Randomized Evaluation of Anagliptin vs Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) Trial: A 52-week, open-label, randomized clinical trial

Abstract

Additional reductions in low-density lipoprotein-cholesterol (LDL-C) via antidiabetic therapies should be considered in statin-using patients with sub-optimal LDL-C levels. We compared the efficacy of anagliptin and sitagliptin, two antidiabetic therapies, in reducing LDL-C in type 2 diabetic patients. A randomized, open-label, parallel-group trial was conducted at 17 centres in Japan between April 2015 and January 2018. Adults (age ≥20 years) with type 2 diabetes, any atherosclerotic vascular lesions, and statin prescriptions were included. Anagliptin or sitagliptin were administered for 52 weeks. Primary and secondary endpoints were changes in LDL-C and haemoglobin A1C (HbA1c) levels, respectively. We assessed the superiority (primary endpoint) and non-inferiority (secondary endpoint) of anagliptin over sitagliptin. This study was registered at Clinicaltrials.gov (NCT02330406). Of 380 participants, 353 were eligible and randomized. Mean participant age was 68 years, and 61% were males. Baseline median LDL-C and HbA1c were 108 mg/dL and 6.9%, respectively. Changes in LDL-C were -3.7 mg/dL with anagliptin and +2.1 mg/dL with sitagliptin at 52 weeks, and the estimated treatment difference was a significant -4.5 mg/dL (P = 0.01 for superiority). Changes in HbA1c were +0.02% with anagliptin and +0.12% with sitagliptin (P < 0.0001 for non-inferiority). Overall, anagliptin was superior to sitagliptin in lowering LDL-C without deteriorating HbA1c.

Conflict of interest statement

Dr. Takeshi Morimoto reports lecturer fees from AbbVie, AstraZeneca, Daiichi Sankyo, Kyorin, Mitsubishi Tanabe, Pfizer, and Bayer; manuscript fees from Pfizer; advisory boards for Asahi Kasei, Boston Scientific, and Bristol-Myers Squibb. Dr. Ichiro Sakuma reports lecturer fees from Apollo Medical, Aska, Astellas, Astellas Amgen Bio Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Fuji Yakuhin, Kissei, Kowa, Kyorin, Kyowa Hakko Kirin, Mochida, MSD, Nipro, Novartis, Novo Nordisk, Ono, Otsuka, Pfizer, Sanofi, Shionogi, Sumitomo Dainippon, Sysmex, Takeda, and Teijin. Dr. Mio Sakuma reports advisory board for Enomoto Pharmaceutical. Dr. Akihiro Tokushige declares no conflicts of interest. Dr. Masahiro Natsuaki reports lecturer fees from Abbott, Astellas, Astellas Amgen Bio Pharma, AstraZeneca, Bayer, Boston Scientific, Daiichi Sankyo, Medtronic, MSD, Sanofi, and Terumo. Dr. Tomohiro Asahi reports lecturer fees from Takeda and Daiichi Sankyo. 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 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; and in sponsored office from Boehringer Ingelheim. 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. Osamu Arasaki reports lecturer 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, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Mebix, Mitsubishi Tanabe, and Teijin; non-purpose research grants from Abbott, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Japan Lifeline, Kissei, Medtronic, Mitsubishi Tanabe, MSD, Novartis, Novo Nordisk, Ono, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda, and Teijin; lecturer 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, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, Mochida, MSD, Nippon Shinyaku, Novartis, Ono, Otsuka, Pfizer, Roche Diagnostics, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon, Taisho Toyama, Takeda, Teijin, and Toa Eiyo; manuscript fee from Takeda; advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mitsubishi Tanabe, MSD, Novo Nordisk, Pfizer, and Takeda. 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 fees from Boehringer Ingelheim, and MSD.

Figures

Figure 1

Participants Flow Chart.

Figure 2

Change in Low-density Lipoprotein-cholesterol. LDL-C: low-density lipoprotein-cholesterol.

Figure 3

Primary endpoint subgroup analyses. LDL-C: Low density lipoprotein-cholesterol. BMI: body mass index. PCI: Percutaneous coronary intervention. CABG: Coronary artery bypass surgery. DPP-4: dipeptidylpeptidase-4. HbA1c: hemoglobin A1c.

Figure 4

Changes in Hemoglobin A1c. HbA1c: hemoglobin A1c.