Preventing new-onset diabetes in thiazide-treated patients
Authors: Giuseppe Mancia
Journal: The Lancet Diabetes & Endocrinology (2015)

Although thiazide diuretics reduce blood pressure as effectively as other drugs,1Law MR Wald NJ Morris JK Jordan RE Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.BMJ. 2003; 326: 1427Crossref PubMed Google Scholar one of the recognised disadvantages of drugs of this class is that they adversely affect lipid and glucose metabolism.2Mancia G Fagard R Narkiewicz K et al.The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 ESH/ESC Guidelines for the management of arterial hypertension.J Hypertens. 2013; 31: 1281-1357Crossref PubMed Scopus (4041) Google Scholar They cause a slight increase in serum LDL cholesterol and triglycerides, a decrease in serum HDL cholesterol, and an increase in blood glucose concentrations both in the fasting state and after a glucose load. The effects on blood glucose have raised special concern because data from clinical trials have shown that, when prolonged for years, thiazide-based treatment is associated with an increased incidence of type 2 diabetes compared with placebo or with drugs such as blockers of the renin–angiotensin system or calcium-channel blockers.3Mancia G Grassi G Zanchetti A New-onset diabetes and antihypertensive drugs.J Hypertens. 2006; 24: 3-10Crossref PubMed Scopus (258) Google Scholar, 4Elliott WJ Meyer PM Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.Lancet. 2007; 369: 201-207Summary Full Text Full Text PDF PubMed Scopus (830) Google Scholar Although in some studies drug-induced diabetes has not been associated with substantial modification of cardiovascular risk,3Mancia G Grassi G Zanchetti A New-onset diabetes and antihypertensive drugs.J Hypertens. 2006; 24: 3-10Crossref PubMed Scopus (258) Google Scholar in others an increased risk of cardiac and cerebrovascular morbid or fatal events has been noted,5Dunder K Lind L Zethelius B Berglund L Lithell H Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study.BMJ. 2003; 326: 681Crossref PubMed Google Scholar leading to the hypothesis that thiazides favour, perhaps in predisposed patients, the development of a so-called true diabetes—ie, diabetes with all the adverse clinical consequences. Some guidelines have therefore downgraded thiazides from their earlier position as first choice antihypertensives;6National Clinical Guideline CentreHypertension: the clinical management of primary hypertension in adults: update of clinical guidelines 18 and 34. Royal College of Physicians (UK), London2011Google Scholar others have issued recommendations that discourage the use of thiazides in some categories of patients—eg, those with metabolic syndrome, in whom the risk of new-onset diabetes is substantially higher.2Mancia G Fagard R Narkiewicz K et al.The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 ESH/ESC Guidelines for the management of arterial hypertension.J Hypertens. 2013; 31: 1281-1357Crossref PubMed Scopus (4041) Google Scholar, 7Mancia G Bombelli M Facchetti R et al.Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population.J Hypertens. 2008; 26: 1602-1611Crossref PubMed Scopus (61) Google Scholar Several possibilities have been investigated to determine whether and to what extent the adverse effects of thiazides on glucose metabolism can be attenuated. It is long established that the adverse effects of thiazides on blood glucose and other metabolic variables increase with increasing doses,8Bakris G Molitch M Hewkin A et al.for the STAR InvestigatorsDifferences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome.Diabetes Care. 2006; 29: 2592-2597Crossref PubMed Scopus (187) Google Scholar which is why the high diuretic doses used previously have been abandoned. Additionally, glucose metabolism might be better preserved if thiazides are given in combination with blockers of the renin–angiotensin system—perhaps because the protective effect of reducing the amount of (or blocking the effect of) angiotensin II offsets at least partly the adverse thiazide-dependent metabolic consequences.8Bakris G Molitch M Hewkin A et al.for the STAR InvestigatorsDifferences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome.Diabetes Care. 2006; 29: 2592-2597Crossref PubMed Scopus (187) Google Scholar Another option to reduce the adverse effects of thiazides is to give potassium supplements, a strategy that stems from the observation that the hyperglycaemic effect of thiazide diuretics is enhanced by potassium depletion and inversely related to the serum potassium concentrations.9Zillich AJ Garg J Basu S Bakris GL Carter BL Thiazide diuretics, potassium, and the development of diabetes: a quantitative review.Hypertension. 2006; 48: 219-224Crossref PubMed Scopus (362) Google Scholar By extension, it is possible that the effect of thiazides on glucose metabolism would also be attenuated by giving them in combination with a potassium-sparing diuretic. In an Article10Brown MJ Williams B Morant S et al.for the PATHWAY Studies GroupEffect 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.Lancet Diabetes Endocrinol. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S2213-8587(15)00377-0Google Scholar by Morris J Brown and colleagues in The Lancet Diabetes & Endocrinology, the combination of a thiazide and potassium-sparing diuretic is shown to be therapeutically valid. Brown and colleagues randomly assigned several hundred patients with hypertension to 24 weeks double-blind treatment with hydrochlorothiazide (25 mg daily), amiloride (10 mg daily), or the combination of the two drugs at half doses (12·5 mg and 5 mg daily); all doses were doubled after 12 weeks. The investigators did 2 h oral glucose tolerance tests at baseline and at 12 and 24 weeks. Compared with baseline, the 2 h blood glucose concentrations increased in patients in the hydrochlorothiazide group and decreased in those taking amiloride, even when amiloride was taken together with hydroclorothiazide (difference between hydrochlorothiazide and combination groups: −0·42 mmol/L [95% CI −0·84 to −0·004]; 0·048). Compared with thiazide monotherapy, blood pressure reduction (as shown by home blood pressure measurements) was not significantly different in the amiloride group and was slightly greater in the combination group. The number of patients with serious side-effects was small in all groups and the mean increase in serum potassium attributable to the potassium-sparing diuretic was negligible. On the basis of these results, Brown and colleagues suggest inclusion of the combination of a low-dose thiazide diuretic with amiloride among the first-choice treatment strategies recommended for hypertension.10Brown MJ Williams B Morant S et al.for the PATHWAY Studies GroupEffect 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.Lancet Diabetes Endocrinol. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S2213-8587(15)00377-0Google Scholar This suggestion is legitimate, because the world is facing an epidemic of diabetes, and use of diuretic-based treatments that do not have dysmetabolic effects could have far-reaching beneficial consequences. However, before this suggestion is incorporated into guidelines, further evidence is needed. A study with longer treatment duration than 24 weeks would be useful to ensure that the favourable metabolic effects of amiloride continue to prevail. Although Brown and colleagues argue that data about 2 h glucose concentrations can be extrapolated to accurately predict the risk of new-onset diabetes,11Stern 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: 575-581Crossref PubMed Scopus (429) Google Scholar direct quantification of diabetes development in patients given a thiazide diuretic compared with those given a thiazide–amiloride combination is needed. Finally, and more generally, long-term studies are needed to clarify previous discrepancies and provide conclusive evidence that the diabetes induced by antihypertensive drugs (thiazides and β blockers)3Mancia G Grassi G Zanchetti A New-onset diabetes and antihypertensive drugs.J Hypertens. 2006; 24: 3-10Crossref PubMed Scopus (258) Google Scholar, 4Elliott WJ Meyer PM Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.Lancet. 2007; 369: 201-207Summary Full Text Full Text PDF PubMed Scopus (830) Google Scholar has the same deleterious effects on macrovascular and microvascular disease as spontaneous diabetes to be sure that the effect of the hydrochlorothiazide–amiloride combination translates from a trial setting into real-life benefit for cardiovascular prevention for patients. I declare no competing interests. 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 trialThe 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. Full-Text PDF Open Access