Rationale and study design of a randomized controlled trial to investigate the renoprotective effect of canagliflozin assessed by test of renal hemodynamics in diabetic kidney disease (the FAGOTTO study)

In recent decades, the number of patients with diabetes and prediabetes has increased worldwide [1] as well as in Japan [2]. Diabetes can damage major organs, including the kidneys, and the most serious consequence is end-stage renal disease, which requires renal replacement therapy [3]. A worldwide report revealed that the global annual incidence of end stage-renal disease (ESRD) among patients with diabetes has increased, but interestingly, in one region in Europe, the rate decreased [4]. Diabetic kidney disease (DKD) is the most common primary disease among prevalent and incident dialysis patients in Japan [5]. In addition, the presence of DKD markedly increases cardiovascular (CV) and mortality risk [6], which is why the prevention of DKD is a crucial global issue.

To delay the onset and progression of DKD, glycemic, blood pressure, and lipid control targets are set for diabetic patients; additionally, they are provided with advice on lifestyle changes, including nutritional management and exercise, to achieve their recommended targets [3]. Nevertheless, patients who cannot achieve the HbA1c target should be prescribed glycemic control drugs [3]. As sodium-glucose cotransporter 2 inhibitors (SGLT2i) are diabetic drugs that inhibit glucose reabsorption in the proximal renal tubule and promote urinary glucose excretion, they not only improve glycemic control independently of insulin-mediated mechanisms, but are also associated with body weight reduction [7]. Thus SGLT2i are thought to exert their glucose-lowering effect by reducing renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, albuminuria, and slow GFR loss through mechanisms that appear to be independent of glycemia [7].

SGLT2i were first approved for use in 2012 in Europe and then in the US and Japan in 2014. Several SGLT2is are already widely used not only glycemic control but also for the reduction of CV mortality [8] and the incidence and exacerbation of DKD [9]. Although the renoprotective effect of SGLT2i is mainly thought to correct intraglomerular hypertension via restoration of tubular glomerular feedback [7], its mechanism is practically difficult to demonstrate. So far, few studies have attempted to elucidate the mechanisms in type 1 [10] and type 2 [11] diabetic patients; however, both trials enrolled patients with glomerular hyperfiltration. In this trial, we demonstrate how SGLT2i changes renal hemodynamics in DKD patients with moderate renal dysfunction. This renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is expected to provide new evidence on the renoprotective effect of SGLT2i.

Several large-scale randomized control studies have provided evidence of the cardioprotective and renoprotective effects of SGLT2i [13]. Among them, a randomized clinical trial of empagliflozin was the seminal study. The trial was designed to assess the cardioprotective effect of empagliflozin in type 2 diabetic patients with > 7.0% of HbA1c and a high risk of CV events [14]. It demonstrated that patients who received empagliflozin had lower rates of hospitalization for heart failure as well as CV and all-cause mortality [8]. The authors also demonstrated renoprotective effects as the secondary microvascular outcome of this trial included a significant relative risk reduction of doubling of serum creatinine level and initiation of renal replacement therapy in patients whose eGFR was at least 30 ml/min/1.73 m² [9]. Notably, eGFR of the empagliflozin group showed a short-term decrease in the first 4 weeks and remained stable from long-term administration to the end of the trial, while that of the placebo group declined steadily [9]. Next, a convincing report from the integrated CANVAS program showed that canagliflozin prevented the progression of albuminuria and renal events; specifically, findings showed a 40% reduction in eGFR, renal replacement therapy, or renal death in type 2 diabetic patients with inadequate glycemic control and an elevated risk of CV diseases with a mean eGFR of approximately 76 ml/min/1.73m² [15, 16]. There was the CREDENCE trial designed primarily to assess the renoprotective effect of canagliflozin in patients with type 2 diabetes [17]. In this trial, the inclusion criteria specified patients with type 2 diabetes with over 6.5% of HbA1c and risk factors for the progression of kidney disease, such as albuminuria, who were treated with renin-angiotensin system blockade; enrollment included approximately 60% patients with stage 3 CKD [17]. Although the subjects in the CREDENCE trial had low eGFR at the start in contrast to those included in the previous CV outcome trials of SGLT2i [9, 16], canagliflozin showed similar effects, including a lower risk of end-stage renal disease, doubling of serum creatinine level, or death from renal causes, compared to placebo [18]. Based on these clinical trials, the renoprotective effect of SGLT2i is now recognized, but the magnitude of its effectiveness in individual patients remains unclear. A systematic review reported that the renoprotective effect of SGLT2i was greater in diabetic patients with preserved renal function at baseline than in those with moderate CKD, whereas the cardioprotective effect was greater in patients with poorer renal function [13]. Although an eGFR dip is observed in the eGFR curve after prescribing SGLT2i, a recent editorial indicated that a larger dip generally resulted in a stronger benefit of SGLT2i than placebo [19]. Thus, to demonstrate whether SGLT2i can modulate renal hemodynamics even in patients at high risk of end-stage renal disease, our trial will evaluate renal hemodynamics during an eGFR dip in patients with moderate renal dysfunction who are administered SGLT2i.

The possible renal protective effects of SGLT2i are diverse, including lowering blood pressure via natriuresis and osmotic diuresis, reducing hypoxia in the proximal tubule via tubular workload reduction, and anti-inflammation-fibrosis action [20‐22]. Among these actions of SGLT2i, correction of intraglomerular hypertension via restoration of tubular glomerular feedback is thought to be the most crucial and dynamic [21]. An experimental study in an animal model of type 1 diabetes demonstrated that SGLT2i induced afferent arteriolar vasoconstriction and decreased the single-nephron glomerular filtration rate via the tubule-glomerular feedback mechanism that resulted in the reduction of intraglomerular pressure, using in vivo multiphoton microscopy imaging techniques [23]. Cherney et al. demonstrated that SGLT2i attenuated glomerular hyperfiltration in patients with type 1 diabetes mellitus with glomerular hyperfiltration defined by eGFR ≥ 135 mL/min/1.73 m²; attenuation of glomerular hyperfiltration was accompanied by a decrease in renal blood flow and an increase in renal vascular resistance [10]. The authors discussed that such a reduction of glomerular hyperfiltration was mediated by preglomerular vasoconstriction by affecting the tubular-glomerular feedback mechanism, and long-term use of SGLT2i might reduce intraglomerular pressure, resulting in an overt renoprotective effect [10]. Interestingly, this trial failed to show this evidence in patients with normal glomerular filtration [10]. Recently, van Bommel et al. conducted a trial to evaluate the renal hemodynamic effect of SGLT2i in patients with type 2 diabetes mellitus with eGFR ≥ 60 mL/min/1.73m² treated with metformin monotherapy [11]. They showed that SGLT2i lowered the mGFR without increasing renal vascular resistance, and these effects were accompanied by postglomerular vasodilation [11]. Interestingly, the ability to lower postglomerular resistance was independent of blood glucose concentration [11]. Although clinical studies have demonstrated a renoprotective effect of SGLT2i in patients with type 2 diabetes who have moderate renal dysfunction, as discussed above, changes in renal hemodynamics after SGLT2i administration in these patients are still unclear. This trial will contribute to research in the field by elucidating the renal hemodynamic mechanism of SGLT2i and, provide a significant basis for the prescription of SGLT2i in patients with DKD if we demonstrate its ability to control intraglomerular pressure in our subjects.

The target number of patients is 110 (1:1 = canagliflozin group: control group). This protocol was approved by the Certified Review Board of the Nagoya University Graduate School of Medicine on November 6, 2020 (Version 1.2), and opened to the public on the website of the Japan Registry of Clinical Trials on November 27, 2020. We enrolled the first patient on December 23, 2020. By the end of June 2022, we enrolled 81 patients from three participating hospitals and further recruitment is ongoing. This study is expected to end in 2025. The FAGOTTO study is the first randomized controlled study of canagliflozin to assess renal hemodynamics in patients with type 2 diabetes and moderate renal dysfunction. Although further studies will be needed, the data from this study will provide evidence for optimal therapy to prevent progression of DKD.