Effect of Anagliptin and Sitagliptin on Low-Density Lipoprotein Cholesterol in Type 2 Diabetic Patients with Dyslipidemia and Cardiovascular Risk: Rationale and Study Design of the REASON Trial

Abstract

Background: Reduction of low-density lipoprotein cholesterol (LDL-C) is important for patients with a high risk for atherosclerotic events, such as patients with diabetes and other risk factors. Anagliptin was reported to reduce LDL-C for 12 weeks in phase III trials regardless of the use of statins, but it is uncertain whether this effect is common to other dipeptidylpeptidase-4 (DPP-4) inhibitors.

Methods: A multicenter, randomized, open-label, parallel-group trial was conducted to confirm the superiority of anagliptin to sitagliptin in terms of the primary endpoint of reduction of LDL-C for 52 weeks in patients with type 2 diabetes and atherosclerotic vascular lesions, as well as the non-inferiority of anagliptin to sitagliptin in terms of change in hemoglobin A1c (HbA1c). Patients are randomly assigned to receive anagliptin or sitagliptin at a ratio of 1:1, with those in the anagliptin group receiving anagliptin 100 mg orally twice per day and those in the sitagliptin group receiving sitagliptin 50 mg orally once per day. During the trial period, hypoglycemic agents and anti-dyslipidemia drugs should not be added and neither should their dosages be changed. A total sample size of 300 was estimated to provide a power of 0.8 with a two-sided alpha of 0.05 for LDL-C, considering a 30% dropout rate. Pre-specified factors for subgroup analyses are HbA1c, use of DPP-4 inhibitors, sex, body mass index, LDL-C, age, and the presence of treatment for existing ischemic heart disease.

Discussion: If anagliptin were to be shown to reduce LDL-C in patients with type 2 diabetes and atherosclerotic vascular lesions despite pre-existing statin treatment, more intensive cholesterol management would be appropriate.

Trial registration: Clinicaltrials.gov NCT02330406.

Keywords: Cardiovascular risk; DPP-4 inhibitors; Dyslipidemia; Low-density lipoprotein cholesterol; Type 2 diabetic patients.

Conflict of interest statement

Declarations

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Ethics Approval and Consent to Participate

Protocol and consent forms were approved by the institutional review boards at the University of the Ryukyus (No. 731) and each participating center. All patients or their legally authorized representatives provided written, informed consent before randomization.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Conflict of Interests

Dr. Shinichiro Ueda reports 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. Dr. Michio Shimabukuro reports research grants from AstraZeneca, Ono, and Sanwa Kagaku Kenkyusho; 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. Dr. Osamu Arasaki reports lecturer’s fees from Abbott, Astellas, Boehringer Ingelheim, Medtronic, and St. Jude Medical. Dr. Koichi Node reports research grants from Abbott, Actelion, Air Water, Asahi Kasei, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Mebix, Mitsubishi Tanabe, Nippon Sigmax, and Teijin; non-purpose research grants from Abbott, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Kissei, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, MSD, Nippon Shinyaku, Novartis, Otsuka, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon, Takeda, and Teijin; lecturer’s fees from Abbott, Actelion, AnGes, Astellas, Astellas Amgen Bio Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Eisai, Eli Lilly, Fukuda Denshi, Fukuda Life Tech Kyusyu, Kissei, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, Mochida, MSD, Nippon Kayaku, Nippon Shinyaku, Novartis, Omron, Ono, Otsuka, Pfizer, Roche Diagnostics, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon, Taisho Toyama, Takeda, Teijin, and Toa Eiyo; manuscript fee from Takeda; advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, Pfizer, Sanofi, Shionogi, and Takeda. Dr. Takashi Nomiyama reports research grants from Eli Lilly, Mitsubishi Tanabe, MSD, and Novartis; lecturer’s fees from Arkray, Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Mitsubishi Tanabe, MSD, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon, Taisho Toyama, Takeda, and Terumo. Dr. Takeshi Morimoto reports a research grant from Nexis; lecturer’s fees from AbbVie, AstraZeneca, Daiichi Sankyo, Kyorin, Mitsubishi Tanabe, and Pfizer; manuscript fee from Pfizer; advisory boards for Asahi Kasei, Boston Scientific, and Bristol-Myers Squibb.

Access to Data

The access to the final trial dataset is rigidly restricted to investigators who are authorized by the steering committee and any activity is recorded. There are contractual agreements that limit such access for investigators.

Confidentiality

Confidentiality in the collection of personal information is protected in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan

Compensation

The compensation to those who suffer death or severe damage requiring hospitalization from trial participation is provided from the clinical trial insurance organized by the trial sponsor (University of the Ryukyus).

Dissemination Policy

Results from this trial are disseminated through publications and conference presentations to participants, healthcare professionals, and the public.

Figures

Fig. 1

Study design. After the statin administration period and informed consent is obtained, eligible patients are randomly allocated to the anagliptin group who receive twice a day anagliptin at 200 mg per day and to the sitagliptin group who receive once a day sitagliptin at 50 mg per day for 52 weeks, the study drug treatment period