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OBJECTIVES:Theβ-adrenergic receptor (βAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of theβ1AR (ADRB1),β2AR (ADRB2),β3AR (ADRB3), Gs protein alpha (GNAS1), to which all threeβ-receptors couple and the G proteinβ3 subunit (GNB3), to whichβ3ARs couple.DESIGN:A case–control genetic association study.SUBJECTS:A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study.MEASUREMENTS:Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made.RESULTS:Polymorphisms in the threeβAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity.CONCLUSIONS:Our study suggests that among American women with suspected coronary heart disease, polymorphisms in theβARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.International Journal of Obesity (2005) 29, 746–754. doi:10.1038/sj.ijo.0802978 Published online 3 May 2005 [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in the α2c adrenergic receptor (ADRA2C) and the β1 adrenergic receptor (ADRB1) genes have been suggested to act synergistically in heart failure (HF) risk. We tested their association (and synergism) with β-blocker (BB) response in HF.Methods: Left ventricular ejection fraction (EF) was determined by echocardiography at baseline and after 5-6 months of metoprolol CR/XL therapy in 54 patients with systolic HF. ADRB1 Arg389Gly and ADRA2C 322-325 Insertion/Deletion (Ins/Del) polymorphisms were determined by pyrosequencing. Linear regression modeling of end of study EF was done with patient age, race, genotypes, HF etiology, spironolactone, digoxin, and furosemide use and final metoprolol CR/XL dose considered in the model. EF response by genotype was compared by t-tests and ANOVA.Results: Significant predictors of the end study EF were baseline EF, Del-carrier status, Arg389Arg genotype and age. The combination of both genotypes (Arg389Arg & Del-carrier) (Gp1) showed the greatest EF change. Adjusting for baseline EF and age, the end study EF of Gp1 was significantly different from the 3 other groups (overall p=0.0012) (table).Conclusions: Polymorphisms in the ADRB1 and ADRA2C genes synergistically influence the left ventricular reverse remodeling response to β-blockers in HF.Clinical Pharmacology & Therapeutics (2005) 79, P31–P31; doi: 10.1016/j.clpt.2005.12.113 [ABSTRACT FROM AUTHOR]

Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.). [ABSTRACT FROM AUTHOR]