Author + information
- Anil K. Pareek, MD∗ (, )
- Ravi T. Mehta, MD,
- Indranil Purkait, MBBS, MGMC and
- Anu Grover, PhD
- ↵∗Medical Affairs and Clinical Research, Ipca Laboratories Ltd., 142 AB, Kandivali Industrial Estate, Mumbai–400067, India
We compliment Messerli et al. (1) on their state-of-the-art paper. We agree that the thiazide-like diuretic drugs chlorthalidone and indapamide are outstanding agents and have an advantage over other antihypertensive drugs when used to prevent heart failure (HF), whereas low-dose, once-daily hydrochlorothiazide should be avoided.
In the Central Illustration (1), the authors have recommended addition of SGLT-2 inhibitors in type 2 diabetes. However, SGLT-2 inhibitors have not yet been evaluated in any clinical study for safety and efficacy in HF, including in patients with diabetes. Moreover, in the U.S. Food and Drug Administration label of empagliflozin, under warnings and precautions, it is stated that initiating empagliflozin therapy in patients with HF and concomitant medications (diuretics, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin receptor blockers [ARBs]) may predispose to acute kidney injury.
Furthermore, the authors have advocated use of calcium channel blockers (CCBs), followed by spironolactone and then a thiazide-like diuretic (in sequence) for patients with HF with preserved ejection fraction (HFpEF) and hypertension. Beta-blockers are usually added once the patient is stabilized by using ACEi and ARB therapy and loop diuretics. Following this, an attempt may be made to wean the patients from loop diuretics and switch to thiazide-like diuretics. In these patients, it is important that CCBs not be given ahead of thiazide-like diuretics because that can precipitate HF. In the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) study, a substantially higher risk of HF was found with amlodipine than with chlorthalidone (relative risk [RR]: 1.38; 95% confidence interval [CI]: 1.25 to 1.52; risk being even higher in patients with diabetes, RR: 1.42; 95% CI: 1.23 to 1.64). Furthermore, in an ALLHAT substudy of HF, investigators reported that chlorthalidone reduced the risk of HFpEF and HF with reduced ejection fraction (HFrEF) compared with amlodipine by 31% (hazard ratio [HR]: 0.69; 95% CI: 0.53 to 0.91; p = 0.009) and 26% (HR: 0.74; 95% CI: 0.59 to 0.94; p = 0.013), respectively (2).
Coexistence of hypertension and diabetes results in a negative synergistic effect on left ventricle (LV) diastolic mechanics and is associated with higher LV filling pressures than either condition alone (3). Elderly diabetic patients who have renal insufficiency are more prone to HF. The benefit of using chlorthalidone in diabetes has been demonstrated in the 14-year follow-up of Systolic Hypertension in Elderly Program subjects (4), wherein diuretic treatment in subjects who had diabetes was strongly associated with lower long-term cardiovascular mortality rate (adjusted HR: 0.688; 95% CI: 0.526 to 0.848) and total mortality rate (adjusted HR: 0.805; 95% CI: 0.680 to 0.952). In the ALLHAT Diabetes Extension study (5), a comparison between participants with incident diabetes receiving chlorthalidone and those with no diabetes had consistently lower risk for cardiovascular disease mortality (HR: 1.04; 95% CI: 0.74 to 1.47), all-cause mortality (HR: 1.04; 95% CI: 0.82 to 1.30), and non-cardiovascular disease mortality (HR: 1.05; 95% CI: 0.77 to 1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range: 1.22 to 1.53). Despite more participants with incident diabetes taking chlorthalidone, cardiovascular mortality was much less than for those receiving lisinopril and amlodipine. This should allay the concerns of physicians in using chlorthalidone in diabetics. Use of amlodipine in diabetic hypertensive patients with diastolic dysfunction is of great clinical concern, particularly when used with saxagliptin and alogliptin, which have been associated with higher risks of HF in the respective cardiovascular outcome trials.
In conclusion, in diabetic hypertensive patients with diastolic dysfunction, thiazide-like diuretics should be preferred ahead of CCBs for blood pressure control.
Please note: Drs. Pareek, Mehta, Purkait, and Grover are employees of Ipca Laboratories, Ltd.; and are involved in research studies of chlorthalidone.
- 2017 American College of Cardiology Foundation
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- Rimoldi S.F.,
- Bangalore S.
- Davis B.R.,
- Kostis J.B.,
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- et al.
- Barzilay J.I.,
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- Pressel S.L.,
- et al.