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Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.
Van Driest, SL, Sleeper, LA, Gelb, BD, Morris, SA, Dietz, HC, Forbus, GA, Goldmuntz, E, Hoskoppal, A, James, J, Lee, TM, et al
The Journal of pediatrics. 2020;:213-220.e5
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Abstract
OBJECTIVE To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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Anti-hypertensive strategies in patients with MEtabolic parameters, DIabetes mellitus and/or NephropAthy (the M E D I N A study).
Spinar, J, Vitovec, J, Soucek, M
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2014;(3):412-21
Abstract
AIMS: The primary questions asked by the MEDINA (MEtabolic parameters, DIabetes mellitus and NephropAthy) study are: 1) Do angiotensin converting enzyme inhibitors (ACE-I) have any advantages over angiotensin receptor blockers (ARB)? 2) Should the other drug for combination be a diuretic or a calcium-channel blocker (CCB)? 3) How are the risks reduced by the co administration of a statin? METHODS A total of 439 hypertensive patients with metabolic syndrome and/or diabetes mellitus were randomized to 2 groups: group 1--ramipril (ACE-I) or perindopril and group 2--losartan (ARB). Hydrochlorothiazide (diuretic) or amlodipine (CCB) were added to both groups. As a third step, a statin was added. RESULTS Blood pressure decreased 24.1/13.3 mmHg in the ACE inhibitor group and 25.9/13.5 in the losartan group. The difference was insignificant. Adding either hydrochlorothiazide or amlodipin was equally effective. There were no significant differences on metabolic parameters in the trial arms. Cholesterol level decreased by 0.95 mmol/L in the ACE-I group and 1.02 mmol/L in the ARB group (ns). CONCLUSION MEDINA has so far confirmed the equivalence of ACE-I and ARB in hypertension treatment. Adding either diuretic or CCB was equally effective. Our data support the current recommendations on adding a statin to reduce cardiovascular risk.
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[Jinshuibao capsule combined losartan potassium intervened early renal damage of hypertension patients of yin and yang deficiency: a clinical research].
Zhang, CQ, Yin, JQ, Xin, Q, Wang, YQ, Ge, ZM
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2013;(6):731-5
Abstract
OBJECTIVE To observe the effects of Jinshuibao Capsule (JC) combined losartan potassium on some indices of early renal damage of hypertension patients of yin and yang deficiency syndrome (YYDS), such as levels of serum cystatin C (Cys C), beta2-microglobulin (beta2-MG), hypersensitive C-reactive protein (hs-CRP), uric acid (UA), blood pressure, blood lipids, and fasting blood glucose (FBG), and to explore their protective effects on early renal damage of hypertension patients and on the metabolisms of blood lipids and blood glucose. METHODS Totally 106 hypertension patients of YYDS were randomly assigned to two groups, 53 patients in the control group (treated by losartan potassium) and 53 patients in the treatment group (treated by JC + losartan potassium). The treatment lasted for 16 weeks. The serum changes of UA, Cys C, beta2-MG, hs-CRP, blood lipids [including total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C)], and FBG levels were measured to evaluate the renal protective effects and to assess their effect on the metabolisms of blood lipids and blood glucose. RESULTS Compared with before treatment in the same group, the systolic blood pressure (SBP) decreased in the two groups after treatment, showing statistical difference (P < 0.05, P < 0.01), but there was no statistical difference between the two groups (P > 0.05). The diastolic blood pressure (DBP) was not obviously declined in the two groups after treatment, showing no statistical difference. Compared with before treatment in the same group, the LDL-C level decreased obviously after treatment in the control group. But there was no obvious change in FBG, TC, HDL-C, and TG in the control group, showing no statistical difference when compared with before treatment (P < 0.05). The FBG, TC, and LDL-C obviously decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05, P < 0.01). There was no statistical difference when compared with the control group after treatment (P > 0.05). Compared with before treatment in the same group, the levels of UA, Cys C, beta2-MG, and hs-CRP all decreased in the two groups, showing statistical difference (P < 0.05, P < 0.01). The SCr level decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05). Compared with the control group after treatment, the levels of Cys C, beta2-MG, and hs-CRP decreased more obviously after treatment in the treatment group, showing statistical difference (P < 0.05). CONCLUSIONS JC combined losartan potassium showed better effects in treating early renal damage of hypertension patients of YYDS. They could protect and stabilize the renal functions more effectively. JC could regulate blood lipids and blood glucose.
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Clusters of metabolic risk factors predict cardiovascular events in hypertension with target-organ damage: the LIFE study.
de Simone, G, Olsen, MH, Wachtell, K, Hille, DA, Dahlöf, B, Ibsen, H, Kjeldsen, SE, Lyle, PA, Devereux, RB
Journal of human hypertension. 2007;(8):625-32
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Abstract
The relation of metabolic syndrome (MetS) with cardiovascular outcome may be less evident when preclinical cardiovascular disease is present. We explored, in a post hoc analysis, whether MetS predicts cardiovascular events in hypertensive patients with electrocardiographic left ventricular hypertrophy (ECG-LVH) in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study. MetS was defined by >or=2 risk factors plus hypertension: body mass index >or=30 kg/m(2), high-density lipoprotein (HDL)-cholesterol <1.0/1.3 mmol/l (<40/50 mg/dl) (men/women), glucose >or=6.1 mmol/l (>or=110 mg/dl) fasting or >or=7.8 mmol/l (>or=140 mg/dl) nonfasting or diabetes. Cardiovascular death and the primary composite end point (CEP) of cardiovascular death, stroke and myocardial infarction were examined. In MetS (1,591 (19.3%) of 8,243 eligible patients), low HDL-cholesterol (72%), obesity (77%) and impaired glucose (73%) were similarly prevalent, with higher blood pressure, serum creatinine and Cornell product, but lower Sokolow-Lyon voltage (all P<0.001). After adjusting for baseline covariates, hazard ratios for CEPs and cardiovascular death (4.8+/-1.1 years follow-up) were 1.47 (95% confidence interval (CI), 1.27-1.71)- and 1.73 (95% CI, 1.38-2.17)-fold higher with MetS (both P<0.0001), and were only marginally reduced when further adjusted for diabetes, obesity, low HDL-cholesterol, non-HDL-cholesterol, pulse pressure and in-treatment systolic blood pressure and heart rate. Thus, MetS is associated with increased cardiovascular events in hypertensive patients with ECG-LVH, independently of single cardiovascular risk factors.
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Effects of telmisartan and losartan on insulin resistance in hypertensive patients with metabolic syndrome.
Bahadir, O, Uzunlulu, M, Oguz, A, Bahadir, MA
Hypertension research : official journal of the Japanese Society of Hypertension. 2007;(1):49-53
Abstract
Partial peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are known to decrease insulin resistance. Experimental studies have shown that the angiotensin type 1 receptor blocker (ARB) telmisartan has a PPAR-gamma-activating property, but there does not appear to be a class effect. To test telmisartan's clinical importance, we here investigated its effect on insulin resistance in hypertensive patients with metabolic syndrome (MetS) in comparison with another ARB, losartan. A total of 42 hypertensive MetS patients (29 female, 13 male) were included (mean age: 50+/-9, range: 20-70 years). NCEP-ATP III criteria were used for the diagnosis of MetS. Patients were randomized to receive either telmisartan 80 mg/day (n=21) or losartan 50 mg/day (n=21) for 8 weeks. Biochemical assessments were made at baseline and at the end of the 8 weeks. Insulin resistance was evaluated by using homeostasis model assessment of insulin resistance (HOMA-IR). Both groups had similar reductions in systolic and diastolic pressures (p>0.05). HOMA-IR did not change significantly in either group throughout the study. In the telmisartan group, the mean HOMA-IR at baseline and at the end of the study were 1.9+/-07 and 1.9+/-0.5, respectively. The figures for the losartan group were 1.8+/-0.6 and 1.8+/-0.6, corresponding. In conclusion, in contrast with the reports that telmisartan may decrease insulin resistance by an effect associated with its molecular structure, 8 weeks of telmisartan treatment in the present study had a neutral effect on insulin resistance in hypertensive MetS patients, and similar results were obtained for losartan.
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11beta-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade.
Kerstens, MN, Buter, H, Navis, GJ, Dullaart, RP
European journal of clinical investigation. 2002;(7):513-8
Abstract
BACKGROUND It has been suggested that an altered setpoint of the 11betaHSD-mediated cortisol to cortisone interconversion towards cortisol contributes to sodium retention in nephrotic syndrome patients. We studied the parameters of 11betaHSD activity in proteinuric patients, in particular its activity at the kidney level. We also studied the effect of angiotensin-II receptor blockade on the parameters of 11betaHSD activity. MATERIALS AND METHODS Serum cortisol/cortisone ratio and the urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone [(THF + allo-THF)/THE] and of urinary free cortisol/free cortisone (UFF/UFE) were measured in eight proteinuric patients and compared with eight matched, healthy subjects. Patients were subsequently studied after 4 weeks' treatment with losartan 50 mg day-1 and placebo, respectively. RESULTS No significant differences between the proteinuric patients and the healthy subjects were observed in the serum cortisol, serum cortisone, serum cortisol to cortisone ratio, or in the urinary excretions of THF, allo-THF, THE, sum of cortisol metabolites, or the (THF + allo-THF)/THE ratio. Urinary free cortisol excretion and the UFF/UFE ratio were lower in the proteinuric patients than in the healthy subjects (56 +/- 21 vs. 85 +/- 24 pmol min-1, P < 0.05, and 0.39 +/- 0.07 vs. 0.63 +/- 0.28, P < 0.05, respectively). Mean arterial pressure and proteinuria were reduced significantly during losartan treatment, but without concomitant changes in peripheral cortisol metabolism. CONCLUSIONS Increased renal inactivation of cortisol in proteinuric patients does not support the contention that altered 11betaHSD activity contributes to sodium retention in patients with nephrotic syndrome. Losartan 50 mg d.d. reduces mean arterial pressure and proteinuria, but does not exert a significant effect on the cortisol to cortisone interconversion.