Type 2 diabetes mellitus (T2DM) is a risk factor for cardiovascular disease (CVD). Recent studies have cast doubt on the benefits of strict glycemic control on CVD in patients with advanced atherosclerosis or longstanding T2DM [
The carotid artery intima-media thickness (IMT) and its progression are considered a marker of progression of atherosclerosis. Recent studies demonstrated that add-on therapy of metformin [
Previous studies demonstrated that several therapies for cardiovascular risk factors including statin could regress carotid IMT in patients with T2DM [
We performed a post hoc analysis from the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). The study design, inclusion and exclusion criteria, study schedule, and measurements were described in detail previously [
Data were reported as mean ± standard deviation. The number and percentage of patients who achieved the regression of IMT ≥0.10 mm from the baseline at the end of the study regression were presented using Fisher’s exact test. Multiple logistic regression analysis was performed to compare target attainment of IMT ≥0.10 mm from the baseline at the end of the study between the two groups. Classical atherosclerotic risk factors based on clinical judgment were included in the model. Adjusted odds ratio (OR) estimates and Wald 95% confidence interval (CI) were calculated. Multivariate logistic regression models were used to identify the factors for regression of IMT ≥0.10 mm from the baseline at the end of the study. Classical atherosclerotic risk factors and changes in some of them based on clinical judgment were included in the model. All statistical tests were two-sided with 5% significance level. All analyses were performed using the SAS software version 9.4 (SAS Institute, Cary, NC).
As described previously [
Clinical characteristics of patients of the two groups.
Parameters | Sitagliptin group ( |
Conventional group ( |
|
---|---|---|---|
Age (years) | 63.8 ± 9.7 | 63.6 ± 1.0 | 0.90 |
Gender (males) (%) | 83 (61) | 82 (60) | 1.00 |
Body mass index | 25.0 ± 4.3 | 25.0 ± 3.8 | 0.88 |
Current smoking | 30 (22) | 29 (21) | 0.22 |
Duration of diabetes (years) | 17.2 ± 8.5 | 17.3 ± 8.7 | 0.94 |
HbA1c at baseline (mmol/mol) | 64.9 ± 11.9 | 63.9 ± 10.6 | 0.45 |
Systolic blood pressure (mmHg) | 130 ± 16 | 132 ± 14 | 0.88 |
Total cholesterol at baseline (mmol/l) | 5.02 ± 0.91 | 4.94 ± 0.86 | 0.50 |
HDL cholesterol at baseline (mmol/l) | 1.46 ± 0.37 | 1.39 ± 0.38 | 0.14 |
Triglyceride at baseline (mmol/l) | 1.13 (0.83, 1.55) | 1.17 (0.90, 1.72) | 0.22 |
eGFR (ml/min/1.73 m2) | 77.7 ± 21.2 | 79.7 ± 24.2 | 0.47 |
Mean IMT (mm) | 0.84 ± 0.19 | 0.84 ± 0.21 | 0.81 |
Right maximum IMT (mm) | 1.04 ± 0.29 | 1.06 ± 0.40 | 0.69 |
Left maximum IMT (mm) | 1.10 ± 0.32 | 1.11 ± 0.41 | 0.87 |
Use of oral glucose-lowering agents | |||
Metformin | 49 (36) | 48 (35) | 1.00 |
Sulfonylurea | 17 (12) | 15 (11) | 0.85 |
Glinides | 2 (1) | 19 (14) | <0.001 |
Thiazolidinediones | 13 (9) | 11 (8) | 0.83 |
|
41 (30) | 42 (31) | 1.00 |
Others | |||
Angiotensin-converting enzyme inhibitors | 8 (6) | 4 (3) | 0.59 |
Angiotensin II receptor blockers | 53 (39) | 69 (50) | 0.07 |
Statins | 66 (48) | 63 (46) | 0.81 |
Antiplatelet agents | 29 (21) | 30 (22) | 1.00 |
Data are number (%) of patients or mean ± SD values.
IMT, intima-media thickness; eGFR, glomerular filtration rate.
Trial schema.
Effects of sitagliptin on glucose metabolism, blood pressure lipid metabolism, and IMT.
Parameters | Sitagliptin group ( |
Conventional group ( |
|
---|---|---|---|
HbA1c at baseline (mmol/mol) | |||
104 weeks (change from baseline) | −5.6 ± 11.4 | −2.2 ± 10.0 | 0.004 |
Systolic blood pressure (mmHg) | |||
104 weeks (change from baseline) | 0 ± 19 | 3 ± 17 | 0.20 |
Total cholesterol at baseline (mmol/l) | |||
104 weeks (% change from baseline) | −2.7 ± 15.6 | −1.8 ± 14.6 | 0.63 |
HDL cholesterol at baseline (mmol/l) | |||
104 weeks (% change from baseline) | 0.2 ± 15.2 | −0.5 ± 14.7 | 0.74 |
Triglyceride at baseline (mmol/l) | |||
104 weeks (% change from baseline) | 0.0 (−25.1, 44.6) | −1.6 (−24.6, 16.7) | 0.35 |
Mean IMT (mm) | |||
104 weeks (change from baseline) | −0.03 ± 0.17 | 0.02 ± 0.14 | 0.008 |
Right maximum IMT | |||
104 weeks (change from baseline) | 0.00 ± 0.35 | 0.02 ± 0.37 | 0.67 |
Left maximum IMT | |||
104 weeks (change from baseline) | −0.06 ± 0.34 | 0.02 ± 0.29 | 0.033 |
Data are mean ± SD or median (range) values. Differences in parameters from baseline to 104 weeks between groups were analyzed by the Student
In this study, we compared the percentage of patients who achieved a decrease of ≥0.10 mm in mean-IMT-CCA and right and left max-IMT-CCA at the end of the study. The percentages of patients with regression of mean-IMT-CCA (28.9% in the sitagliptin group versus 16.4% in the conventional group,
Results of adjustment randomized comparisons.
Adjusted odds ratio (95% CI) |
| |
---|---|---|
Mean intima-media thickness | ||
Model 1 | 2.29 (1.17–4.47) | 0.015 |
Model 2 | 2.27 (1.16–4.44) | 0.016 |
Model 3 | 2.48 (1.24–4.93) | 0.010 |
Model 4 | 2.60 (1.29–5.28) | 0.008 |
Model 5 | 2.89 (1.34–6.24) | 0.007 |
Right maximum intima-media thickness | ||
Model 1 | 1.77 (1.00–3.13) | 0.049 |
Model 2 | 1.78 (1.00–3.14) | 0.049 |
Model 3 | 1.87 (1.04–3.34) | 0.036 |
Model 4 | 1.88 (1.05–3.40) | 0.035 |
Model 5 | 2.15 (1.12–4.14) | 0.022 |
Left maximum intima-media thickness | ||
Model 1 | 2.22 (1.25–3.92) | 0.006 |
Model 2 | 2.24 (1.26–3.98) | 0.006 |
Model 3 | 2.33 (1.28–4.22) | 0.006 |
Model 4 | 2.43 (1.32–4.48) | 0.004 |
Model 5 | 2.46 (1.28–4.73) | 0.007 |
Multiple logistic regression analysis included the treatment group, age, gender, and baseline IMT (model 1); model 1 plus body mass index and current smoking (model 2); model 2 plus HbA1c, total cholesterol, high-density lipoprotein cholesterol, triglyceride, and systolic blood pressure (model 3); model 3 plus eGFR, use of angiotensin-converting enzyme/angiotensin II receptor blocker, use of statin, and use of antiplatelets (model 4); model 4 plus the use of oral hypoglycemic agents (model 5).
Next, multivariate logistic regression models were performed to identify predictive factors for regression of mean-IMT-CCA and right and left max-IMT-CCA. Sitagliptin treatment and higher IMT at baseline were mainly associated with the regression of carotid IMT (Table
Results of multivariate logistic regression models for the regression of IMT of ≥0.10 mm from baseline at the end of the study.
Factor | Mean IMT | Right max IMT | Left max IMT | |||
---|---|---|---|---|---|---|
Adjusted odds ratio (95% CI) |
|
Adjusted odds ratio (95% CI) |
|
Adjusted odds ratio (95% CI) |
| |
Age (1 year) | 1.01 (0.95–1.06) | 0.83 | 0.98 (0.94–1.02) | 0.37 | 1.01 (0.97–1.06) | 0.61 |
Gender (male/female) | 1.99 (0.83–4.79) | 0.12 | 0.67 (0.33–1.35) | 0.26 | 1.02 (0.49–2.14) | 0.95 |
Body mass index (1 kg/m2) | 1.07 (0.95–1.20) | 0.26 | 1.03 (0.94–1.13) | 0.56 | 1.00 (0.91–1.10) | 0.98 |
Estimated duration of diabetes (1 year) | 1.02 (0.97–1.07) | 0.42 | 0.99 (0.95–1.03) | 0.65 | 1.02 (0.98–1.07) | 0.26 |
Smoking (yes/no) | 1.93 (0.67–5.52) | 0.22 | 0.72 (0.30–1.74) | 0.47 | 1.83 (0.77–4.35) | 0.17 |
HbA1c (1 mmol/l) | 1.04 (0.69–1.56) | 0.87 | 1.07 (0.76–1.51) | 0.68 | 1.00 (0.70–1.44) | 0.99 |
Systolic BP (1 mmHg) | 0.99 (0.96–1.02) | 0.40 | 1.03 (1.01–1.06) | 0.012 | 0.97 (0.94–0.99) | 0.02 |
Total cholesterol (1 mmol/l) | 0.64 (0.35–1.18) | 0.16 | 1.11 (0.69–1.79) | 0.68 | 1.19 (0.72–1.95) | 0.49 |
HDL cholesterol (1 mmol/l) | 0.44 (0.11–1.78) | 0.25 | 1.19 (0.38–3.75) | 0.76 | 0.69 (0.22–2.15) | 0.52 |
Triglyceride (1 mmol/l) | 0.92 (0.58–1.44) | 0.71 | 0.87 (0.59–1.29) | 0.5 | 1.00 (0.72–1.38) | 1.00 |
eGFR (1 ml/min/1.73 m2) | 1.01 (0.99–1.03) | 0.27 | 1.00 (0.98–1.01) | 0.74 | 1.01 (0.99–1.03) | 0.22 |
Baseline cIMT (0.01 mm) | 1.05 (1.03–1.08) | <0.001 | 1.02 (1.01–1.03) | <0.001 | 1.02 (1.01–1.03) | <0.001 |
Treatment group (sitagliptin |
3.58 (1.60–7.99) | 0.002 | 2.02 (1.07–3.84) | 0.031 | 2.38 (1.23–4.58) | 0.01 |
ACE/ARB (yes/no) | 1.10 (0.50–2.45) | 0.81 | 0.86 (0.45–1.68) | 0.67 | 1.31 (0.66–2.63) | 0.44 |
Statins (yes/no) | 0.76 (0.33–1.74) | 0.51 | 1.27 (0.64–2.49) | 0.49 | 0.88 (0.44–1.76) | 0.72 |
Antiplatelets (yes/no) | 0.34 (0.12–0.96) | 0.04 | 0.79 (0.35–1.79) | 0.57 | 0.40 (0.17–0.97) | 0.042 |
OHA (yes/no) | 0.55 (0.26–1.18) | 0.12 | 0.83 (0.43–1.58) | 0.56 | 0.53 (0.27–1.04) | 0.064 |
Changes in systolic BP at 104 weeks |
1.00 (0.98–1.03) | 0.94 | 1.02 (1.00–1.04) | 0.079 | 0.99 (0.97–1.01) | 0.45 |
Changes in HbA1c at 104 weeks from |
1.25 (0.84–1.87) | 0.27 | 1.13 (0.80–1.60) | 0.49 | 0.91 (0.64–1.29) | 0.59 |
Changes in total cholesterol at 104 weeks |
0.97 (0.94–1.00) | 0.051 | 0.99 (0.97–1.02) | 0.45 | 0.99 (0.96–1.01) | 0.30 |
Changes in HDL cholesterol at 104 weeks |
1.00 (0.97–1.02) | 0.76 | 1.01 (0.99–1.03) | 0.33 | 1.01 (0.98–1.03) | 0.59 |
Changes in triglyceride at 104 weeks from baseline (1 mmol/l) | 1.00 (0.99–1.00) | 0.39 | 1.00 (1.00–1.01) | 0.22 | 1.00 (0.99–1.01) | 0.85 |
Multivariate logistic regression models were used to identify the determination of the regression of IMT of ≥0.10 mm from baseline at the end of the study.
ACE/ARB, angiotensin-converting enzyme/angiotensin II receptor blocker; BP, blood pressure; IMT, intima-media thickness; eGFR, glomerular filtration rate; OHA, oral hypoglycemic agents.
Previous study demonstrated that aggressive lipid-lowering therapies with a statin alone or statin and ezetimibe resulted in regression of carotid IMT in patients with T2DM [
There are several certain limitations. First, because the limit of detection of IMT measured by ultrasound scanner used in this study was <0.1 mm, we defined a decrease of ≥0.10 mm in IMT as IMT regression in terms of measurement sensitivity in these exploratory post hoc analyses. There are very few studies to investigate the effect of drugs on IMT regression. In a previous study, IMT regression was defined as a decrease of >0.020 mm in mean IMT without reasonable scientific grounds [
In conclusion, our data suggested that DPP-4 inhibitors were associated with the regression of carotid atherosclerosis in insulin-treated T2DM patients free of apparent CVD.
Confidence interval
Cardiovascular disease
Dipeptidyl peptidase-4
Intima-media thickness
Maximum IMT of the common carotid artery
Mean IMT of the common carotid artery
Oral hypoglycemic agents
Odds ratio
Sitagliptin Preventive Study of Intima-Media Thickness Evaluation
Type 2 diabetes mellitus.
This protocol was approved by the Institutional Review Board of each participating institution (Jiyugaoka Medical Clinic, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University Graduate School of Medicine, Kansai Rosai Hospital, Naka Memorial Clinic, Osaka General Medical Center, Osaka Police Hospital, Osaka University Graduate School of Medicine, and Sasebo Chuo Hospital) in compliance with the Declaration of Helsinki and current legal regulations in Japan.
Written informed consent was obtained from all the participants after full explanation of the study.
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Tomoya Mita received research funds from MSD and Takeda Pharma K.K. and has received lecture fees from AstraZeneca K.K., Boehringer Ingelheim, Eli Lilly, Kowa Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., MSD, Ono Pharmaceutical Co., and Takeda Pharmaceutical Co. Naoto Katakami is a staff member of the endowed chair (Department of Metabolism and Atherosclerosis) established by funds from Kowa Pharmaceutical Co. and has received research funds from MSD and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Daiichi Sankyo Inc., Dainippon Sumitomo Pharma Co., Eisai Co., Eli Lilly, Kowa Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Otsuka Pharmaceutical, Shionogi & Co., Takeda Pharmaceutical Co., Sanofi-Aventis, and Shionogi & Co. Toshihiko Shiraiwa has received lecture fees from Boehringer Ingelheim, Sanofi-Aventis, Novo Nordisk Pharma, Novartis Pharmaceuticals, Eli Lilly, Abbott Japan, Takeda Pharmaceutical Co., Sanwa Kagaku Kenkyusho Co. Ltd., Mitsubishi Tanabe Pharma Co., Daiichi Sankyo Inc., Astellas Pharma Inc., Ono Pharmaceutical Co., MSD, Shionogi, Pharma, and Taisho Toyama Pharmaceutical Co. Masahiko Gosho received lecture fees from Novartis and Tiho Pharma K.K., received travel fees from Takeda Pharmaceutical Co., and received manuscript fee from Kowa Co., Ltd. Iichiro Shimomura has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceutical Co., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Daiichi Sankyo Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Bayer Yakuhin, Pfizer Japan Inc., Bristol-Myers K.K., Mochida Pharmaceutical Co., Shionogi & Co., Taisho Toyama Pharmaceutical Co., and Shionogi & Co. and research funds from Astellas Pharma Inc., AstraZeneca K.K., Eisai Co., MSD K.K., Otsuka Pharmaceutical Co., Ono Pharmaceutical Co., Kaken Pharmaceutical Co., Kissei Pharmaceutical Co., Kyowa Hakko Kirin Co., Ltd., Sanofi K.K., Shionogi & Co., Daiichi Sankyo Co., Dainippon Sumitomo Pharma Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Pfizer Japan Inc., Bristol-Myers K.K., Mochida Pharmaceutical Co., Eli Lilly Japan K.K., Kowa Co., Ltd., Kowa Pharmaceutical Co., and Taisho Toyama Pharmaceutical Co. Hirotaka Watada has received lecture fees from Novo Nordisk, Inc., Eli Lilly and Company, Sanofi, Dainippon Sumitomo Pharma Co., Fujifilm, Bayer Health Care, Kissei Pharmaceutical Company, Mochida Pharmaceutical Company, MSD, Takeda Pharmaceutical Company, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo, Ono Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corporation, Mitsubishi Tanabe Pharma Corporation, AstraZeneca LP, Kyowa Hakko Kirin Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Company Ltd., and Astellas Pharma, Inc., advisory fees from Novo Nordisk, Inc., Mochida Pharma Company, AstraZeneca LP, Kowa Company, Astellas Pharma, Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., MSD, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Dainippon Sumitomo Pharma Co., Takeda Pharmaceutical Company, Ono Pharmaceutical Co., Pfizer, Inc., and Kowa Company, and research funds from Boehringer Ingelheim, Pfizer, Mochida Pharmaceutical Co., Sanofi-Aventis, Novo Nordisk Pharma, Novartis Pharmaceuticals, Sanwa Kagaku Kenkyusho Co., Ltd., Terumo Corp., Eli Lilly, Mitsubishi Tanabe Pharma, Daiichi Sankyo Inc., Takeda Pharmaceutical Co., MSD, Shionogi, Pharma, Dainippon Sumitomo Pharma, Kissei Pharma, and AstraZeneca.
The authors meet the criteria for authorship recommended by the International Committee of Medical Journal Editors and take full responsibility for all contents of the manuscript and editorial decisions. Tomoya Mita, Naoto Katakami, Toshihiko Shiraiwa, Hidenori Yoshii, Masahiko Gosho, Iichiro Shimomura, and Hirotaka Watada contributed to the study design and were involved in all stages of manuscript development. Tomoya Mita and Naoto Katakami drafted the manuscript. Masahiko Gosho contributed to the analysis of research data. Tomoya Mita, Naoto Katakami, Toshihiko Shiraiwa, Hidenori Yoshii, Masahiko Gosho, Iichiro Shimomura, and Hirotaka Watada were involved in the analysis and interpretation of data, reviewed/edited the manuscript, and approved the final manuscript. Iichiro Shimomura and Hirotaka Watada were the principal guarantors of this work and have full access to all the data and take responsibility for the integrity of the data and accuracy of data analysis.
Authors acknowledge the SPIKE trial site investigators listed (in alphabetical order) as follows. The SPIKE study is a multicenter collaboration. In addition to the listed authors, the following SPIKE study investigators were involved in this study: