Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors

KEYWORDS:

• Sodium-glucose co-transporter 2 inhibitors
• arterial hypertension
• blood pressure
• uric acid
• body weight

1. Introduction

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are associated with a decrease in blood pressure (BP) levels. BP reduction was confirmed using 24-h ambulatory blood pressure monitoring in the EMPA-REG BP (12 week efficacy and safety study of empagliflozin in hypertensive patients with type 2 diabetes mellitus) trial, which showed that empagliflozin administration in both the 10 and 25 mg/d doses resulted in a decrease in 24-h systolic blood pressure (SBP) by 3.44 and 4.16 mmHg, respectively, and a smaller decrease in diastolic blood pressure (DBP) by 1.36 and 1.72 mmHg, respectively [1]. The drug modestly decreased nighttime BP values and seemed to beneficially affect surrogate markers of arterial stiffness in patients with type 2 diabetes mellitus and hypertension [2]. The SGLT2 inhibitor-induced decrease in BP seems to be higher in patients with baseline SBP >140 mmHg and may play a prominent role in the beneficial effects of empagliflozin in the EMPA-REG OUTCOME (empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients) trial [3]. It has been shown that BP reduction is a class effect of SGLT2 inhibitors, since they induce a considerable decrease in SBP and a lesser decrease in DBP compared with other glucose-lowering drugs, without any differences among the different agents within this group of antidiabetic drugs [4]. The BP reduction with these drugs exhibited a statistically significant dose dependency only for canagliflozin (−3.9 and −5.3 mmHg with 100 and 300 mg/d, respectively, for SBP and −2.1 and −2.5 mmHg with 100 and 300 mg/d, respectively, for DBP) [4]. Additionally, a meta-analysis of studies with empagliflozin, dapagliflozin, and canagliflozin showed a positive effect on sitting BP [5]. Importantly, although orthostatic dizziness has been reported with these agents, it has been emphasized that the SGLT2 inhibitor-induced BP reduction is not associated with orthostatic hypotension (relative risk compared with control treatment 0.72; 95% confidence interval 0.47–1.09) and this finding has been verified by the recent results of the EMPA-REG OUTCOME trial [3,4].

A number of possible mechanisms, which may be interrelated, have been proposed for the BP reduction with SGLT2 inhibitors (Table 1).

Table 1. Possible interrelated mechanisms of blood pressure (BP) reduction with sodium-glucose co-transporter 2 inhibitors.

Volume depletion due to diuresis and natriuresis Loop-diuretic-like action leading to conversion of salt-sensitive profile of BP to a non-salt-sensitive one Weight loss Improvement of arterial stiffness Uric acid reduction Inhibition of sympathetic nervous system activity

1.1. Hemodynamic mechanisms

Drug-associated hemodynamic changes may, at least in part, explain the decrease in BP. An approximate decrease in plasma volume by 7.3% measured by ¹²⁵I-labeled human serum albumin, maintained after 8 weeks of therapy, was found in patients treated with dapagliflozin. In fact, this decrease in plasma volume was associated with an increase in hematocrit by 2.2% [6]. Plasma volume reduction has been ascribed to the drugs’ diuretic and mild natriuretic effects, which are attributed to the inhibition of sodium reabsorption in the proximal tubules but also to osmotic diuresis. However, since the initial natriuresis can be compensated by a chronic increased sodium re-absorption in the distal tubules, the contribution of natriuresis may be small.

1.2. Loop diuretic-like effects

It has recently been suggested that SGLT2 inhibitors act as loop diuretics. Since diabetes-induced hypertension is characterized as salt-sensitive hypertension, with a prominent increase in SBP, and commonly exhibits a non-dipper pattern, SGLT2 inhibitors acting as diuretics could result in a decrease in BP and subsequently in a conversion of salt-sensitive profile of BP to a non-salt-sensitive one [7]. Experimental data have clearly shown that empagliflozin not only improved glucose metabolism but also decreased salt loading-mediated BP elevation and normalized abnormal diurnal BP profile to a dipper one through its ability to increase sodium excretion [8]. In fact, these drugs despite their diuretic ability and also the volume-depletion activation of renin-angiotensin system are not followed by a decrease in serum potassium, the most common and important side effect of the commonly used diuretics. On the contrary, a mild increase in serum potassium has been documented with canagliflozin [9]. It is possible that the SGLT2 inhibitor-induced decrease in plasma glucose levels could result in a reduction in insulin levels, leading to a redistribution of potassium from the cells to the extracellular compartment; this redistribution of potassium ions can counterbalance the renal potassium wasting and thus potassium homeostasis is preserved [7]. The diuretic effect of SGLT2 inhibitors has been highlighted in clinical studies. A recently published randomized double-blind placebo-controlled trial, which randomized 449 patients with residual BP elevation despite treatment with a renin-angiotensin system (RAS) blocker to dapagliflozin 10 mg/day or placebo, showed that dapagliflozin decreased seated SBP by 4.3 mmHg (p = 0.002) [10]. Interestingly, a post hoc analysis of this trial suggested that dapagliflozin can potentiate the antihypertensive effects of calcium channel blockers (by 5.1 mmHg) and beta-blockers (by 5.7 mmHg) in patients already receiving RAS blockers [10], a finding which suggests a diuretic-like volume depleting antihypertensive mechanism of action and also hints that these drugs could replace diuretics in the treatment of hypertensive patients with type 2 diabetes mellitus. Notably, no further reduction in BP was noticed in patients already receiving diuretics [10].

Interestingly, it has been shown that urine volumes return to baseline values a few weeks after the initiation of SGLT2 inhibitors, while their antihypertensive effects remain stable, a finding indicating that increased diuresis and natriuresis are not the only mechanisms underlying the BP-lowering effects of these drugs [1]. In line with this observation are data indicating that the antihypertensive effects of these compounds persist even in patients with reduced estimated glomerular filtration rate and attenuated diuresis and natriuresis [11].

1.3. Weight loss

Weight loss and visceral fat reduction related to increased diuresis and glucosuria-associated loss of calories may play a role in BP decrease. A meta-analysis of 25 randomized controlled trials showed that BP reductions expressed per kilogram of weight loss averaged −1.05 and −0.92 mmHg for SBP and DBP, respectively [12]. Thus, the reduction of body weight by approximately 2–3 kg over 24–52 weeks with SGLT2 inhibitors results in a decrease in BP; however, this BP reduction seems to be higher than that expected due to body weight decrease. In fact, it has been shown that only 40% of the SBP reduction observed with canagliflozin could be ascribed to weight loss [13].

1.4. Arterial stiffness and endothelial function improvement

A number of mechanisms including improved glycemic control and insulin sensitivity, decreased obesity and hyperglycemia-related oxidative stress and inflammation of the vascular wall, as well as improved endothelial function through protection of endothelial glucocalyx from sodium overload can lead to an improvement in arterial stiffness and vascular resistance [2,14].

1.5. Reduction of uric acid levels

SGLT2 inhibitors have been associated with a reduction of serum uric acid levels, possibly attributed to glycosuria-induced alteration of uric acid transport activity, which involves glucose transporter 9 isoform 2, in renal tubule [15]. The decrease in serum uric acid may play a role in BP reduction, since short-term clinical trials have shown that treatment of hyperuricemia is followed by a decrease in BP [16].

1.6. Inhibition of the sympathetic nervous system activity

An inhibitory effect of SGLT2 inhibitors on the sympathetic nervous system activity has been reported [17]. However, other authors have not shown significant changes in sympathetic nervous activity markers with empagliflozin in type 1 diabetic patients [18].

In conclusion, SGLT2 inhibitors decrease BP levels through various possible mechanisms, including diuretic and natriuretic effects, weight loss, improvement in arterial stiffness and vascular resistance.

2. Expert opinion

The decrease of BP levels with SGLT2 inhibitors, especially of SBP (an effect that can be speculated to be due to the reduction of blood volume and the decrease of pulse pressure and other markers of arterial stiffness [2,18]), might have played a role in the impressive cardiovascular results of the EMPA-REG OUTCOME. However, it is obvious that the rapid onset of these beneficial effects is not fully compatible with the BP decrease theory. The decrease in BP may also play a role in the potential long-term renoprotective effects of these drugs [8]. In this context, it has recently been shown that dapagliflozin reduces albuminuria in diabetic patients with hypertension receiving RAS blockers [19].

It should be mentioned that, despite the decrease in BP, SGLT2 inhibitors do not increase heart rate [1,4]. It is possible that this absence of an increase in heart rate is related to an inhibitory effect of these compounds on the sympathetic nervous system. However, the underlying mechanisms are not clear yet. On the other hand, these drugs should be carefully administrated in patients treated with diuretics to avoid hypovolemia and hypotension [7,20]. Interestingly, in the EMPA-REG, in which 43.7% of the study population were on diuretics, empagliflozin administration was associated with a small (statistically insignificant) increase in stroke incidence, which is speculated to be related to increase diuresis-associated hypovolemia and compromised cerebral blood supply. This possible association needs further investigation in future outcome trials.

The BP-decreasing effects of SGLT2 inhibitors, combined with the fact that they do not reduce serum potassium levels, highlight SGLT2 inhibitors as unique diuretics. However, more research is needed to clarify the implicated mechanisms as well as the possible future glucose-lowering-independent indications of these drugs.

Declaration of interest

This editorial was written independently; no company or institution supported it financially. No competing financial interests exist. M.S. Elisaf has received speaker honoraria, consulting fees, and research funding from AstraZeneca, Schering Plough, Merck, Pfizer, Solvay, Abbott, Boehringer Ingelheim and Fournier, and has participated in clinical trials with AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, GlaxoSmithKline, Novartis, Pfizer and Fournier. TD Filippatos has given talks and attended conferences sponsored by Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and Merck Sharp & Dohme. V. Tsimihodimos has given talks and attended conferences sponsored by Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and Merck Sharp & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.