title: The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial.
abstract: BACKGROUND
  Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).
  
  
  RESULTS
  We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.
  
  
  CONCLUSIONS
  In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.
  
  
  BACKGROUND
  University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Oyama
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: Department of Clinical Laboratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizu
authors.affiliation: Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
authors.affiliation: Division of Cardiology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Kamiya
authors.affiliation: Department of Cardiovascular Internal Medicine, Tosei General Hospital, Seto, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ajioka
authors.affiliation: Division of Cardiovascular Medicine and Coronary Heart Disease, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ishihara
authors.affiliation: Department of Cardiology, Hiroshima City Hospital, Hiroshima, Japan.
authors.forename: Kazuoki
authors.initials: K
authors.lastname: Dai
authors.affiliation: Cardiovascular Center, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Mamoru
authors.identifier: http://orcid.org/0586-9181-7500-7156
authors.initials: M
authors.lastname: Nanasato
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Maemura
authors.affiliation: Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomiyama
authors.affiliation: Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
authors.affiliation: Department of Cardiovascular Medicine, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Hirotsugu
authors.identifier: http://orcid.org/0000-0003-3741-5560
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan.
authors.forename: Munehide
authors.initials: M
authors.lastname: Matsuhisa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine and National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine and National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology; D002339:Carotid Arteries / Q000187:drug effects*; D059168:Carotid Intima-Media Thickness; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000068900:Sitagliptin Phosphate / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D000068900:Sitagliptin Phosphate