β-AR Polymorphisms and Glycemic and Lipid Parameters in Hypertensive Individuals Receiving Carvedilol or Metoprolol

Abstract

Background β-blocker therapy and β-adrenergic receptor (β-AR) polymorphisms are associated with increases in glucose and lipid levels. We investigated associations of common β1 and β2- AR single nucleotide polymorphisms (SNPs) with metabolic and lipid variables, and examined interactions with β-blocker treatment assignment to affect these parameters. Methods This was a Post hoc analysis of a double-blinded clinical trial of non-diabetic, hypertensive individuals that were randomized to receive carvedilol or metoprolol succinate. Fasting glucose, insulin, and lipid levels were measured at baseline, 3, and after 6 months. Genotypes for β1-AR SNPs Ser49Gly & Gly389Arg and β2-AR Arg16Gly & Gln27Glu were determined. Multivariable mixed models were used to examine associations between β-AR polymorphisms, metabolic parameters, and SNP interactions with β-blocker therapy (pinteraction). Results The 322 subjects were mean (standard deviation) 51.5 (11.2) years old. After 6 months, insulin levels increased by 35.6% on metoprolol but decreased by 9.9% on carvedilol (p=0.015). In univariate models, the Gln27Gln genotype had higher overall insulin levels with β-blockade compared to the Glu27Glu genotype (p=0.006). Both Arg16Gly (p=0.012) and Gln27Glu (p=0.037) SNPs were associated with triglycerides levels. An interaction between the Arg16Gly SNP and treatment was identified (pint=0.048). Conclusions These data suggest that insulin and triglycerides may be influenced by β2-AR polymorphisms in patients taking β–blockers.

The Impact of β 2 Adrenergic Receptor Polymorphisms on the Outcomes in Cardiovascular Diseases

“…14 Another study observed that metoprolol succinate or carvedilol treatments were associated with a significant increase of baseline insulin and triglycerides levels in hypertensive patients with the Glu27Glu and Gly16Gly genotypes compared with the Gln27Gln and Arg16Arg genotypes; moreover the magnitude of triglycerides elevation over time following β-blocker treatment was significantly higher among the subjects with the Arg16Arg genotypes, despite lower initial concentrations. 138 These data are in line with those of Iwamoto et al 117 who described the same association between the β 2 AR Glu27 variant and hypertriglyceridemia in unselected populations. According with these data, Daghestani et al 139 observed that in overweight and obese subjects, while did not differ in the genotype and allele frequencies of Glu27, the subjects Glu27 homozygote have greater BMI, waist and hip circumference, higher triglyceride, insulin and leptin levels.…”

Peripheral Adrenoceptors: The Impetus Behind Glucose Dysregulation and Insulin Resistance

“…However, clinical studies on the use of third‐generation β‐blockers, comprising agents that block β 1 /β 2 and α 1 ARs (carvedilol and nebivolol), report a metabolically neutral or beneficial outcome, which has been attributed to the apparent influence of nitric oxide levels and α 1 ‐mediated vasodilatory effects . Interestingly, post‐hoc analysis of data obtained from a double‐blind clinical trial with nondiabetic, hypertensive patients treated with carvedilol or metoprolol indicated that the SNP of the glutamate 27 allele (Gln27Glu) was associated with higher overall insulin levels after β‐blockade treatment . As such, factors relating to differences in AR pharmacology, genetic predispositions and their interactions may be ultimately responsible for β‐ligand induced glucose abnormalities.…”

Association of Common Polymorphisms in β1-adrenergic Receptor With Antihypertensive Response to Carvedilol

“…1 Compared with conventional b-blockers, carvedilol maintains cardiac output and reduces blood pressure by decreasing vascular resistance. [5][6][7][8][9][10] However, the association of polymorphisms in ADRB1 or ADRB2 and carvedilol responsiveness in antihypertensive therapy has not been reported. 3,4 Two major single nucleotide polymorphisms (SNPs) are known in the ADRB1 gene (Ser49Gly and Arg389Gly) and 2 major SNPs in the ADRB2 gene (Arg16Gly and Gln27Glu).…”