Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials

1.

Limiting salt intake has effects on fluid status and vascular health resembling diuretic use, an important tool in the antihypertensive armamentarium. Here, we discuss salt sensitivity and dietary salt restriction and consider major clinical trials in hypertension and cardiovascular disease (CVD) that have demonstrated mortality reductions and incorporated thiazide‐like diuretics. The particular benefits of thiazide‐like diuretics are compared with those of sodium‐glucose cotransport‐2 (SGLT2) inhibitors, glucose‐lowering agents with diuretic effects. We define thiazide‐like diuretics and SGLT2 inhibitors as powerful diuretics. The conjoint consideration of salt sensitivity, thiazide‐like diuretics, and SGLT2 inhibitors is intended to focus consideration on targeted therapy in patients with type 2 diabetes mellitus with hypertension.

1. SALT SENSITIVITY AND SALT RESTRICTION

With salt sensitivity, higher blood pressure (BP) is needed for sufficient sodium excretion. As recently reviewed in the American Heart Association Scientific Statement on the salt sensitivity of BP,1 its formal identification involves a 2‐day hospitalization. Salt sensitivity is signaled by a ≥10‐mm Hg decrease in mean arterial BP from after saline loading/high dietary salt intake day to after the diuresis/low salt intake day.2, 3 Among 576 individuals, salt sensitivity was detected among 51% of individuals with hypertension and 26% of individuals with normotension. Age predicted salt sensitivity in both, and African descent was predictive in those with hypertension. There is evidence of impact of salt reduction on BP levels in patients with chronic kidney disease, diabetes mellitus, and obesity.1, 4, 5, 6 A high salt diet is also associated with lower insulin sensitivity.7 Salt‐sensitive individuals exhibit lower endothelium‐dependent vascular dilation and an abnormal pressor response to salt, independent of BP.8

The first interventions to reduce BP focused on limiting salt,9 as Allen proposed in 1920.10 In 1948, the low sodium “rice and fruit” diet demonstrated BP lowering.11 More recently, a meta‐analysis of randomized controlled trials,13 including the DASH (Dietary Approaches to Stop Hypertension) trials,5, 14 demonstrated that a >4 g/d lower salt intake led to an average 5.39‐mm Hg lower SBP in individuals with hypertension and a 2.42‐mm Hg lower SBP level in individuals with normotension, compared with controls. This led to recommendations to moderate salt intake and reduce the salt content of the food supply.15 The greatest BP‐lowering effect of such reductions in salt intake and salt content is in individuals with hypertension. While lower salt intake and lowered BP may contribute to lower CVD risk in these individuals, other features of this phenotype (eg, insulin resistance) or other actions of salt sensitivity–associated genes may have independent prognostic factors.1, 16

Given the impact of salt intake in salt‐sensitive individuals, it is not surprising that diuretics are effective antihypertensive agents. Thiazide‐type and thiazide‐like diuretics (eg, chlorthalidone and indapamide) lower BP and reduce CVD events. However, diuretics also induce sympathetic stimulation, with activation of the renin‐angiotensin‐aldosterone system.17 Both diuretics and salt restriction increase renin release, making BP more dependent on angiotensin II and, consequently, more responsive to angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers.18 Diuretics are associated with hyperglycemia.17 Severe and excessive salt restriction are linked to insulin resistance, elevated blood lipids, and increased uric acid production. Insulin resistance in these scenarios has largely been attributed to the activation of the renin‐angiotensin‐aldosterone and sympathetic nervous systems.19, 20, 21, 22, 23 There are thus similarities in the benefits and adverse effects of thiazide diuretics, thiazide‐like diuretics, and salt restriction.

2. DEVELOPMENT OF DIURETICS AND EVIDENCE OF IMPACT

The diuretic effect observed in some patients treated with sulfonamide antibiotics in the 1950s led to the development of hydrochlorothiazide. In the 1960s, the Veterans Cooperative Study24, 25 (500 men with diastolic BP between 90 and 130 mm Hg) compared hydrochlorothiazide with reserpine and hydralazine vs placebo. They demonstrated 25 strokes in the placebo arm vs six in the active treatment arm. Diuretics emerged as a mainstay of hypertension therapy.

3. LONGER‐ACTING DIURETICS AND KEY CLINICAL TRIALS

Both thiazide‐type diuretics (hydrochlorothiazide) and thiazide‐like diuretics (chlorthalidone and indapamide) block the sodium chloride transporter in the distal tubule (Figure), reducing sodium reabsorption. The thiazide‐like diuretics have a longer half‐life (50–60 hours) than the thiazide‐type diuretics (6–15 hours) because of binding at the erythrocyte. A meta‐analysis26 demonstrated a 12% additional risk reduction for CVD events and a 21% additional reduction in heart failure for thiazide‐like diuretics vs thiazide‐type diuretics, with similar adverse event rates. Key trials that incorporated long‐acting thiazides are (Table):

Figure 1.

Sites of action of agents with diuretic effects. SGLT2 indicates sodium‐glucose cotransporter‐2

Table 1.

Summary of key trials discussed

Trial	Publication Year	Population	Intervention	Comparator	Main results	Follow‐up
SHEP	1991	4736 participants aged ≥60 y	Step 1: dose 1 was chlorthalidone 12.5 mg/d; dose 2 was 25 mg/dStep 2: dose 1 was atenolol, 25 mg/d; dose 2 was 50 mg/d	Placebo	HR for nonfatal and fatal (total) stroke was 0.64 (95% CI, 0.50–0.82)HR for clinical nonfatal MI plus coronary death was 0.73 (95% CI, 0.57–0.94)HR for major cardiovascular events was 0.68 (95% CI, 0.58–0.79)HR for deaths from all causes was 0.87 (95% CI, 0.73–1.05)	Mean: 4.5 y
ALLHAT	2002	33 357 individuals with hypertension aged ≥55 y with one additional cardiovascular risk factor	Chlorthalidone	Amlodipine vs lisinopril	In comparison to chlorthalidone, HR for CHD was 0.98 (95% CI, 0.90–1.07) for amlodipine and 0.99 (95% CI, 0.91–1.08) for lisinoprilHR for heart failure was 1.38 (95% CI, 1.25‐1.52) for amlodipine and 1.19 (95% CI, 1.07–1.31) for lisinoprilHR for other cardiovascular disease was similar for amlodipine and lisinopril 1.10 (95% CI, 1.05–1.16)All‐cause mortality did not differ between the groups	Mean: 4.9 y
ADVANCE	2007	11 140 patients with type 2 diabetes mellitus	Fixed combination of perindopril and indapamide	Placebo	In patients assigned to intervention compared with placebo, HR for a major macrovascular or microvascular event was 0.91 (95% CI, 0.83–1.00)The separate reductions in macrovascular and microvascular events were similar but were not independently conclusiveHR for death from cardiovascular disease was 0.82 (95% CI, 0.68–0.98) and death from any cause was 0.86 (95% CI, 0.75–0.98)	Mean: 4.3 y
HYVET	2008	3845 very elderly (aged >80 y)	Indapamide (sustained‐release, 1.5 mg)	Placebo	Intervention (vs placebo) was associated with a 30% reduction in rate of fatal or nonfatal stroke (95% CI, −1 to 51)A 39% reduction in rate of death from stroke (95% CI, 1–62)A 21% reduction in rate of death from any cause (95% CI, 4–35)A 23% reduction in rate of death from cardiovascular causes (95% CI, −1 to 40)A 64% reduction in rate of heart failure (95% CI, 42–78)Fewer serious adverse events (358 vs 448)	Median: 1.8 y
SPRINT	2015	9361 patients with high vascular risk with an SBP ≥130 mm Hg who were aged ≥50 y and had no history of diabetes mellitus or strokeThey were required to have ≥1 of the following: CKD with a glomerular filtration rate 20–60 mL/min per 1.73 m2 of body surface area, a Framingham risk score ≥15%, age >75 y, and/or clinical or subclinical CVD*SPRINT participants included patients at risk for salt sensitivity and sodium retention (31% blacks, patients with CKD, obesity, and 28% elderly)	Intensive target strategy (SBP <120 mm Hg), thiazide‐like diuretics encouraged	Standard target strategy (SBP <140 mm Hg)	Intensive treatment strategy was associated with a 13‐mm Hg reduction in SBPIn intensive treatment group vs standard treatment group, HR was 0.75 (95% CI, 0.64–0.89) for composite end point and 0.73 (95% CI, 0.60–0.90) for all‐cause mortalityRates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group	Median: 3.26 y
HOPE‐3	2016	12 705 participants at intermediate CVD riskParticipants were required to have one of the following: high waist–hip ratio, low HDL, current/recent smoking, prediabetes/diet‐controlled diabetes mellitus, premature coronary disease in first‐degree relatives, or early renal dysfunction	Thiazide‐type diuretic (fixed‐dose hydrochlorothiazide) and candesartan	Placebo	Despite SBP dropping by 10 mm Hg in the intervention group relative to the placebo group, there was no impact on the first coprimary outcome (composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke) and the second coprimary outcome (additionally included resuscitated cardiac arrest, heart failure, and revascularization) with HRs of 0.93 (95% CI, 0.79–1.10) and 0.95 (95% CI, 0.81–1.11), respectively	Median: 5.6 y
EMPA‐REG	2015	7020 individuals with type 2 diabetes mellitus and established CVD (MI, stroke, amputation, multivessel CAD, or coronary artery bypass surgery)	Empagliflozin	Placebo	Participants treated with empagloflozin vs those treated with placebo had HRs of 0.86 (95% CI, 0.74–0.99) in first coprimary outcome (death from cardiovascular causes, nonfatal MI, or nonfatal stroke; 0.89 (95% CI, 0.78–1.01) in the second coprimary outcome (death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina); 0.68 (95% CI, 0.57–0.82) for death from any cause; and 0.62 (95% CI, 0.49–0.77) for death from cardiovascular causes	Median: 3.1 y
CANVAS	2017	10 142 patients with type 2 diabetes mellitus aged ≥30 y with established CVD or ≥50 y of age with ≥2 of the following: diabetes mellitus duration of at least a decade, SBP >140 mm Hg on antihypertensive therapy, current smoking, exceeding microalbuminuria thresholds, and/or HDL <1 mmol/L	Canagliflozin	Placebo	HRs for canagliflozin vs the placebo group were 0.86 (95% CI, 0.75–0.97) for the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke; 0.73 (95% CI, 0.67–0.79) for progression of albuminuria; and 0.60 (95% CI, 0.47–0.77) for the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal replacement therapy, or death from renal causesWhile adverse reactions were consistent with the previously reported risks associated with canagliflozin an HR of 1.97 (95% CI, 1.41–2.75) was observed for amputations	Mean: 188.2 wk

Abbreviations: ADVANCE, Action in Diabetes and Vascular Disease trial; ALLHAT, Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial; CAD, coronary artery disease; CANVAS, Canagliflozin Cardiovascular Assessment Study; CHD, coronary heart disease; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; EMPA‐REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HDL, high‐density lipoprotein; HOPE‐3, Heart Outcomes Prevention Evaluation; HR, hazard ratio; HYVET, Hypertension in the Very Elderly Trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SHEP, Systolic Hypertension in the Elderly Program.

• SHEP (Systolic Hypertension in the Elderly Program)27 included low‐dose chlorthalidone as the first‐line agent and demonstrated reductions in CVD events with treatment of isolated systolic hypertension in the elderly.

• ALLHAT (Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial) in 200228 compared chlorthalidone, amlodipine, and lisinopril treatment in individuals with hypertension. Coronary heart disease and mortality were similar across treatment arms but the chlorthalidone arm demonstrated less heart failure than the amlodipine arm and lower CVD rates than the lisinopril arm.

• The ADVANCE (Action in Diabetes and Vascular Disease) trial29 compared a fixed combination of perindopril and indapamide with placebo. There were reductions in vascular end points, CVD mortality, and all‐cause mortality. While the independent effects of the combination drug components cannot be distinguished, it is notable that the diuretic component of the combination was a thiazide‐type diuretic.

• HYVET (Hypertension in the Very Elderly Trial)30 in which the initial therapy was indapamide, proved that hypertension treatment in individuals older than 80 years reduced CVD and mortality events.

Contrasting outcomes from recent landmark trials, SPRINT (Systolic blood Pressure Intervention Trial)31 published in 2015 and HOPE‐3 (Heart Outcomes Prevention Evaluation)32 in 2016, are also arguably consistent with benefits of thiazide‐like diuretics. Conclusive CVD benefits were observed in SPRINT, in contrast to HOPE‐3. Thiazide‐like diuretics predominated in SPRINT, whereas thiazide‐type diuretics were a mainstay of therapy in HOPE‐3. While there were other differences in the trials as discussed below, the difference in diuretic type was arguably a factor. HOPE‐3 included 12 705 participants at intermediate CVD risk. The mean baseline BP was 138/82 mm Hg. Participants were randomized to fixed‐dose hydrochlorothiazide and candesartan vs placebo. After a median of 5.6 years, SBP dropped by 10 mm Hg in the active treatment group relative to the placebo group. HOPE‐3 did not demonstrate impact on heart failure or CVD mortality. SPRINT enrolled 9361 participants with an SBP of ≥130 mm Hg who were 50 years or older without diabetes mellitus or stroke; they additionally required CVD, glomerular filtration rate between 20 to 60 mL/min per 1.73 m² body surface area, a Framingham risk score >15%, and/or age older than 75 years. SPRINT randomized patients to an SBP target <120 mm Hg vs a standard target <140 mm Hg. The intensive treatment strategy was associated with a 13‐mm Hg SBP reduction and a 27% reduction in the composite end point of myocardial infarction, other acute coronary syndromes, heart failure, stroke, and CVD death at a median follow‐up of 2.6 years. The composite end point was driven primarily by reductions in mortality and heart failure.

SPRINT encouraged the use of thiazide‐like diuretics. These agents were prescribed in 55% of the intensive target patients and 33% of the standard target group. The powerful diuretic effect of thiazide‐like diuretics in a high‐risk salt‐sensitive population (31% blacks, patients with chronic kidney disease, obesity, and 28% elderly) may have contributed to reductions in heart failure and perhaps heart failure–related mortality.

Nonetheless, hydrochlorothiazide remains the most widely used diuretic in clinical practice, with the prescribing of long‐acting thiazide diuretics significantly underutilized in both Canada33 and the United States.21 In an examination of diuretic prescribing in the treatment of resistant hypertension across the United States, over 50% of patients received hydrochlorothiazide but only 1.2% of patients received long‐acting thiazide‐like diuretics such as chlorthalidone.34 The disproportionate use may be attributable, in part, to the lower cost per pill of hydrochlorothiazide compared with longer‐acting agents in the United States; however, both types of diuretics are readily available and, in general, diuretics are relatively low‐cost antihypertensive agents.

In Hypertension Canada's 2017 clinical practice guidelines,35 longer‐acting (thiazide‐like) diuretics are explicitly preferred over shorter‐acting agents (thiazide‐type) when diuretics are selected. We do acknowledge, however, that it is not clearly established whether the “diuretic” effect of diuretics is the only mechanism whereby CVD benefits are realized with chronic use. In fact, there is some evidence that extracellular volume does not differ between diuretic‐treated and diuretic‐untreated patients.36 Diuretic agents may have other effects on hemodynamics with chronic use; for example, indapamide has vasorelaxant effects similar to calcium channel antagonists.37, 38 While consideration of these therapies is warranted, there must be efforts to monitor for adverse effects,37 including electrolyte imbalances, hypotension, and orthostasis, to prevent sequelae such as sudden death, falls, and syncope. In contrast to thiazide‐type diuretics and chlorthalidone, indapamide does not appear to have adverse effects on glucose or lipid metabolism.39

4. A NEW DIABETES MELLLITUS DRUG CLASS WITH DIURETIC EFFECTS

The observed benefits of a new class of antihyperglycemic agents, the SGLT2 inhibitors, further illustrates the merits of powerful diuretics in salt‐sensitive clinical populations such as those with type 2 diabetes mellitus. In addition to the antihyperglycemic effects, SGLT2 inhibitors have osmotic diuretic and natriuretic effects inhibiting the sodium‐glucose cotransporter at the proximal convoluted tubule, where approximately 65% of filtered sodium is absorbed (Figure). SGLT2 inhibitors may also have further downstream effects on the loop of Henle.40, 41

These agents were associated with significant reductions in 24‐hour ambulatory systolic BP (SBP) (−4.16 [95% CI, −5.50 to −2.83] mm Hg) and diastolic BP (−1.72 [95% CI, −2.51 to −0.93] mm Hg).42 Two recent trials in patients with type 2 diabetes mellitus demonstrated the cardiovascular benefits of SGLT2 inhibitors: the EMPA‐REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients)43 and the recent CANVAS (Canagliflozin Cardiovascular Assessment Study).44

EMPA‐REG43 studied over 7000 individuals with type 2 diabetes mellitus and CVD (myocardial infarction, stroke, amputation, multivessel coronary artery disease, or coronary artery bypass surgery), aiming to establish cardiovascular safety as add‐on antihyperglycemic therapy. Participants treated with empagloflozin experienced a 38% reduction in CVD death, a 35% reduction in heart failure hospitalization, and a 32% reduction in all‐cause mortality.

The glucose‐lowering effects of empagliflozin alone were not appreciably different from other antihyperglycemic agents in the 0.5% glycated hemoglobin–lowering range. SBP in EMPA‐REG was lowered by 4 to 5 mm Hg.42 We speculate that the importance of the SGLT2‐induced diuretic effect in the trial may have manifested because less than half of participants were on conventional diuretic therapy: while 81% of patients received angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker therapy in the trial, only 43% received diuretic therapy. We acknowledge that neither the glucose‐lowering nor the BP‐lowering effects of empagliflozin alone may completely account for the benefits observed. It has been postulated that empagliflozin treatment in EMPA‐REG may have resulted in important afterload and preload reductions that conferred benefit in patients with subclinical or undetected heart failure. It should be acknowledged, however, that inhibition of SGLT2 may result in upregulation of SGLT1 and increased sodium resorption.45

The CANVAS program involved a combined analysis of two trials evaluating the cardiovascular and renal outcomes of canagliflozin in over 10 000 patients with type 2 diabetes mellitus. Included patients were 30 years and older with established CVD or 50 years and older with two or more of the following: diabetes duration ≥10 years, SBP >140 mm Hg on antihypertensive therapy, current smoking, microalbuminuria, and/or high‐density lipoprotein level <1 mmol/L. Glycated hemoglobin and SBP reduction were similar to that observed in EMPA‐REG, as was the 14% reduction in the composite end point (CVD death, nonfatal myocardial infarction, and nonfatal stroke). In subgroup analyses, the composite end point was reduced in those on diuretic therapy but not in those who were not receiving diuretics and in those with CVD but not in those without CVD. Important adverse events included a doubling of lower limb amputation rates and an increase in fractures that may have resulted from hypoperfusion related to diuretic effects. This underscores the importance of not only leveraging the benefits of powerful diuresis but also to exercise appropriate surveillance of BP and perfusion. SGLT2 inhibitors may play an important adjunctive role the treatment of hypertension in patients with type 2 diabetes mellitus; however, further research is needed to establish this and whether they provide a cardiovascular advantage over lower‐cost, long‐acting thiazide diuretic therapy.

5. CONCLUSIONS

There is justification for the use of long‐acting thiazide‐like diuretics for hypertension management over hydrochlorothiazide. The benefits observed with at least two SGLT2 inhibitors may attributable, in part, to their diuretic effects and therefore may be a promising new adjunct in the treatment of hypertension in patients with type 2 diabetes mellitus. Perhaps, particularly in salt‐sensitive demographic and clinical populations, there is an opportunity to leverage the potential benefits of powerful diuresis, with long‐acting thiazide‐like diuretics and/or SGLT2 inhibitors in type 2 diabetes mellitus. However, careful monitoring is required for prevention of hypoperfusion and hypotension. Counseling and support for adoption of a DASH‐type diet with moderated salt intake offers important benefits and should be offered throughout the course of hypertension management. In patients with type 2 diabetes mellitus with hypertension, the risks and benefits of including and/or combining salt restriction, thiazide‐like diuretics, and SGLT2 inhibitors warrants further study and careful consideration in clinical decision making.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Dasgupta K, Sapir‐Pichhadze R, Khan N. Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials. J Clin Hypertens. 2018;20:136‐142. 10.1111/jch.13151