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

Jun Ichi Oyama, Toyoaki Murohara, Masafumi Kitakaze, Tomoko Ishizu, Yasunori Sato, Kazuo Kitagawa, Haruo Kamiya, Masayoshi Ajioka, Masaharu Ishihara, Kazuoki Dai, Mamoru Nanasato, Masataka Sata, Koji Maemura, Hirofumi Tomiyama, Yukihito Higashi, Kohei Kaku, Hirotsugu Yamada, Munehide Matsuhisa, Kentaro Yamashita, Yasuko K. BandoNaoki Kashihara, Shinichiro Ueda, Teruo Inoue, Atsushi Tanaka, Koichi Node

Research output: Contribution to journalArticle

30 Citations (Scopus)

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

Original languageEnglish
Article numbere1002051
JournalPLoS Medicine
Volume13
Issue number6
DOIs
Publication statusPublished - 2016 Jun 1
Externally publishedYes

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Carotid Artery Diseases
Carotid Arteries
Type 2 Diabetes Mellitus
Randomized Controlled Trials
Carotid Intima-Media Thickness
Group Psychotherapy
Biomarkers
Dipeptidyl-Peptidase IV Inhibitors
Diet Therapy
Incretins
Therapeutics
Information Services
Common Carotid Artery
Hypoglycemia
Registries
Sitagliptin Phosphate
Atherosclerosis
Cardiovascular Diseases
Placebos
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

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The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes : The PROLOGUE Randomized Controlled Trial. / Oyama, Jun Ichi; Murohara, Toyoaki; Kitakaze, Masafumi; Ishizu, Tomoko; Sato, Yasunori; Kitagawa, Kazuo; Kamiya, Haruo; Ajioka, Masayoshi; Ishihara, Masaharu; Dai, Kazuoki; Nanasato, Mamoru; Sata, Masataka; Maemura, Koji; Tomiyama, Hirofumi; Higashi, Yukihito; Kaku, Kohei; Yamada, Hirotsugu; Matsuhisa, Munehide; Yamashita, Kentaro; Bando, Yasuko K.; Kashihara, Naoki; Ueda, Shinichiro; Inoue, Teruo; Tanaka, Atsushi; Node, Koichi.

In: PLoS Medicine, Vol. 13, No. 6, e1002051, 01.06.2016.

Research output: Contribution to journalArticle

Oyama, JI, Murohara, T, Kitakaze, M, Ishizu, T, Sato, Y, Kitagawa, K, Kamiya, H, Ajioka, M, Ishihara, M, Dai, K, Nanasato, M, Sata, M, Maemura, K, Tomiyama, H, Higashi, Y, Kaku, K, Yamada, H, Matsuhisa, M, Yamashita, K, Bando, YK, Kashihara, N, Ueda, S, Inoue, T, Tanaka, A & Node, K 2016, 'The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial', PLoS Medicine, vol. 13, no. 6, e1002051. https://doi.org/10.1371/journal.pmed.1002051
Oyama, Jun Ichi ; Murohara, Toyoaki ; Kitakaze, Masafumi ; Ishizu, Tomoko ; Sato, Yasunori ; Kitagawa, Kazuo ; Kamiya, Haruo ; Ajioka, Masayoshi ; Ishihara, Masaharu ; Dai, Kazuoki ; Nanasato, Mamoru ; Sata, Masataka ; Maemura, Koji ; Tomiyama, Hirofumi ; Higashi, Yukihito ; Kaku, Kohei ; Yamada, Hirotsugu ; Matsuhisa, Munehide ; Yamashita, Kentaro ; Bando, Yasuko K. ; Kashihara, Naoki ; Ueda, Shinichiro ; Inoue, Teruo ; Tanaka, Atsushi ; Node, Koichi. / The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes : The PROLOGUE Randomized Controlled Trial. In: PLoS Medicine. 2016 ; Vol. 13, No. 6.
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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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T1 - The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes

T2 - The PROLOGUE Randomized Controlled Trial

AU - Oyama, Jun Ichi

AU - Murohara, Toyoaki

AU - Kitakaze, Masafumi

AU - Ishizu, Tomoko

AU - Sato, Yasunori

AU - Kitagawa, Kazuo

AU - Kamiya, Haruo

AU - Ajioka, Masayoshi

AU - Ishihara, Masaharu

AU - Dai, Kazuoki

AU - Nanasato, Mamoru

AU - Sata, Masataka

AU - Maemura, Koji

AU - Tomiyama, Hirofumi

AU - Higashi, Yukihito

AU - Kaku, Kohei

AU - Yamada, Hirotsugu

AU - Matsuhisa, Munehide

AU - Yamashita, Kentaro

AU - Bando, Yasuko K.

AU - Kashihara, Naoki

AU - Ueda, Shinichiro

AU - Inoue, Teruo

AU - Tanaka, Atsushi

AU - Node, Koichi

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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

AB - 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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