Effect of Anagliptin versus Sitagliptin on Renal Function: Subanalyzes from the REASON Trial

Abstract

Purpose

The effects of two types of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function remain unclear. Thus, we investigated the effect of anagliptin (ANA) and sitagliptin (SITA) on renal function in patients with type 2 diabetes who participated in the randomized evaluation of ANA versus SITA on low-density lipoprotein-cholesterol (LDL-C) in diabetes (REASON) trial.

Patients and methods

We measured the estimated glomerular filtration rate (eGFR) and urinary albumin–creatinine ratio (UACR) before and after the REASON trial. ANA 200 mg/day was administered to 177 patients for 52 weeks, while SITA 50 mg/day was given to 176 patients. We investigated the relationship between differences in renal function and differences in hemoglobin A1c (HbA1c) levels, LDL-C levels, and blood pressure (BP).

Results

No significant differences were found in baseline eGFR and UACR between the two groups. The eGFR levels were significantly decreased in both groups; however, the UACR level was unchanged in the ANA group but elevated in the SITA group, although the difference did not reach significance between the two groups. The difference in eGFR was affected by the differences in HbA1c level and BP, and the difference in the UACR was affected by the differences in LDL-C level and BP, which were reduced only in the ANA group.

Conclusion

These findings imply that the effects of DPP-4 inhibitors on renal function, especially on UACR, may be different between the types of DPP-4 inhibitors.

Keywords:

• glomerular filtration rate
• dipeptidyl peptidase 4
• dipeptidyl peptidase 4 inhibitors
• albuminuria

Abbreviations

ANA, anagliptin; BP, blood pressure; CKD, chronic kidney disease; DM, diabetes mellitus; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1-RA, glucagon-like peptide-1 receptor agonist; HbA1c, hemoglobin A1c; LDL-C, low-density lipoprotein cholesterol; RAAS, renin-angiotensin-aldosterone system; REASON trial, Randomized Evaluation of Anagliptin and sitagliptin in reducing low-density lipoprotein cholesterol in diabetes trial; SGLT2, sodium-glucose co-transporter 2; SITA, sitagliptin; UACR, urinary albumin-creatinine ratio.

Data Sharing Statement

The data sets analysed during the current study are available from the corresponding author on reasonable request ([email protected]).

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The institutional review boards of the University of the Ryukyus (No. 731) and each participating center gave their approval for this study. This trial was registered on ClinicalTrials.gov (NCT02330406).

Informed Consent

All patients or their legally authorized representatives provided written informed consent prior to randomization.

Acknowledgments

Data management was handled by Ms. Makiko Ohtroii, Ms. Ai Sunagawa, Ms. Sachiko Kitamura, Ms. Kaori Yamamoto, Ms. Hirono Saito, and Ms. Saeko Nagano, while project management was handled by Ms. Takako Okumura.

Disclosure

Dr H.T. reports lecturer fees from Daichi Sankyo, Mitsubish Tanabe, Bayer, Kowa, and Nihon Medi-Physics. Dr. T.M. has lecturer fees from AbbVie, AstraZeneca, Daiichi Sankyo, Japan Lifeline, Kowa, Toray, Tsumura, Kyorin, Mitsubishi Tanabe, Pfizer, and Bayer, as well as manuscript payments from Pfizer and advisory board roles with Asahi Kasei, Boston Scientific, Bristol-Myers Squibb, and Novartis. Dr. Y.F. and T.U. declare that they have no competing interests. Dr. M.S. is a member of Enomoto Pharmaceutical’s advisory board. Dr. M.S. has received research grants from AstraZeneca, Ono, and Sanwa Kagaku Kenkyusho, as well as nonpurpose 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 Astella. Dr O.A. reports lecturer fees from Abbott, Astellas, Boehringer Ingelheim, Medtronic, and St. Jude Medical. Dr. K.N. reports research grants from Abbott, Actelion, Air Water, Asahi Kasei, Astellas, Bayer, Terumo, Boehringer Ingelheim Japan, Mochida Pharmaceutical, Fuji Yakuhin, Medtronic, Daiichi Sankyo, Eli Lilly Japan, Takeda Pharmaceutical, GlaxoSmithKline, Mebix, Mitsubishi Tanabe, MSD, Novartis, Novo Nordia, Ono Pharmaceutical, and Teijin; nonpurpose research grants from Abbott, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb. Dr. T.N. has received research grants from Eli Lilly, Mitsubishi Tanabe, MSD, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon, Taisho Toyama, Takeda, and Terumo, as well as lecturer fees from Arkray, Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson Dr. S.U. has received research funding from Bristol-Myers Squibb and Kowa, as well as non-purpose research grants from Bristol-Myers Squibb, Chugai, MSD, Pfizer, and Takeda. He also has lecturer fees from Boehringer Ingelheim and MSD. The authors report no other conflicts of interest in this work.

Additional information

Funding

Kowa Company, Ltd. contributed to the REASON trial. Kowa had a representative participate in the research idea and evaluation of the final draft of the REASON trial’s main report. The academic authors, on the other hand, were exclusively responsible for the study design, operation, data collection, statistical analysis, and paper drafting.