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Differential effect of concomitant antidiabetic agents on carotid atherosclerosis: a subgroup analysis of the PROLOGUE study

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Abstract

Accumulated evidence shows that some antidiabetic agents attenuate the progression of carotid atherosclerosis assessed as intima-media thickness (IMT). Although some studies have demonstrated an inhibitory effect of dipeptidyl peptidase-4 inhibitors on carotid IMT progression, in the PROLOGUE study sitagliptin failed to slow progression relative to conventional therapy for 24 months. We hypothesized that differences in the concomitant antidiabetic agents between the groups have influenced the progression of carotid IMT. We performed a post hoc analysis of the PROLOGUE study using subgroups stratified by concomitant antidiabetic agents. Although no subgroup with any combination of agents in the overall patients showed a significant difference between sitagliptin group and conventional therapy group in the changes from baseline in mean common carotid artery (CCA)-IMT at 24 months, a significant attenuation of mean CCA-IMT progression was observed in the sitagliptin group relative to conventional therapy group only in three combination subgroups aged < 70 years, namely no thiazolidinedione; no thiazolidinedione or biguanide; and no thiazolidinedione, biguanide or α-glucosidase inhibitor, even after adjustment for multiple confounding factors. In the three subgroups, no significant difference between sitagliptin group and conventional therapy group in the changes from baseline in HbA1c at 24 months was detected. Our data suggest that some concomitant agents, whose prescription frequencies were increased in the conventional therapy group, may have masked the inhibitory effect of sitagliptin on carotid IMT progression in the PROLOGUE study.

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Acknowledgements

The authors thank the participants and staff for their essential contributions to the PROLOGUE study.

Funding

The Clinical Research Promotion Foundation (No.1026).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Saga University, Saga, Japan

    Atsushi Tanaka, Jun-ichi Oyama & Koichi Node

  2. Clinical Research Center, Saga University, Saga, Japan

    Atsushi Kawaguchi

  3. Department of Clinical Laboratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Tomoko Ishizu

  4. Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan

    Hiroshi Ito

  5. Division of Cardiology, Hokusho Central Hospital, Sasebo, Japan

    Jun Fukui

  6. Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan

    Taizo Kondo

  7. Division of Internal Medicine, Eguchi Hospital, Ogi, Japan

    Shigetaka Kuroki

  8. Cardiovascular Center, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan

    Mamoru Nanasato

  9. Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Yukihito Higashi

  10. Department of General Internal Medicine, Kawasaki Medical School, Kurashiki, Japan

    Kohei Kaku

  11. Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan

    Teruo Inoue

  12. Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Toyoaki Murohara

Authors
  1. Atsushi Tanaka
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  2. Atsushi Kawaguchi
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  3. Jun-ichi Oyama
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  4. Tomoko Ishizu
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  5. Hiroshi Ito
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  6. Jun Fukui
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  7. Taizo Kondo
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  8. Shigetaka Kuroki
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  9. Mamoru Nanasato
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  10. Yukihito Higashi
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  11. Kohei Kaku
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  13. Toyoaki Murohara
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  14. Koichi Node
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Contributions

All authors were PROLOGUE Study Investigators, contributed to the planning and conduct of the study, and critically reviewed the manuscript. A.T. prepared the first draft of the manuscript. A.K. was responsible for the statistical analyses. K.N. critically supervised the study. All authors read and approved the final version of manuscript.

Corresponding authors

Correspondence to Atsushi Tanaka or Koichi Node.

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Conflict of interest

A.T. and A.K. declared no conflict of interest. J.O. belongs to the research program faculty (chair course) sponsored by Fukuda Denshi. T.Is. H.I. J.F. T.K. S.K. and M.N. declared no conflict of interest. Y.H. has received honoraria from Astellas, MSD, Boehringer Ingelheim, Teijin, AstraZeneca, Takeda, Sanofi, and Shionogi; research grant from Kao; scholarships or donations from Takeda, Boehringer Ingelheim, MSD, Mitsubishi Tanabe, and Shionogi. K.K. has received honoraria from Astellas, MSD, Ono, Kowa, Novo Nordisk, Boehringer Ingelheim, Sanofi, Taisho Toyama, Takeda, and Mitsubishi Tanabe. T.In. has received honoraria from Mochida and Bayer; scholarships or donations from Kaatsu Japan, Goodman, Clinico, Shionogi, St. Jude Medical, Daiichi Sankyo, Takeda, Teijin, Boehringer Ingelheim, Boston Scientific, Union Tool, and Bayer. T.M. has received honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Mitsubishi Tanabe, MSD, Pfizer, Sumitomo Dainippon, and Takeda; scholarships or donations from Astellas, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Mitsubishi Tanabe, MSD, Novartis, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda, and Teijin. K.N. has received honoraria from Daiichi Sankyo, Merck, Pfizer, Eli Lilly, Amgen, Boehringer Ingelheim, Mitsubishi Tanabe, and Astellas; research funding from Bayer, Teijin, Mitsubishi Tanabe, Astellas, Boehringer Ingelheim, and Asahi Kasei; and scholarships from Astellas, Daiichi Sankyo, Sumitomo Dainippon, Takeda, Mitsubishi Tanabe, and Boehringer Ingelheim.

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Tanaka, A., Kawaguchi, A., Oyama, Ji. et al. Differential effect of concomitant antidiabetic agents on carotid atherosclerosis: a subgroup analysis of the PROLOGUE study. Heart Vessels 34, 375–384 (2019). https://doi.org/10.1007/s00380-018-1275-5

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