Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial

Atsuko Chihara, Atsushi Tanaka, Takeshi Morimoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Shinichiro Ueda, Koichi Node, Atsuko Chihara, Atsushi Tanaka, Takeshi Morimoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Shinichiro Ueda, Koichi Node

Abstract

Background: Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.

Aim and methods: We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).

Results: There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).

Conclusion: These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://ichgcp.net/clinical-trials-registry/NCT02330406; registered January 5, 2015.

Keywords: Anagliptin; Lathosterol; Lipid metabolisms; Sitagliptin; Type 2 diabetes.

Conflict of interest statement

AC. declares no potential conflict of interest. A.T. has received modest honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Kowa, MSD, Mitsubishi Tanabe, Novo Nordisk, Taisho Toyama, and Takeda. T.M. has received lecturer’s fees from Daiichi Sankyo, Japan Lifeline, Kyocera, and Novartis; manuscript fee from Pfizer. M.Sa. has received advisory board for Enomoto Pharmaceutical. M.Sh. reports research grants from AstraZeneca, and Ono; 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’s fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Eli Lilly, Kowa, Mitsubishi Tanabe, Mochida, MSD, Novo Nordisk, Ono, Taisho Toyama, and Takeda; advisory board for Novo Nordisk; sponsored office from Boehringer Ingelheim. T.N. has received research grants from Eli Lilly; lecturer’s fees from Boehringer Ingelheim, Eli Lilly, MSD, and Sumitomo Dainippon. O.A. has received lecturer’s fees from Abbott, Astellas, Boehringer Ingelheim, Medtronic, and St. Jude Medical. S.U. has received research grants from Bristol-Myers Squibb, and Kowa; non-purpose research grants from Bristol-Myers Squibb, Chugai, MSD, Pfizer, and Takeda; lecturer’s fees from Boehringer Ingelheim, and MSD. K.N. has received research grants from Actelion, Asahi Kasei, Astellas, Astellas Amgen Bio Pharma, Boehringer Ingelheim, GlaxoSmithKline, Mitsubishi Tanabe, Novo Nordisk, Teijin, and Terumo; non-purpose research grants from Astellas, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, MSD, Novartis, Novo Nordisk, Ono, Otsuka, Pfizer, Sanofi, and Teijin; lecturer’s fees from Actelion, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Edwards Lifesciences, Eli Lilly, FUJIFILM, Fukuda Denshi, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, MSD, Novartis, Ono, Otsuka, Pfizer, Roche Diagnostics, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama, Takeda, and Teijin; manuscript fees from Astellas, and Takeda; advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.

Figures

Fig. 1
Fig. 1
Changes in the markers of lipid metabolism. Comparison of a campesterol, c sitosterol, e lathosterol at 0 and 52 weeks and absolute change in b campesterol, d sitosterol, f lathosterol at 52 weeks

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