1.
Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial.
Brown, MJ, Williams, B, Morant, SV, Webb, DJ, Caulfield, MJ, Cruickshank, JK, Ford, I, McInnes, G, Sever, P, Salsbury, J, et al
The lancet. Diabetes & endocrinology. 2016;(2):136-47
Abstract
BACKGROUND Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. METHODS We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. FINDINGS Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. INTERPRETATION The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. FUNDING British Heart Foundation and National Institute for Health Research.
2.
Prevalence of premorbid metabolic syndrome in Spanish adult workers using IDF and ATPIII diagnostic criteria: relationship with cardiovascular risk factors.
Tauler, P, Bennasar-Veny, M, Morales-Asencio, JM, Lopez-Gonzalez, AA, Vicente-Herrero, T, De Pedro-Gomez, J, Royo, V, Pericas-Beltran, J, Aguilo, A
PloS one. 2014;(2):e89281
Abstract
BACKGROUND Metabolic Syndrome (MetS) is a complex disorder defined as a cluster of interconnected risk factors such as hypertension, dyslipidemia, obesity and high blood glucose levels. Premorbid metabolic syndrome (PMetS) is defined by excluding patients with previously diagnosed cardiovascular disease or diabetes mellitus from those suffering MetS. We aimed to determine the prevalence of PMetS in a working population, and to analyse the relationship between the diagnostic criteria of the International Diabetes Federation (IDF) and of the National Cholesterol Education Program Adult Treatment Panel III (ATPIII). The relationship between the presence of PMetS and cardiovascular risk factors was also analysed. RESEARCH METHODOLOGY/FINDINGS A cross-sectional study was conducted in 24,529 male and 18,736 female Spanish (white western European) adult workers (20-65 years) randomly selected during their work health periodic examinations. Anthropometrics, blood pressure and serum parameters were measured. The presence of MetS and PMetS was ascertained using ATPIII and IDF criteria. Cardiovascular risk was determined using the Framingham-REGICOR equation. The results showed MetS had an adjusted global prevalence of 12.39% using ATPIII criteria and 16.46% using IDF criteria. The prevalence of PMetS was slightly lower (11.21% using ATPIII criteria and 14.72% using IDF criteria). Prevalence in males was always higher than in females. Participants with PMetS displayed higher values of BMI, waist circumference, blood pressure, glucose and triglycerides, and lower HDL-cholesterol levels. Logistic regression models reported lower PMetS risk for females, non-obese subjects, non-smokers and younger participants. Cardiovascular risk determined with Framingham-REGICOR was higher in participants with PMetS. CONCLUSIONS PMetS could be a reliable tool for the early identification of apparently healthy individuals who have a significant risk for developing cardiovascular events and type 2 diabetes.
3.
The effect of carvedilol on metabolic parameters in patients with metabolic syndrome.
Uzunlulu, M, Oguz, A, Yorulmaz, E
International heart journal. 2006;(3):421-30
Abstract
The objective of the present study was to explore the effect of carvedilol treatment on metabolic parameters in patients with metabolic syndrome. A total of 77 patients > or = 20 years of age (59 females, 18 males, mean age, 52.3 +/- 10.3) with stage 1 hypertension who fulfilled at least 3 of the metabolic syndrome criteria proposed by NCEP-ATP III were included in this prospective, randomized, controlled study. Patients were randomly assigned to receive daily treatment with carvedilol (n = 27, 12.5 mg/day orally for the first 2 days and 25 mg/day thereafter), atenolol (n = 26, 50 mg/day orally), or doxazosin (n = 24, 2 mg/day orally) for 90 days. Doses were doubled at the end of the 3rd week in patients whose blood pressure was inadequately controlled and amlodipine 10 mg was added to the treatment if the target blood pressure was still not reached at the end of week 6. The biochemical parameters and insulin sensitivity based on the HOMA-IR model were evaluated at baseline and at the end of treatment. Similar reductions in systolic and diastolic blood pressure were observed in all groups (P > 0.05). A significant decrease in HDL cholesterol levels occurred in the doxazosin and atenolol groups compared to the carvedilol group (percent change: -5.6 +/- 13.5 and -8 +/- 9.8 versus -0.1 +/- 12.2, respectively; P < 0.05) and a significant increase in apolipoprotein A1 level was observed in the carvedilol group compared to the doxazosin and atenolol groups (percent change: + 4.3 +/- 9.6 versus - 0.5 +/- 10.6 and -2.3 +/- 6.6, respectively; P < 0.05). There were no significant differences among the groups with respect to other parameters. It is concluded antihypertensive treatment with carvedilol in patients with metabolic syndrome effectively reduces blood pressure without adversely affecting metabolic parameters.