SGLT2 Inhibitors in Resistant Hypertension: A Sweet Solution

Hypertension is an established risk factor for cardiovascular disease, myocardial infarction, heart failure, stroke, dementia, and chronic kidney disease. Those individuals with resistant hypertension (RHT), most often defined as blood pressure (BP) above target despite being on 3 or more antihypertensive medications at optimal doses, preferably including a diuretic, are at much higher risk of cardiovascular disease compared with those without RHT.1,2 It is postulated that this increased risk occurs due to longer duration of uncontrolled hypertension, associated comorbidities, including diabetes, obesity, excessive sodium intake, and the interplay between activation of the renin–angiotensin–aldosterone system, sympathetic nervous system, and arterial stiffness.1,3 It is expected that with the increase in aging population, diabetes, and obesity, there will be a parallel increase in RHT prevalence and its associated morbidity. Traditionally, the backbone of pharmacological management of hypertension involves using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, and thiazide-like diuretics, referred to as the A–C–D combination. The Prevention and Treatment of Hypertension With Algorithm Based Therapy-2 (PATHWAY-2) trial compared the effect of 3 antihypertensive medications as add-on to the ACD combination (spironolactone, bisoprolol [beta-blocker], and doxazosin [alpha1-blocker]) vs. placebo on home BP in patients with confirmed RHT using a crossover design.4 The primary outcome, which was a reduction in home systolic BP (SBP) compared with placebo at 12 weeks, was greatest with spironolactone (−8.7 mm Hg [95% confidence interval, CI −9.7 to −7.7]), as compared with doxazosin (−4.0 mm Hg [−5.0 to −3.0]) and bisoprolol (−4.5 mm Hg [−5.5 to −3.5]). Achieved BP control for spironolactone, bisoprolol, and doxazosin was 58%, 44%, and 42%, respectively. Like most randomized controlled trials evaluating pharmacotherapies for RHT this was a short duration trial and assessed BP lowering efficacy, rather than cardiovascular morbidity or mortality. Most trials in this area are fraught with variability in definitions of RHT (apparent vs. true RHT), different BP measurement methodologies (office vs. home vs. 24-hour ambulatory BP monitoring), and heterogeneous distribution of comorbidities (RHT alone, RHT and diabetes, RHT and chronic kidney disease). Most importantly, the lack of clinical outcome data is a barrier, especially since epidemiological study findings which do report outcome data do not align with the randomized controlled trials.5 Given the significant burden of RHT on the public health system, novel therapies that both lower BP and improve cardiovascular outcomes are urgently needed. Rather than inventing new classes of antihypertensive medications, one strategy is to leverage existing classes of medications, which have demonstrated efficacy in BP lowering. Sodium-glucose cotransporter-2 (SGLT2) inhibitors selectively decrease renal glucose reabsorption and increase urinary glucose excretion. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) Outcome trial demonstrated that when empagliflozin was added to standard of care diabetes management there was a significant reduction in the primary outcome of death from cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio [HR] 0.86, 95% CI 0.74–0.99, P = 0.04).6 When compared with placebo, empagliflozin significantly reduced death from cardiovascular cause (HR 0.62; 95% CI 0.49–0.77), death from any cause (HR 0.68; 95% CI 0.57–0.82), and hospitalization for heart failure (HR 0.65; 95% CI 0.5–0.85). These results have been reproduced by other SGLT2 inhibitors, including dapagliflozin and canagliflozin.7,8 More recently, SGLT2 inhibitors have expanded its role outside of being simply a “diabetes medication,” and have been shown to improve kidney and heart failure outcomes as well.9,10 Interestingly, the mechanism of the clinical benefits are postulated to be mediated via both glucose and nonglucose lowering effects of this class of medication, including natriuresis, reduction in BP, weight loss, improvement in arterial stiffness and uric acid levels. In a 12 week trial, empagliflozin (10–25 mg daily) reduced 24-hour SBP and diastolic BP (DBP) by about 3–4 and 1–2 mm Hg, respectively.11 Interestingly, there was no dose–response relationship, with similar effect from either 10 or 25 mg empagliflozin. The BP lowering did not vary much based on the concomitant BP lowering drugs, mainly renin–angiotensin–aldosterone system blockade or diuretics. A subsequent meta-analysis synthesizes additional data, confirming that SGLT2 inhibitors compared with placebo significantly reduce 24-hour ambulatory BP monitoring by 3.7 (95% CI 2.3–4.2) and 1.8 (95% CI 1.3–2.4) mm Hg, for SBP and DBP, respectively.12 The literature supporting the BP lowering effects of SGLT2 inhibitors are summarized in Table 1.8,10,13–15 Summary of major trials of SGLT2 inhibitors on blood pressure Figures in parentheses refer to 95% confidence intervals. Abbreviations: ABPM, ambulatory blood pressure monitoring; BB, beta-blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic blood pressure; DM, diabetes mellitus; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; HTN, hypertension; MACE, major adverse cardiovascular events; MI, myocardial infarction; RCT, randomized controlled trial; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter-2. Summary of major trials of SGLT2 inhibitors on blood pressure Figures in parentheses refer to 95% confidence intervals. Abbreviations: ABPM, ambulatory blood pressure monitoring; BB, beta-blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic blood pressure; DM, diabetes mellitus; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; HTN, hypertension; MACE, major adverse cardiovascular events; MI, myocardial infarction; RCT, randomized controlled trial; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter-2. Greater drops in BP than these have been reported in 2 other subpopulations. Kario et al. and Ferdinand et al. have shown that empagliflozin dramatically reduces BP in diabetics with lack of nocturnal dipping and African Americans, respectively.16,17 Both these patient populations have hypertension phenotypes characterized by increased sodium sensitivity and fluid retention. The BP lowering was about 7/3 mm Hg, compared with the 4/2 mm Hg in previous meta-analysis.12 This may suggest that these patient populations have increased salt sensitivity and may potentially benefit more from SGLT2 inhibitors for BP lowering due to the natriuretic and osmotic diuretics effects. In this issue of the journal, Ferreira et al. performed a post hoc analysis of the EMPA-REG outcome trial, specifically assessing the glycemic and BP effects of empagliflozin on individuals with presumed resistant hypertension (pRHT).18 This was defined as baseline use of 3 or more classes of antihypertensive medications, including a diuretic, and uncontrolled office BP (SBP ≥140 and/or DBP ≥90 mm Hg) or use of ≥4 classes of antihypertensive medications.18 Approximately 22% of the population in this trial had pRHT, which is similar to the prevalence of RHT among those with diabetics. The proportion of participants with pRHT prescribed angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blockers, diuretics, and mineralocorticoid antagonists were 96.6%, 85.9%, 100%, and 17.2%, respectively, highlighting that the majority of participants with pRHT were indeed on optimal pharmacotherapy. Although BP was not the primary outcome in this trial, empagliflozin did reduce SBP and DBP by 4.5 (95% CI 3.1–5.9) and 1.7 (95% CI 0.9–2.5) mm Hg after 12 weeks compared with placebo, respectively, in line with the previous systematic review. Additionally, a significantly greater proportion of pRHT patients treated with empagliflozin achieved SBP less than 130 mm Hg (38% vs. 26% for placebo). This BP lowering effect of empagliflozin, which is similar to previous reported data with SGLT2 inhibitors, however is less when compared with spironolactone from PATHWAY-2 trial (SBP reduction of 8.7 mm Hg). Also different from other RHT trials, empagliflozin compared with placebo reduced cardiovascular death (HR 0.60), hospitalization for heart failure (HR 0.78), all-cause mortality (HR 0.75), and progression of nephropathy (HR 0.64) in those with pRHT. Limitations of the study by Ferreira et al. are that it is a post hoc analysis and not truly designed as an efficacy trial of a BP lowering drug. Hence, the definition of RHT did not account for medication adherence, therapeutic inertia, accurate BP measurement, and white coat hypertension, which are important in this subpopulation.1 BP was measured in the office with nonstandardized measurement techniques which can misclassify RHT especially compared with ambulatory BP monitoring, a more sensitive predictor of cardiovascular disease. Given that the mainstay therapy for RHT after baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, calcium channel blocker, diuretics are mineralocorticoid antagonist, additional data on the safety of add-on SGLT-2i, possibly from the other large randomized controlled trials already done, will be useful. SGLT2 inhibitors are generally well tolerated, and their metabolic effects are potentially useful in this setting: the lack of hyperkalemia, reduction in magnesium wasting, and lowering of serum uric acid, without a notable change in renin or aldosterone activity or heart rate.19,20 Should these drugs advance to being the fourth drug of choice after the ACD combination? That would seem to be premature, despite the promising outcome data. Among diabetic patients, SGLT2 inhibitors are moving up in the hierarchy to be among the first line drugs, and their use in patients with diabetes and hypertension is a fait accompli. The RHT population however, is enriched with patients having aldosterone excess and sodium retention, and from the PATHWAY-2 trial, the BP lowering effect of spironolactone was ~20 mm Hg in those with low renin states.4 In contrast, at the other end with extremely high renin levels, bisoprolol demonstrated greater BP lowering than doxazosin or spironolactone. A phenotype-driven decision making driven by mechanistic thinking may be more wise than a simple algorithm-driven brute addition of BP lowering drugs. Future trials with SGLT2 inhibitors in RHT must also ensure individuals have true RHT, use out-of-office BP measurement (home or ambulatory BP monitoring), assess medication adherence, and use optimal antihypertensive medications. RHT is a challenging condition to manage given its complex interplay of sodium and fluid retention, renin–angiotensin–aldosterone system and sympathetic nervous system activation, and individuals who are at high risk of cardiovascular disease. SGLT2 inhibitors are promising agents that not only reduce BP, but also improve cardiovascular and renal morbidity and mortality. Greater understanding of the effects of SGLT2 inhibitors, especially in comparison to existing fourth line drugs, and their effects on BP in nondiabetic patients will help us find their correct place in the RHT armamentarium. SH receives research salary support from the Department of Medicine, University of Ottawa. The authors declared no conflict of interest.

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