patients were reviewed by pharmacists and physicians who specialize in heart failure management. No significant differences were observed in diuretic therapy or renal function between racial groups; however, African-Americans were receiving higher doses of ACE inhibitors. African-Americans had lower serum potassium concentrations (4.2 ± 0.4 vs 4.5 ± 0.5 mEq/L, p<0.01) and a higher prevalence of potassium supplementation (48% vs 15%, p<0.01). In a subset of patients, spironolactone therapy was associated with a 2-fold greater increase in serum potassium concentration and a 3-fold greater reduction in potassium supplement use among Caucasians than African-Americans. Conclusion. Our findings suggest that a large percentage of patients with heart failure, particularly African-Americans, still require potassium supplementation despite treatment with spironolactone and standard vasodilator therapy. [ABSTRACT FROM AUTHOR]