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Publisher: Elsevier: Lancet
Journal: The Lancet Diabetes & Endocrinology
Languages: English
Types: Article
Subjects: Treatment of Hypertension with Algorithm-based Therapy (PATHWAY) Studies Group, /dk/atira/pure/subjectarea/asjc/1300/1310, Articles, Internal Medicine, Endocrinology, Diabetes and Metabolism, /dk/atira/pure/subjectarea/asjc/2700/2724, British Hypertension Society's Prevention, /dk/atira/pure/subjectarea/asjc/2700/2712, Endocrinology

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.

  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1 Brown MJ. The choice of diuretic in hypertension: saving the baby from the bathwater. Heart 2011; 97: 1547-51.
    • 2 Messerli FH, Bangalore S. Half a century of hydrochlorothiazide: facts, fads, fiction, and follies. Am J Med 2011; 124: 896-99.
    • 3 Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension 2006; 48: 219-24.
    • 4 Cutler JA. Thiazide-Associated glucose abnormalities: prognosis, etiology, and prevention: is potassium balance the key? Hypertension 2006; 48: 198-200.
    • 5 Murphy MB, Kohner E, Lewis PJ, Schumer B, Dollery CT. Glucose intolerance in hypertensive patients treated with diuretics; a fourteen-year follow-up. Lancet 1982; 320: 1293-95.
    • 6 Carter BL, Einhorn PT, Brands M, et al. Thiazide-induced dysglycemia: call for research from a working group from the National Heart, Lung, and Blood Institute. Hypertension 2008; 52: 30-36.
    • 7 Manrique C, Johnson M, Sowers JR. Thiazide diuretics alone or with beta-blockers impair glucose metabolism in hypertensive patients with abdominal obesity. Hypertension 2010; 55: 15-17.
    • 8 Duarte JD, Cooper-DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovasc Ther 2010; 8: 793-802.
    • 9 Mackenzie IS, Brown MJ. Molecular and clinical investigations in patients with low- renin hypertension. Clin Exp Nephrol 2009; 13: 1-8.
    • 10 Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560-72.
    • 11 Girvin B, Johnston GD. A randomized comparison of a conventional dose, a low dose and alternate-day dosing of bendrofluazide in hypertensive patients. J Hypertens 1998; 16: 1049-54.
    • 12 Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990; 300: 975-78.
    • 13 Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with once-daily calcium channel blockade or diuretic in the INTERNATIONAL Nifedipine GITS study: intervention as a goal in hypertension treatment (INSIGHT). Lancet 2000; 356: 366-42.
    • 14 Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio. Circulation 2007; 116: 268-75.
    • 15 Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006; 24: 3-10.
    • 16 Mason JM, Dickinson HO, Nicolson DJ, Campbell F, Ford GA, Williams B. The diabetogenic potential of thiazide-type diuretic and beta-blocker combinations in patients with hypertension. J Hypertens 2005; 23: 1777-81.
    • 17 Medical Research Council Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405-12.
    • 18 Bakris G, Molitch M, Hewkin A, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care 2006; 29: 2592-97.
    • 19 Stears A, Woods S, Watts M, et al. A double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension. Hypertension 2012; 59: 939-42.
    • 20 Hood SJ, Picton DE, Taylor KP, Brown MJ. Value of routine plasma renin assay in the detection, treatment-titration or cure of low-renin patients with salt-dependent hypertension. J Human Hypertension 2009; 23: 693.
    • 21 Brown MJ, Williams B, MacDonald TM, et al. Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension. BMJ Open 2015; 5: e008086.
    • 22 Morganti A, European study group for the validation of DiaSorin Liaison Direct Renin Assay. A comparative study on inter and intralaboratory reproducibility of renin measurement with a conventional enzymatic method and a new chemiluminescent assay of immunoreactive renin. J Hypertens 2010; 28: 1307-12.
    • 23 Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362: 1527-35.
    • 24 ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000; 283: 1967-75.
    • 25 Thomas JP, Thomson WH. Comparison of thiazides and amiloride in treatment of moderate hypertension. BMJ (Clin Res Ed) 1983; 286: 2015-18.
    • 26 Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D'Agostino RB, Sr. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med 2007; 167: 1068-74.
    • 27 Stern MP, Williams K, Haffner SM. Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Ann Intern Med 2002; 136: 575-81.
    • 28 McNeely MJ, Boyko EJ, Leonetti DL, Kahn SE, Fujimoto WY. Comparison of a clinical model, the oral glucose tolerance test, and fasting glucose for prediction of type 2 diabetes risk in Japanese Americans. Diabetes Care 2003; 26: 758-63.
    • 29 Decode Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 2001; 161: 397-405.
    • 30 Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study. Lancet 1980; 1: 1373-76.
    • 31 Burton TJ, Mackenzie IS, Balan K, et al. Evaluation of the sensitivity and specificity of (11)C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas. J Clin Endocrinol Metab 2012; 97: 100-09.
    • 32 Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure? J Renin Angiotensin Aldosterone Syst 2004; 5: 155-60.
    • 33 Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL, the Atherosclerosis Risk in Communities Study. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. N Engl J Med 2000; 342: 905-12.
    • 34 Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201-07.
    • 35 NAVIGATOR Study Group, McMurray JJ, Holman RR, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362: 1477-90.
    • 36 Dagogo-Jack S. Pitfalls in the use of HbA1c as a diagnostic test: the ethnic conundrum. Nat Rev Endocrinol 2010; 6: 589-93.
    • 37 Swaminathan K, Davies J, George J, Rajendra NS, Morris AD, Struthers AD. Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles. Diabetologia 2008; 51: 762-68.
    • 38 National Institute for Health and Care Excellence. Hypertension (update): full guideline. https://www.nice.org.uk/guidance/cg127/ evidence/cg127-hypertension-full-guideline3 (accessed Oct 4, 2015).
    • 39 Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; published online Sept 21. DOI:10.1016/S0140-6736(15)00257-3.
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