Some studies that compared efficacy and safety of thiazide diuretics, including hydrochlorothiazide (HCTZ), have demonstrated a small but statistically significant increase in blood sugar levels compared to some other antihypertensive medications.2–5 While the increases in blood glucose that have been reported to occur in some patients taking thiazide diuretics are, on average, small (2 to 5 mg/dL over baseline)4–6 and usually lessen over time, the long term effects have not been thoroughly studied.2
Greater increases in blood sugar have resulted, in some cases, in new-onset diabetes among patients taking HCTZ, but because diabetes may develop in people not taking medication, it can be difficult to determine how many cases can be attributed to the use of the thiazide diuretic.2 In several observational studies, the relative risk of new-onset diabetes in hypertensive participants taking a thiazide diuretic compared with those not taking a thiazide was 1.20 (95% confidence interval [CI] [1.08 – 1.33]) in the Nurses’ Health Study I (n=41 193), 1.45 (95% CI [1.17 – 1.79]) in the Nurses’ Health Study II (n=14 151), and 1.36 (95% CI [1.17 – 1.58]) in the Health Professionals Follow-Up Study (n=19 472).7
A meta-analysis of 22 clinical trials of antihypertensive medications (n= 143 153) found the odds ratio of developing new-onset diabetes among patients taking placebo was 0.77 (95% CI [0.63 – 0.94]) when compared to patients taking thiazide diuretics.8 Using a network meta-analysis of data from these 22 trials, with diuretics at baseline as the standard of comparison, taking angiotensin receptor blockers, ACE-inhibitors, calcium channel blockers, or placebo at baseline were each associated with few cases on new-onset diabetes.
In one long-term cohort study of 795 hypertensive patients, 6.5% had type 2 diabetes at baseline.9 Both ambulatory blood pressure and electrocardiography was obtained at baseline and repeated throughout the study period of up to 16 years. New-onset diabetes occurred in 5.8% of the study participants, 11.1% of whom were taking a diuretic. Plasma glucose at entry (p=0.0001) and use of diuretic treatment on follow-up (p= 0.004) were independent predictors of the development of new-onset diabetes. (Ninety percent of those on diuretics were taking either HCTZ or chlorthalidone). During the period of the study, 63 patients experienced a new cardiovascular event. After adjustment for other factors that contribute to cardiovascular risk, including ambulatory blood pressure, the relative risk of cardiovascular events was 2.92 (95% CI [1.33 – 6.41], p=0.007) among those with new-onset diabetes, and 3.57 (CI [1.65 – 7.73], p=0.001) in those with diabetes at baseline, when compared to patients who stayed free of diabetes throughout the study period. The authors point out that while the use of diuretics increases the risk of developing new-onset diabetes compared to those not receiving diuretics, the use of diuretics did not show any independent relation with subsequent cardiovascular events.
In a 2014 review article, Barzilay et al. summarized what was known at that time about the glycemic effects of antihypertensive medications.10 The authors concluded that the cardiovascular protective effects of thiazide diuretics outweigh their negative effects on blood sugar and other metabolic parameters. The 2017 American College of Cardiology and American Heart Association guidelines consider all first-line classes of antihypertensive medications (including thiazide diuretics) useful and effective for use in patients with diabetes.11 It is the opinion of the authors of these guidelines and others that the importance of lowering blood pressure is particularly relevant among patients with diabetes because of their increased risk of adverse cardiovascular outcomes. The choice of antihypertensive medication should primarily be determined by their relative efficacy in reducing blood pressure and cardiovascular morbidity and mortality, along with the safety profile.10,12–14
The manufacturer’s product information for HCTZ warns that the medication may raise blood sugar levels.1 The dosage of insulin and other medications that are taken to stabilize blood sugar may need to be adjusted in people who are also taking hydrochlorothiazide.
References
- Hydrochlorothiazide [package insert]: Morgantown, WV: Mylan Pharmaceuticals; 2011.
- 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 (1): 30-36.
- Emeriau JP, Knauf H, Pujadas JO, et al. A comparison of indapamide SR 1.5 mg with both amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients: a randomized double-blind controlled study. J Hypertens 2001; 19 (2): 343-350.
- Mukete BN, Rosendorff C. Effects of low-dose thiazide diuretics on fasting plasma glucose and serum potassium-a meta-analysis. J Am Soc Hypertens 2013; 7 (6): 454-466.
- Zhang X, Zhao Q. Association of thiazide-type diuretics with glycemic changes in hypertensive patients: a systematic review and meta-analysis of randomized controlled clinical trials. J Clin Hypertens 2016; 18 (4): 342-351.
- Moore MJ, Gong Y, Hou W, et al. Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide. Pharmacotherapy 2014; 34 (11): 1132-1140.
- Taylor EN, Hu FB, Curhan GC. Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 2006; 29 (5): 1065-1070.
- Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369 (9557): 201-207.
- Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004; 43 (5): 963-969.
- Barzilay JI, Davis BR, Whelton PK. The glycemic effects of antihypertensive medications. Curr Hypertens Rep 2014; 16 (1).
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71 (19): e127-e248.
- Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015; 313 (6): 603-615.
- Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev 2013;(10): CD008277.
- Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362 (17): 1575-1585.
