BP-lowering effects of SGLT-2 inhibitors and finerenone: an indirect comparison in patients with chronic kidney disease and type 2 diabetes

KEYWORDS:

• Blood pressure
• chronic kidney disease
• finerenone
• hypertension
• SGLT-2 inhibition
• type 2 diabetes

1. Introduction

Sodium-glucose co-transporter type 2 (SGLT-2) inhibitors have been originally developed for the improvement of glycemic control in patients with type 2 diabetes (T2D) [1,2]. However, evidence from subsequent trials demonstrated that their main treatment effect is the reduction of the risk for adverse cardiovascular and kidney failure events [1]. Three landmark trials conducted specifically in patients with chronic kidney disease (CKD) were prematurely terminated due to an impressive cardiorenal protective benefit of SGLT-2 inhibitors relative to placebo [3–5]. Notably, the improvement of cardiorenal outcomes was similar in magnitude in patients with or without T2D [3,4].

Finerenone, a highly selective non-steroidal mineralocorticoid-receptor-antagonist (MRA), provoked a placebo-subtracted reduction of 18% in the primary composite kidney outcome over the course of the FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) trial [6]. Furthermore, relative to placebo, finerenone lowered by 13% the occurrence of the primary composite cardiovascular outcome in the FIGARO-DKD (FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease) trial [7].

On this scientific basis, both SGLT-2 inhibitors and finerenone are now guideline-directed therapies for patients with CKD associated with T2D [8]. Although these agents are recommended with the indication of cardiorenal protection and not for their antihypertensive actions [8], there is evidence that SGLT-2 inhibitors and finerenone provoke clinically meaningful reductions in blood pressure (BP) levels. In this editorial, we provide an indirect comparison of the BP-lowering efficacy of SGLT-2 inhibitors with that of finerenone. We explore the significance of these hemodynamic effects as a mediator of the cardiorenal protection afforded by these 2 novel drug categories in patients with CKD associated with T2D.

2. BP reduction with SGLT-2 inhibitors

A 2017 meta-analysis of 43 trials showed that among patients with T2D, as compared with placebo, the change from baseline with SGLT-2 inhibitor therapy was −2.46 mmHg [95% confidence interval (CI): −2.86 to −2.06] for office systolic BP and −1.46 mmHg (95% CI: −1.82 to −1.09) for office diastolic BP [9]. The BP-lowering efficacy of SGLT-2 inhibitors was quantified more precisely in a subsequent meta-analysis of 7 randomized trials that incorporated the reference-standard technique of ambulatory BP monitoring (ABPM) [10]. The weighted mean difference between SGLT-2 inhibitor and placebo groups in change from baseline of 24-hour ambulatory systolic BP was −3.66 mmHg (95% CI: −4.29 to −2.94). The placebo-subtracted change from baseline in 24-hour ambulatory diastolic BP was −1.70 mmHg (95% CI: −2.13 to −1.26) [10]. There was no relationship between the dose and response of ambulatory BP to SGLT-2 inhibitor therapy. The ambulatory BP reduction provoked by SGLT-2 inhibitors was similar in magnitude with the BP-lowering effect of low-dose hydrochlorothiazide [10].

The mechanisms through which SGLT-2 inhibitors provoke the above-mentioned reductions in office and ambulatory BP are not yet fully clear. These drugs act primarily by inhibiting the reabsorption of sodium and glucose in the proximal convoluted tubule [1]. Accordingly, the resulting natriuresis and osmotic diuresis have been proposed as the main mechanisms to explain the contraction in intravascular volume and the reduction in BP seen in response to SGLT-2 inhibitor therapy [11]. However, other natriuretic-independent mechanisms may be also involved [11]. For example, in neurogenic hypertensive Schlager mice, a recent experimental study showed that chemical denervation down-regulated the renal expression of SGLT-2 protein, and that dapagliflozin reduced the release of norepinephrine in the kidney tissue, evidence suggesting a potential cross-talk between sympathetic overactivity and SGLT-2 regulation [12]. Other experimental and clinical studies showed that SGLT-2 inhibition results in suppression of the renin-angiotensin-system axis, regression of aortic stiffness and improvement in endothelial dysfunction. Additional support to this notion is provided by the observation that the antihypertensive effect of SGLT-2 inhibitors persists even in patients with moderate-to-advanced CKD, although the glycosuric action of these agents is progressively diminished in parallel with the decline in the levels of estimated-glomerular-filtration-rate (eGFR) [13].

Irrespective of the underlying mechanisms, the modest BP-lowering efficacy of SGLT-2 inhibitors is unlikely to fully explain the remarkable improvement in cardiorenal outcomes with these agents. This was illustrated in a post-hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial [14]. CREDENCE enrolled 4,401 patients with albuminuric CKD and T2D. Of these, 3,361 patients (76.4%) had baseline office systolic BP ≥130 mmHg and 1,371 patients (31.2%) fulfilled the diagnostic criteria of apparent-treatment resistant hypertension (i.e. uncontrolled office BP ≥ 130/80 mmHg despite concurrent use of ≥ 3 antihypertensive medications, inclusive of a diuretic). Over the first 3 weeks of follow-up, canagliflozin provoked a placebo-subtracted change of −3.50 mmHg (95% CI: −4.27 to −2.72) in office systolic BP, a BP-lowering effect that was maintained till the completion of the trial. In addition, relative to placebo, canagliflozin reduced by 32% the need for intensification of background antihypertensive therapy [hazard ratio (HR): 0.68; 95% CI: 0.61–0.75] [14]. However, in mediation analysis, the modest reduction in office systolic BP provoked by canagliflozin could explain only 2.6% of the treatment effect of this agent on the primary composite outcome and only 4.0% of the treatment effect on the kidney-specific composite outcome of doubling of serum creatinine, kidney failure or death from renal causes [14].

3. BP reduction with finerenone

There is the impression that the non-steroidal MRA finerenone confers end-organ protection in patients with CKD and T2D that is primarily mediated through non-hemodynamic mechanisms, such as downregulation of inflammatory and fibrotic pathways in the heart and the kidneys [15]. Evidence to support this original hypothesis has been provided by a post-hoc analysis of the FIDELIO-DKD trial aiming to explore the relationship between treatment-induced changes in office systolic BP and improvement in cardiorenal outcomes with finerenone [16]. The least squares mean difference in the change from baseline of office systolic BP between finerenone and placebo groups over the course of the FIDELIO-DKD trial was −2.71 mmHg (95% CI: −3.29 to −2.12). The corresponding least squares between-group mean difference in the change from baseline of office diastolic BP was −1.03 mmHg (95% CI: −1.37 to −0.69) [16]. Relative to placebo, finerenone consistently improved the primary kidney and key secondary composite cardiovascular outcome regardless of the severity of hypertension at baseline. However, time-varying mediation analysis showed that only 13.8% and 12.6% of the benefit of finerenone could be explained by treatment-induced changes in office systolic BP for the primary composite kidney outcome and the key secondary composite cardiovascular outcome, respectively [16]. A similarly modest impact of finerenone on office BP was confirmed in patients with T2D and a broader spectrum of CKD over the course of the FIGARO-DKD trial [7].

As the evidence from FIDELIO-DKD and FIGARO-DKD trials is limited to office BP data [6,7], the hemodynamic effects of finerenone on vasculature and the relative contribution of these hemodynamic effects to the cardiorenal protection afforded by this novel non-steroidal MRA remain uncertain. In contrast, the technique of ABPM is based on a large number of BP measurements taken over an entire 24-hour period. ABPM facilitates the better evaluation of BP-lowering response to antihypertensive therapy [17]. In addition, a huge body of evidence suggests that as compared with office BP, 24-hour ambulatory BP is a stronger predictor of future risk for adverse cardiorenal outcomes [18].

A recent sub-analysis of the ARTS-DN (Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy) trial indicates that despite its short plasma half-life and the lack of active metabolites [13], finerenone provokes a substantially greater reduction in the levels of ambulatory BP [19]. ARTS-DN was a phase 2b trial that explored the albuminuria-lowering effect of finerenone (administered at doses of 1.25 up to 20 mg once daily in the morning) versus placebo in 823 patients with albuminuric CKD and T2D [20]. In a subgroup of 240 patients, the technique of ABPM was utilized at screening, Day 60 and Day 90 with the aim to investigate the BP-lowering properties of finerenone. Relative to placebo, the change in 24-hour systolic BP from baseline to Day 90 was −8.3 mmHg (95% CI: −16.6 to 0.1) with finerenone 10 mg/day, −11.2 mmHg (95% CI: −18.8 to −3.6) with finerenone 15 mg/day, and −9.9 mmHg (95% CI: −17.7 to −2.0) with finerenone 20 mg/day [19]. Despite its short plasma half-life, finerenone consistently reduced ambulatory systolic BP during both awake and asleep periods [19]. These hemodynamic actions can possibly explain the higher incidence of the adverse event of hypotension and the lower incidence of the adverse event of hypertension seen with finerenone in the long-term phase 3 FIDELIO-DKD and FIGARO-DKD trials [6,7]. This potent effect on ambulatory BP may be also a plausible mechanistic explanation for the early separation of the Kaplan-Meier curves for the composite cardiovascular outcome between finerenone and placebo [6,7].

Multiple pathways may be involved to explain the potent effect of finerenone on ambulatory BP. For example, finerenone can possibly modulate cardiac output and peripheral vascular resistance through the selective suppression of the overactivity of mineralocorticoid receptor [15]19]. Downstream effects on sodium handling by the kidney, neurohormonal activity, immune function and endothelial function have been described in experimental models [15]19]. The persistent BP-lowering effect over the entire 24-hour period with once-daily administration of this drug suggests that transcriptional effects of finerenone, instead of its short plasma half-life, are probably much more important in mediating this potent hemodynamic action.

4. Expert opinion

In contrast to the modest reduction of 3.66/1.70 mmHg in 24-hour ambulatory BP seen with SGLT-2 inhibitor therapy [10], recent ABPM data from the ARTS-DN trial indicate that the non-steroidal MRA finerenone provokes a much higher reduction of 9–11 mmHg in 24-hour ambulatory systolic BP in patients with CKD and T2D [19] (Table 1). This indirect comparison indicates that the BP-lowering properties of SGLT-2 inhibitors and finerenone may substantially differ. Accordingly, hemodynamic effects might be a more important contributor to the cardiorenal protection afforded by finerenone as compared to the BP-mediated improvement in cardiorenal outcomes seen with SGLT-2 inhibition. In any case, the hemodynamic effects of these 2 novel drug categories should be carefully monitored in everyday clinical practice for the appropriate adjustment of background antihypertensive therapy and the prevention of the risk of orthostatic hypotension, particularly when SGLT-2 inhibitors and finerenone are used as a combination therapy. The ongoing CONFIDENCE (COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint) trial is planning to recruit 807 patients with type 2 diabetes and albuminuric CKD with the aim to investigate whether combination therapy with the SGLT-2 inhibitor empagliflozin and the non-steroidal MRA finerenone results in an additive albuminuria-lowering effect as compared with either agent alone [21]. The safety of combination therapy will be also assessed. As the use of both agents has been associated with an initial decrease in BP, ABPM for 24 hours will be performed before the administration of the first dose of the study drug to assess the occurrence of symptomatic hypotension [21]. Randomized trials incorporating the reference-standard technique of ABPM are clearly needed to provide a direct head-to-head comparison of the BP-lowering efficacy between SGLT-2 inhibitors, finerenone and their combination in the future.

Table 1. Blood pressure lowering effects of SGLT-2 inhibitors and finerenone in patients with chronic kidney disease and type 2 diabetes.

	SGLT-2 inhibitors	Finerenone
Primary indication	Cardiorenal protection	Cardiorenal protection
Initiation of treatment	Patients with diabetic or non-diabetic CKD, if the levels of eGFR are at least 20 or 25 ml/min/1.73 m^2	Patients with albuminuric CKD associated with T2D, if the levels of eGFR are at least 25 ml/min/1.73 m^2 and serum potassium is lower than 5.0 mmol/l
Effect on office systolic BP	↓ 2–3 mmHg	↓ 2–3 mmHg
Effect on 24-hour ambulatory systolic BP	↓3–4 mmHg	↓9–11 mmHg
Potential mechanisms for the BP-lowering effect	Osmotic diuresis and natriuresis; Natriuretic-independent mechanisms, such as suppression of neurohormonal overactivity, regression of aortic stiffness and improvement in endothelial function	Potent and selective blockade of the MR and downstream effects of sodium homeostasis by the kidney, neural function, immune function and endothelial function.

Abbreviations: BP = blood pressure; CKD= chronic kidney disease; eGFR = estimated glomerular filtration rate; MR = mineralocorticoid receptor; T2D = type 2 diabetes.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contribution

Literature search: P.I. Georgianos; C Kourtidou; Writing the initial draft of the manuscript: P.I. Georgianos; C Kourtidou; Reviewing and Editing the manuscript: M Divani; V Liakopoulos; Supervision: V Liakopoulos.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.