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.
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.
3.
Effect of the angiotensin receptor blocker irbesartan on metabolic parameters in clinical practice: the DO-IT prospective observational study.
Parhofer, KG, Münzel, F, Krekler, M
Cardiovascular diabetology. 2007;:36
Abstract
AIMS: A number of intervention studies have shown that therapy with angiotensin receptor blockers, such as irbesartan, can improve metabolic parameters and reduce the incidence of diabetes mellitus. It is unknown whether this observation also holds true in routine clinical settings. METHODS We evaluated the effect of irbesartan (150 mg or 300 mg/d) together with or without hydrochlorothiazide (12.5 mg/d) in 3259 German patients. A total of 750 primary care physicians evaluated up to 5 subsequent patients with metabolic syndrome (58.9% diabetic), in whom irbesartan therapy was newly initiated (87%) or continued (13%). RESULTS Six months of irbesartan therapy decreased systolic blood pressure by 14% (157.4 +/- 14.7 vs. 135.0 +/- 10.7 mmHg) and diastolic blood pressure by 13% (92.9 +/- 9.2 vs. 80.8 +/- 6.8 mmHg). This was associated with a decrease in body weight (-2.3%), fasting glucose (-9.5%), HbA1c (-4.6%), LDL-cholesterol (-11%), triglycerides (-16%) and gamma-GT (-12%) and an increase in HDL-cholesterol (+5%). These changes were somewhat more pronounced in male than in female patients and in obese than in lean patients. Changes in glucose concentration and HbA1c were much more prominent in diabetic patients. CONCLUSION Irbesartan therapy improves metabolic parameters in routine clinical settings. Thus, our study confirms previously published results from large intervention trials and extends the findings to routine clinical practice.