Chlorthalidone is a type of thiazide diuretic approved by the FDA in 1981 for the management of hypertension and as adjunctive therapy for edema.1,2 Chlorthalidone is a first-line antihypertensive according to the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guidelines, and it is considered a safe option for people with diabetes mellitus (DM).3 However, its impact on glycemic dysregulation has been questioned. Drug manufacturers warn that chlorthalidone may raise blood glucose levels and impact glucose tolerance.1,2
Studies have consistently demonstrated that chlorthalidone increases fasting glucose levels no matter baseline fasting blood sugar levels and has a dose-dependent effect.4 Because of this, studies have also shown that chlorthalidone can increase blood sugar levels enough to increase incidence of new-onset diabetes in hypertensive populations. However, these increases may not affect long-term cardiovascular disease (CVD) risk.
A 2014 Cochrane review analyzed three trials (n=394) that compared the effect of chlorthalidone vs placebo on serum blood glucose and further examined the results by dosage. Averaging all dosages, there was a statistically significant increase in blood sugar of 6.12 mg/dL between chlorthalidone and placebo (95% Confidence Interval [CI] [2.16-9.90]). Among those taking 25-30 mg/day (n=80), blood glucose levels rose by 10.44 mg/dL compared to placebo (95% CI [4.14-16.74]). However, differences in blood glucose in the 12.5 mg, 50 mg, and 75 mg groups were not significant.5
A 2013 meta-analysis of ten randomized control trials (n=17,947) examined the metabolic profile of low-dose usage of thiazide diuretics including chlorthalidone (≤25 mg/day), hydrochlorothiazide (≤25 mg/day), and bendroflumethiazide (≤5 mg/day). On average, thiazide diuretics cumulatively increased fasting plasma glucose by 3.5 mg/dL compared to 2.2 mg/dL in the control arm (Hazard Ratio [HR] 1.22, 95% CI [1.11-1.33], p<0.01). While this increase was significant, the authors concluded that it didn’t appear to place patients at clinically significant risk.6
A 2016 meta-analysis evaluated 26 trials (n=16,162) that investigated the impact of thiazide diuretics on glycemic control. The thiazide diuretics included were hydrochlorothiazide, chlorthalidone, bendrofluazide, and indapamide and were compared to control groups, which included non-thiazide agents, placebo, or nontreatment. There was a significant increase in fasting plasma glucose levels with thiazide diuretics compared to control groups (mean difference of 4.86 mg/dL, 95% CI [2.7-7.02], p<0.0001).4
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), conducted from 1994-2002, compared the effectiveness of chlorthalidone, amlodipine, and lisinopril as well as biochemical changes and effects on cardiovascular outcomes. Researchers randomly assigned participants (n=33,357) with stage 1 or stage 2 hypertension with an additional risk factor for coronary heart disease events to receive chlorthalidone, amlodipine, or lisinopril with a mean follow-up of 4.9 years. Among all participants taking chlorthalidone (n=11,273), the mean fasting glucose levels increased by 4.1 mg/dL (from 123.5 at baseline to 127.6 at two-year follow-up). Among nondiabetic participants, mean fasting glucose increased by 9.1 mg/dL (from 93.1 to 102.2) at two-year follow-up and by 11.3 mg/dL (from 93.1 to 104.4) at the four-year follow-up.7,8
The ALLHAT study also found rates of new-onset diabetes, defined as fasting glucose >126 mg/dL, were higher among those taking chlorthalidone. Among participants who were nondiabetic at baseline, the incidence of diabetes was 11.6% for those receiving chlorthalidone compared to 9.8% (p=0.04) and 8.1% (p<0.001) in the amlodipine and lisinopril groups, respectively. However, the study did not account for participants with borderline values at baseline.8
Despite the increased incidence of new-onset diabetes, chlorthalidone was not associated with increased CVD risk but rather was slightly more effective at reducing CVD risk compared to the other antihypertensive agents. Comparing amlodipine and chlorthalidone, they had similar rates of CVD outcomes with the exception of heart failure, which was more prevalent in those taking amlodipine (6-year rate of 10.2% vs 7.7%, Relative Risk [RR] 1.38, 95% CI [1.25-1.52]). Comparing lisinopril and chlorthalidone, lisinopril had higher rates of combined CVD (33.3% vs 30.9%, RR 1.10, 95% CI [1.05-1.16]), stroke (6.3% vs 5.6%, RR 1.15, 95% CI [1.02-1.30]), and heart failure (8.7% vs 7.7%, RR 1.19, 95% CI [1.07-1.31]). Given that chlorthalidone was shown to be more effective at lowering blood pressure (systolic BP was 0.8 mmHg higher in the amlodipine group and 2 mmHg higher in the lisinopril group compared to chlorthalidone) as well as superior at lowering CVD risk, the authors suggested that thiazide-diuretics should be the preferred agent despite any associated metabolic changes.8
A 2021 a priori subgroup analysis of the Prevention of Hypertension in Patients with Pre-Hypertension (PREVER-Treatment) trial compared treatment with a chlorthalidone and amiloride combination pill to losartan in patients with DM (n=97). This study was a double-blind, randomized trial across 21 medical centers. Diuretic combination therapy had significantly higher systolic blood pressure reduction compared to losartan (15.2 mmHg [143.6 at baseline to 128.4 at 18 months] vs 8.9 mmHg [142.4 to 133.5], p<0.001). In the diuretic group, 83.7% of patients achieved blood pressure <140/90 mmHg compared to 66.0% of patients on losartan (p=0.09). There was no significant difference in serum glucose between the groups (158.7 mg/dL for diuretics vs 145.9 for losartan, p=0.33).9
Overall, evidence suggests that chlorthalidone may raise fasting blood glucose levels when compared to non-thiazide agents, placebo, or nontreatment. However, it is unclear how clinically significant this increase is, and experts have concluded that it is a safe option for people with DM. Furthermore, studies show that this glycemic dysregulation can be attenuated by taking doses <25 mg/day.
References:
- Chlorthalidone [package insert]. Morgantown, WV: Mylan Pharmaceuticals; 2019.
- Thalitone [package insert]. East Brunswick, NJ: Casper Pharma; 2019.
- 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 Pr. Hypertension. 2018-06-01 2018;71(6):e13-e115. doi:10.1161/hyp.0000000000000065
- 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. Journal of clinical hypertension (Greenwich, Conn). Apr 2016;18(4):342-51. doi:10.1111/jch.12679
- Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev. May 29 2014;(5):Cd003824. doi:10.1002/14651858.CD003824.pub2
- Mukete BN, Rosendorff C. Effects of low-dose thiazide diuretics on fasting plasma glucose and serum potassium-a meta-analysis. J Am Soc Hypertens. Nov-Dec 2013;7(6):454-66. doi:10.1016/j.jash.2013.05.004
- Black HR, Davis B, Barzilay J, et al. Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Diabetes Care. Feb 2008;31(2):353-60. doi:10.2337/dc07-1452
- Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Jama. Dec 18 2002;288(23):2981-97. doi:10.1001/jama.288.23.2981
- Fuchs FD, Scala LCN, Vilela-Martin JF, et al. Effectiveness of chlorthalidone/amiloride versus losartan in patients with stage I hypertension and diabetes mellitus: results from the PREVER-treatment randomized controlled trial. Acta Diabetol. Feb 2021;58(2):215-220. doi:10.1007/s00592-020-01611-8
