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Randomized Controlled Trial
. 2016 Jun 28;13(6):e1002051.
doi: 10.1371/journal.pmed.1002051. eCollection 2016 Jun.

The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial

Jun-Ichi Oyama  1 , Toyoaki Murohara  2 , Masafumi Kitakaze  3 , Tomoko Ishizu  4 , Yasunori Sato  5 , Kazuo Kitagawa  6 , Haruo Kamiya  7 , Masayoshi Ajioka  8 , Masaharu Ishihara  9 , Kazuoki Dai  10 , Mamoru Nanasato  11 , Masataka Sata  12 , Koji Maemura  13 , Hirofumi Tomiyama  14 , Yukihito Higashi  15 , Kohei Kaku  16 , Hirotsugu Yamada  17 , Munehide Matsuhisa  18 , Kentaro Yamashita  19 , Yasuko K Bando  19 , Naoki Kashihara  20 , Shinichiro Ueda  21 , Teruo Inoue  22 , Atsushi Tanaka  1 , Koichi Node  1 ; PROLOGUE Study Investigators
Affiliations
Randomized Controlled Trial

The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial

Jun-Ichi Oyama et al. PLoS Med. .

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).

Methods and findings: 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.

Trial registration: University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.

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Conflict of interest statement

JO belongs to the research program faculty (chair course) sponsored by Fukuda Denshi. YKB MI KKa NK MK KM TM MS SU HY received honoraria from pharmaceutical companies including MSD. MI MK KM received honoraria from pharmaceutical companies including Ono. KN received honoraria from pharmaceutical companies including Merck. YKB MI NK KM TM MS SU HY received research grants from pharmaceutical companies including MSD. MI MK MS HY received research grants from pharmaceutical companies including Ono. KKi MM YS HT received honoraria from pharmaceutical companies. KKa KKi MM KN YS received research grants from pharmaceutical companies. All other authors declare that they have no conflict of interest. A full list of competing interests is provided in S6 Text.

Figures

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Fig 1. Participant disposition.
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