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. 2020 Jun 13;19(1):85.
doi: 10.1186/s12933-020-01065-w.

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial

Atsushi Tanaka  1 , Michio Shimabukuro  2 , Yosuke Okada  3 , Kazuhiro Sugimoto  4 , Akira Kurozumi  5 , Keiichi Torimoto  3 , Hiroyuki Hirai  2   6 , Koichi Node  7 ; PROCEED trial investigators
Affiliations

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial

Atsushi Tanaka et al. Cardiovasc Diabetol. .

Abstract

Background: Type 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD.

Methods: The PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0-9.0%) and established CKD (30 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m2 or ≥ 45 mL/min/1.73 m2), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks.

Discussion: PROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials. Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).

Keywords: Chronic kidney disease (CKD); Endothelial dysfunction; Ipragliflozin; Reactive hyperemia peripheral arterial tonometry (RH-PAT); Sodium glucose cotransporter 2 inhibitor (SGLT2i); Type 2 diabetes (T2D).

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Conflict of interest statement

AT received modest honoraria from Ono, Kowa, Daiichi Sankyo, Taisho Toyama, Takeda, Mitsubishi Tanabe, Teijin, Novo Nordisk, Bayer, Fukuda Denshi, and Boehringer Ingelheim, and a research grant from GlaxoSmithKline. MS received grants non-purpose research grants from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Eli Lilly, Kowa, Mitsubishi Tanabe, MSD, Novo Nordisk, Ono, Taisho Toyama, and Takeda; lecturer fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Eli Lilly, Kowa, Mitsubishi Tanabe, Mochida, MSD, Novo Nordisk, Ono, Taisho Toyama, and Takeda; and advisory board for Novo Nordisk. YO received lecture fees from Astellas, AstraZeneca, Ono, Mitsubishi Tanabe, Bayer, Novo Nordisk, Kowa, and Sanofi. KN received honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, MSD, Ono, Otsuka, and Takeda, research grants from Asahi Kasei, Astellas, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe, Teijin, and Terumo, and scholarships from Astellas, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Takeda, and Teijin. Other authors declare no potential competing interests.

Figures

Fig. 1
Fig. 1
Rationale for the PROCEED trial. Endothelial dysfunction is closely associated with T2D and CKD and forms a pathological triangle. The objective of our trial is to test the hypothesis that SGLT2-mediated inhibition breaks this triangle by ameliorating endothelial dysfunction. Another aim is to elucidate the mechanisms by which SGLT2 inhibitors confer cardiovascular and renal benefits in patients with T2D and CKD. CKD: chronic kidney disease; SGLT2: sodium-glucose cotransporter 2; T2D: type 2 diabetes
Fig. 2
Fig. 2
Trial design. SGLT2is: sodium-glucose cotransporter 2 inhibitors; T2D: type 2 diabetes
See this image and copyright information in PMC

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