# Sitagliptin on Carotid Intima-Media Thickness in Type 2 Diabetes Mellitus Patients and Anemia: A Subgroup Analysis of the PROLOGUE Study

Authors: Zhengri Lu; Genshan Ma; Lijuan Chen
Journal: Mediators of Inflammation
 (2020)

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## Abstract

Introduction. Randomized clinical trials have not shown an additional clinical benefit of sitagliptin treatment over conventional treatment alone. However, studies of sitagliptin treatment have not examined the relationship between anemia and treatment group outcomes. Methods. The PROLOGUE study is a prospective clinical trial of 442 participants with type 2 diabetes mellitus (T2DM) randomized to sitagliptin treatment or conventional treatment which showed no treatment differences [Estimated mean (± standard error) common carotid intima-media thickness (CIMT) was 0.827±0.007mm and 0.837±0.007mm, respectively, with a mean difference of -0.009 mm (97.2% CI −0.028 to 0.011, p=0.309) at 24 mo of follow-up]. This is a post hoc subanalysis using data obtained from the PROLOGUE study; the study population was divided into anemic groups (n=94) and nonanemic group (n=343) based on hemoglobin level. And we analyzed for the changes in each CIMT parameter from baseline to 24 months in subgroups. Results. The treatment group difference in baseline-adjusted mean common carotid artery- (CCA-) IMT at 24 months was −0.003 mm (95% CI −0.022 to 0.015, p=0.718) in the nonanemic subgroup and −0.007 mm (95% CI −0.043 to 0.030, p=0.724) in the anemic subgroup. Although there were no significant differences in the other CIMT parameters between the treatment groups in the anemic subgroup, the changes in mean and max ICA-IMT at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.104 mm (95% CI −0.182 to −0.026), p=0.009 and −0.142 mm (−0.252 to −0.033), p=0.011, respectively]. Conclusion. These data suggest that nonanemia may indicate a potentially large subgroup of those with T2DM patients that sitagliptin therapy has a better antiatherosclerotic effect than conventional therapy. Further research is needed to confirm these preliminary observations.


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## Body

## 1. Introduction

Atherosclerosis is an inflammatory disease involving the interaction of genetic and environmental factors. It is usually caused by hypertension, hyperlipidemia, diabetes, smoking, and unhealthy diet, which is the leading cause of vascular disease globally. Among them, diabetes mellitus is not only a disorder of glucose metabolism but is also considered to be a high-risk disease that is causing atherosclerosis. A prospective cohort study has shown that the lifetime risk of vascular death in diabetic patients without previous coronary heart disease (CHD) is as high as the risk of CHD only [1]. Therefore, active and effective interventions are needed, including dietary change, physical exercise, and medication to reduce the prevalence of diabetes.The carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis, which is the combined thickness of the tunica intima and media of a circulatory vessel detectable noninvasively with ultrasonographic techniques [2]. On the one hand, CIMT is directly associated with the risk of myocardial infarction and stroke and is considered to be an effective tool for early diagnosis of atherosclerosis [3, 4]. Some studies suggest that the progression of carotid IMT in coronary artery disease (CAD) can be used to predict coronary events and related mortality [5–7]. The link between CIMT and CAD may be related to inflammation, which is recognized to play a critical role in the pathogenesis of atherosclerosis [8]. It has been recognized that the pathogenesis of increased CIMT and CAD are both related to atherosclerosis. These findings emphasize the importance of recognizing and managing the early stages of atherosclerosis for effective prevention of CAD. On the other hand, assessing the efficacy of drugs for diabetes is an active area of therapeutic research in metabolic diseases. Some studies have attempted to evaluate the effects of various drugs on CIMT changes. A systematic review demonstrated that statins can reduce CIMT by lipid decrease [9]. Another meta-analysis suggested that alpha-glucosidase inhibitors (alpha-GIs) can attenuate the CIMT progression in patients with impaired glucose tolerance or type 2 diabetes mellitus (T2DM) [10]. However, to date, there are less data on dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists associated with CIMT progression. A meta-analysis of 5 studies revealed that there was no statistically significant decrease in IMT by GLP-1 based therapies [11]. DPP-4 inhibitors are a class of antihyperglycemic drugs that can effectively increase the concentration of insulin and control blood glucose levels. In addition, DPP-4 inhibitors may have additional effects beyond blood glucose control, such as antiatherosclerotic effects [12, 13]. Several researches using animal models have confirmed that DPP-4 inhibitors significantly suppressed atherosclerotic lesions mainly through the actions of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) [14–18]. In addition, clinical studies have also demonstrated the anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors [19, 20]. However, some large-scale clinical trials have found that the DPP-4 inhibitors neither increase nor decrease the incidence of cardiovascular events [21–23]. In addition, some studies have shown that DPP-4 inhibitors can reduce the CIMT increase [24, 25]. Sitagliptin (a DPP-4 inhibitor) and liraglutide (a GLP-1 receptor agonist) treatment improved arterial stiffness by reducing oxidative stress in T2DM patients [26, 27]. But the PROLOGUE trial did not find that sitagliptin showed an additional effect in inhibiting the progression of CIMT. Therefore, the antiatherosclerotic effect of DPP-4 inhibitors has not been fully elucidated.Diabetes patients are often accompanied by anemia, which is associated with an increased risk of adverse cardiovascular events and kidney disease [28–30]. The prevalence of anemia in patients with diabetic nephropathy is higher than that with other types of chronic kidney disease (CKD), and the severity of anemia is increasing gradually with the deterioration of renal function. Hemoglobin concentration in patients with diabetes continued to decrease significantly even without nephropathy [31]. Although previous studies have reported abnormal hemoglobin concentrations in patients with diabetes [31, 32], other studies have also shown an association between anemia and cardiovascular disease (CVD) in patients with diabetes mellitus and in those with chronic kidney disease (CKD) [33, 34]. But the relationship between anemia and subclinical atherosclerosis markers in patients with T2DM remains somewhat elusive. In general, we rarely consider anemia as a factor in the development of atherosclerosis in patients with diabetes. Although the prospective randomized clinical trial of sitagliptin has not shown other clinical benefits, the effects of baseline anemia events on CIMT after sitagliptin treatment are unclear. We used data from the PROLOGUE study to test the hypothesis that certain patients in low- and high-risk subgroups were more likely to benefit from sitagliptin.


## 2. Methods

### 2.1. Study Design

This is apost hoc analysis using data from the PROLOGUE study, a multicenter, randomized, prospective, open-label, blinded endpoint trial carried out at 48 institutions in Japan that evaluated 442 patients with T2DM between June 2011 and September 2012 [35]. The inclusion criteria were age≥30 years and presence of T2DM with HbA1c (JDS) 6.2–9.4% (JDS indicates Japan Diabetes Society value that is expressed as 0.4% lower than National Glycohemoglobin Standardization Program value) despite treatment with diet, exercise, and/or conventional antidiabetic agents (except incretin-related therapy) [36]. Patients with the administration of DPP-4 inhibitors and/or GLP-1 analogues before randomization and heart failure with New York Heart Association functional class III or IV were excluded. Study inclusion and exclusion criteria have been published previously. There were two treatment groups in PROLOGUE: sitagliptin treatment (“sitagliptin group”, n=222) and conventional glucose-lowering treatment (“conventional group”, n=220). The PROLOGUE study primary endpoint was the change in mean common carotid artery- (CCA-) IMT at 24 months after treatment randomization. Other CIMT parameters, including the internal carotid artery- (ICA-) IMT, were secondary endpoints. The study was approved by all participating institutional review boards, and all study participants gave informed consent. The full study protocol can be found in previously published research.In thepost hoc analysis, anemia was defined according to the concentration of hemoglobin, which is the standard index of anemia. According to the World Health Organization (WHO) definition of anemia: hemoglobin<13g/DL in men and <12 g/DL in women [37]. The study population was divided into the anemic group (n=94) and the nonanemic group (n=343) based on this definition. And we analyzed for the changes in each CIMT parameter from baseline to 24 months in subgroups.


### 2.2. Statistical Analysis

Normally distributed continuous data were shown asmean±standarddeviation and compared using a two-tailed unpaired Student’s t-test. Categorical variables were expressed as frequencies (%) and compared using the Chi-squared test wherever appropriate. The baseline-adjusted means of each parameter were estimated by analysis of covariance with treatment effect and age, sex, statin use, prerandomization treatment type, baseline HbA1c, baseline office systolic blood pressure, baseline maximum IMT, and the baseline value of each parameter as covariates. A two-tailed p value < 0.05 was definitely statistically significant. Statistical analyses were performed with SPSS Statistics Software (version 25.0; IBM SPSS, Armonk, New York, United States of America).


## 2.1. Study Design

This is apost hoc analysis using data from the PROLOGUE study, a multicenter, randomized, prospective, open-label, blinded endpoint trial carried out at 48 institutions in Japan that evaluated 442 patients with T2DM between June 2011 and September 2012 [35]. The inclusion criteria were age≥30 years and presence of T2DM with HbA1c (JDS) 6.2–9.4% (JDS indicates Japan Diabetes Society value that is expressed as 0.4% lower than National Glycohemoglobin Standardization Program value) despite treatment with diet, exercise, and/or conventional antidiabetic agents (except incretin-related therapy) [36]. Patients with the administration of DPP-4 inhibitors and/or GLP-1 analogues before randomization and heart failure with New York Heart Association functional class III or IV were excluded. Study inclusion and exclusion criteria have been published previously. There were two treatment groups in PROLOGUE: sitagliptin treatment (“sitagliptin group”, n=222) and conventional glucose-lowering treatment (“conventional group”, n=220). The PROLOGUE study primary endpoint was the change in mean common carotid artery- (CCA-) IMT at 24 months after treatment randomization. Other CIMT parameters, including the internal carotid artery- (ICA-) IMT, were secondary endpoints. The study was approved by all participating institutional review boards, and all study participants gave informed consent. The full study protocol can be found in previously published research.In thepost hoc analysis, anemia was defined according to the concentration of hemoglobin, which is the standard index of anemia. According to the World Health Organization (WHO) definition of anemia: hemoglobin<13g/DL in men and <12 g/DL in women [37]. The study population was divided into the anemic group (n=94) and the nonanemic group (n=343) based on this definition. And we analyzed for the changes in each CIMT parameter from baseline to 24 months in subgroups.


## 2.2. Statistical Analysis

Normally distributed continuous data were shown asmean±standarddeviation and compared using a two-tailed unpaired Student’s t-test. Categorical variables were expressed as frequencies (%) and compared using the Chi-squared test wherever appropriate. The baseline-adjusted means of each parameter were estimated by analysis of covariance with treatment effect and age, sex, statin use, prerandomization treatment type, baseline HbA1c, baseline office systolic blood pressure, baseline maximum IMT, and the baseline value of each parameter as covariates. A two-tailed p value < 0.05 was definitely statistically significant. Statistical analyses were performed with SPSS Statistics Software (version 25.0; IBM SPSS, Armonk, New York, United States of America).


## 3. Results

### 3.1. Baseline Characteristics of Study Subjects

The baseline demographic and clinical characteristics of the 442 study participants (222 subjects in the sitagliptin group and 220 in the conventional treatment group) have been previously reported. There were no significant differences in terms of the clinical parameters between the two groups. In thispost hoc analysis, we compared the baseline demographics and clinical variables in subgroups (Table 1). As shown by the baseline hemoglobin distribution in Figure 1, the hemoglobin concentrations of male and female nonanemic patients were 14.642±1.030g/DL and 13.366±0.807g/DL, respectively. And the hemoglobin concentrations of male and female anemic patients were 11.944±0.732g/DL and 10.988±1.018g/DL, respectively. The baseline variables were similar between treatment groups, except more prevalent prior to chronic heart failure in patients treated with conventional in the anemic subgroup. The average body mass index, diastolic blood pressure, fasting plasma glucose, and prevalence of dyslipidemia were modestly higher in the nonanemic subgroup. Baseline HbA1c levels in the two subgroups were around 7.0%. No significant difference in CIMT parameters between the treatment groups in each subgroup.Table 1
Baseline clinical characteristics of the study population.
Variable
Anemia (NO,n=343)
P
Anemia (YES,n=94)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
Mean age (years)
68.18±8.87
68.16±9.34
0.982
73.95±8.27
73.56±6.95
0.802
Gender (male),n (%)
118 (67.4%)
114 (67.9%)
0.932
25 (56.8%)
36 (72.0%)
0.124
BMI (kg/m2)
25.55±4.14
25.25±4.05
0.504
24.24±3.83
23.75±3.54
0.521
Dyslipidemia (%)
132 (75.4%)
117 (69.6%)
0.230
28 (63.6%)
30 (60.0%)
0.717
Cerebral infarction (%)
16 (9.1%)
17 (10.1%)
0.759
4 (9.1%)
8 (16.0%)
0.317
Myocardial infarction (%)
34 (19.4%)
38 (22.6%)
0.468
10 (22.7%)
17 (34.0%)
0.228
PCI (%)
42 (24.0%)
50 (29.8%)
0.229
16 (36.4%)
19 (38.0%)
0.870
CABG (%)
16 (9.1%)
11 (6.5%)
0.372
3 (6.8%)
5 (10.0%)
0.581
Chronic heart failure (%)
14 (8.0%)
16 (9.5%)
0.618
1 (2.3%)
10 (20.0%)
0.008
Arrhythmia (%)
28 (16.0%)
23 (13.7%)
0.548
4 (9.1%)
9 (18.0%)
0.212
Stroke (%)
21 (12.0%)
21 (12.5%)
0.888
5 (11.4%)
9 (18.0%)
0.367
SBP (mmHg)
130.19±15.76
128.08±15.73
0.215
130.18±14.87
131.02±19.10
0.812
DBP (mmHg)
73.50±10.65
72.81±11.20
0.560
70.36±10.70
68.06±11.80
0.327
HbA1c (%)
6.99±0.69
6.96±0.54
0.652
6.80±0.36
6.95±0.59
0.138
FPG (mg/dL)
140.15±43.86
137.31±35.10
0.520
130.52±32.32
126.06±42.18
0.579
Non-HDL cholesterol (mg/dL)
126.16±29.02
125.99±31.19
0.958
107.12±28.32
103.34±24.23
0.494
Serum creatinine (mg/dL)
0.83±0.21
0.82±0.22
0.937
0.97±0.29
0.97±0.27
0.997
eGFR (mL/min/1.73m2)
68.85±16.66
69.64±17.55
0.671
56.83±17.57
58.58±16.23
0.617
Mean CCA IMT (mm)
0.819±0.146
0.816±0.161
0.860
0.833±0.222
0.904±0.255
0.673
Mean bulb IMT (mm)
1.060±0.381
1.129±0.451
0.182
1.330±0.550
1.173±0.352
0.154
Mean ICA IMT (mm)
0.782±0.279
0.772±0.319
0.780
0.799±0.246
0.816±0.268
0.793
Max CCA IMT (mm)
1.037±0.197
1.047±0.215
0.659
1.132±0.316
1.185±0.370
0.463
Max bulb IMT (mm)
1.522±0.570
1.603±0.677
0.286
1.865±0.843
1.741±0.537
0.459
Max ICA IMT (mm)
1.059±0.375
1.039±0.440
0.700
1.057±0.333
1.135±0.397
0.399
Plaque area (mm2)
11.083±7.311
11.283±6.656
0.837
12.903±7.992
13.085±14.233
0.955
Plaque gray scale median
52.335±23.765
51.094±18.747
0.675
44.525±15.908
55.956±28.407
0.077
Abbreviation: BMI: body mass index; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; HDL: high-density lipoprotein; eGFR: estimated glomerular filtration rate; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.Figure 1
Distribution of the baseline hemoglobin concentrations across the entire cohort of male and female patients. (a) and (b) indicate the number of male and female nonanemic patients, respectively. While (c) and (d) indicate the number of male and female anemic patients, respectively.
(a)
(b)
(c)
(d)


### 3.2. Effect of Sitagliptin on Metabolic Factors and Carotid IMT in Subgroups

The effects of sitagliptin on metabolic factors and CIMT have been previously reported. In conclusion, sitagliptin treatment has a more effective hypoglycemic effect than conventional treatment. In thispost hoc analysis of the PROLOGUE study, we also found a similar result. The changes in HbA1c at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.146 mm (95% CI −0.282 to −0.010), p=0.035]. However, regarding blood pressure, non-HDL cholesterol, serum creatinine, and estimated glomerular filtration rate (eGFR), there was no significance between treatment group differences in changes from baseline to 24 months. As shown in Figure 2, hemoglobin concentration was slightly higher in patients treated with sitagliptin than in patients treated with conventional in the anemic subgroup (11.981±0.180g/DL and 11.473±0.178g/DL, p=0.027). The treatment group difference in baseline-adjusted mean CCA-IMT at 24 months was −0.003 mm (95% CI −0.022 to 0.015, p=0.718) in the nonanemic subgroup and − 0.007 mm (95% CI −0.043 to 0.030, p=0.724) in the anemic subgroup (Tables 2 and 3). Although there were no significant differences in the other CIMT parameters between the treatment groups in the anemic subgroup, the changes in mean and max ICA-IMT at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.104 mm (95% CI −0.182 to −0.026), p=0.009 and −0.142 mm (−0.252 to −0.033), p=0.011, respectively].Figure 2
Time course of hemoglobin concentration of anemic and nonanemic subgroups during treatment. Graph shows sex-, age- and baseline-adjusted mean (±standard error) at 12 and 24 months. Hemoglobin at 12 months shows a significant difference in the anemic subgroup.∗p=0.027 vs. conventional subgroup.Table 2
Baseline-adjusted mean and group difference between treatment groups.
Variable
Time point
Anemia (NO,n=343)
Anemia (YES,n=94)
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
BMI (kg/m2)
12 mo
25.289±0.099
25.154±0.101
0.135 (−0.118 to 0.388)
0.294
24.104±0.191
24.294±0.193
−0.190 (−0.669 to 0.290)
0.433
24 mo
25.112±0.124
25.382±0.128
−0.270 (−0.585 to 0.046)
0.094
24.154±0.220
24.281±0.222
−0.127 (−0.693 to 0.439)
0.655
SBP (mmHg)
12 mo
128.561±1.221
130.439±1.238
−1.878 (−4.968 to 1.213)
0.233
129.517±2.754
128.137±2.677
1.381 (−5.621 to 8.382)
0.695
24 mo
129.209±1.392
129.383±1.385
−0.174 (−3.679 to 3.331)
0.922
132.486±2.862
131.188±2.698
1.298 (−5.787 to 8.382)
0.716
DBP (mmHg)
12 mo
72.438±0.879
74.408±0.894
−1.970 (−4.199 to 0.260)
0.083
68.025±1.673
69.585±1.641
−1.560 (−5.882 to 2.762)
0.474
24 mo
72.801±0.905
72.817±0.904
−0.016 (−2.302 to 2.269)
0.989
72.786±1.808
69.435±1.723
3.351 (−1.216 to 7.918)
0.148
HbA1c (%)
12 mo
6.604±0.049
6.711±0.049
−0.107 (−0.230 to 0.017)
0.090
6.386±0.069
6.471±0.067
−0.085 (−0.260 to 0.090)
0.337
24 mo
6.575±0.054
6.721±0.054
−0.146 (−0.282 to −0.010)
0.035
6.513±0.112
6.687±0.103
−0.175 (−0.450 to 0.101)
0.210
FPG (mg/dL)
12 mo
132.904±3.020
131.049±2.945
1.854 (−5.590 to 9.299)
0.624
122.157±5.343
118.647±5.152
3.510 (−9.977 to 16.998)
0.605
24 mo
129.971±3.083
130.994±2.994
−1.023 (−8.747 to 6.702)
0.795
118.844±5.938
117.265±5.689
1.579 (−13.422 to 16.580)
0.834
Non-HDL cholesterol (mg/dL)
12 mo
124.406±2.061
127.221±2.065
−2.814 (−7.969 to 2.341)
0.284
110.024±3.506
105.687±3.552
4.337 (−4.462 to 13.136)
0.329
24 mo
125.432±2.193
126.784±2.223
−1.353 (−6.914 to 4.209)
0.632
101.153±4.287
103.960±3.994
−2.806 (−13.142 to 7.529)
0.589
Serum creatinine (mg/dL)
12 mo
0.840±0.009
0.826±0.009
0.014 (−0.008 to 0.035)
0.212
0.981±0.023
0.975±0.023
0.006 (−0.052 to 0.065)
0.828
24 mo
0.861±0.014
0.850±0.014
0.011 (−0.023 to 0.045)
0.540
1.002±0.038
0.999±0.035
0.004 (−0.090 to 0.097)
0.938
eGFR (mL/min/1.73m2)
12 mo
67.663±0.770
68.850±0.787
−1.187 (−3.143 to 0.768)
0.233
57.007±1.224
57.781±1.207
−0.774 (−3.899 to 2.350)
0.623
24 mo
66.450±0.838
66.696±0.847
−0.247 (−2.375 to 1.881)
0.820
55.854±1.946
57.659±1.797
−1.805 (−6.585 to 2.975)
0.453
Mean CCA IMT (mm)
12 mo
0.812±0.008
0.808±0.008
0.005 (−0.015 to 0.024)
0.655
0.877±0.018
0.898±0.019
−0.021 (−0.066 to 0.024)
0.349
24 mo
0.819±0.007
0.823±0.007
−0.003 (−0.022 to 0.015)
0.718
0.894±0.015
0.900±0.015
−0.007 (−0.043 to 0.030)
0.724
Mean bulb IMT (mm)
12 mo
1.145±0.037
1.171±0.037
−0.026 (−0.118 to 0.066)
0.583
1.299±0.079
1.221±0.091
0.078 (−0.113 to 0.270)
0.412
24 mo
1.164±0.036
1.167±0.036
−0.003 (−0.093 to 0.087)
0.945
1.308±0.070
1.226±0.068
0.082 (−0.088 to 0.252)
0.335
Mean ICA IMT (mm)
12 mo
0.908±0.041
0.931±0.040
−0.023 (−0.126 to 0.081)
0.666
0.909±0.099
0.840±0.105
0.068 (−0.165 to 0.302)
0.557
24 mo
0.740±0.031
0.844±0.030
−0.104 (−0.182 to −0.026)
0.009
0.878±0.058
0.814±0.051
0.064 (−0.069 to 0.196)
0.337
Max CCA IMT (mm)
12 mo
1.035±0.013
1.017±0.013
0.018 (−0.014 to 0.049)
0.278
1.157±0.027
1.154±0.029
0.003 (−0.065 to 0.071)
0.937
24 mo
1.046±0.013
1.042±0.013
0.004 (−0.029 to 0.036)
0.816
1.182±0.024
1.145±0.023
0.037 (−0.022 to 0.096)
0.217
Max bulb IMT (mm)
12 mo
1.560±0.051
1.606±0.051
−0.046 (−0.171 to 0.080)
0.473
1.704±0.108
1.516±0.121
0.188 (−0.068 to 0.445)
0.146
24 mo
1.656±0.049
1.656±0.049
0.000 (−0.122 to 0.121)
0.996
1.831±0.097
1.664±0.093
0.167 (−0.062 to 0.396)
0.149
Max ICA IMT (mm)
12 mo
1.207±0.054
1.223±0.052
−0.016 (−0.149 to 0.118)
0.816
1.232±0.131
1.165±0.136
0.067 (−0.239 to 0.373)
0.659
24 mo
1.012±0.043
1.154±0.043
−0.142 (−0.252 to −0.033)
0.011
1.176±0.090
1.129±0.077
0.047 (−0.155 to 0.249)
0.641
Plaque area (mm2)
12 mo
12.141±0.810
12.504±0.678
−0.363 (−2.271 to 1.545)
0.707
17.922±3.381
14.411±4.695
3.511 (−2.935 to 9.957)
0.267
24 mo
11.743±0.619
10.568±0.569
1.175 (−0.334 to 2.684)
0.126
13.401±1.739
11.910±1.452
1.491 (−2.062 to 5.045)
0.401
Plaque gray scale median
12 mo
60.939±5.327
62.247±4.424
−1.308 (−13.856 to 11.239)
0.837
57.477±8.156
55.640±11.599
1.837 (−13.740 to 17.415)
0.807
24 mo
49.202±2.738
54.482±2.518
−5.280 (−11.967 to 1.407)
0.121
49.298±5.505
48.248±4.532
1.050 (−10.193 to 12.293)
0.851
Abbreviation: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.Table 3
Changes in baseline-adjusted mean and group difference between treatment groups.
Variable
Time point
Anemia (NO,n=343)
Anemia (YES,n=94)
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
BMI (kg/m2)
12 mo
−0.019±0.099
−0.154±0.101
0.135 (−0.118 to 0.388)
0.294
−0.102±0.191
0.087±0.193
−0.190 (−0.669 to 0.290)
0.433
24 mo
−0.381±0.124
−0.112±0.128
−0.270 (−0.585 to 0.046)
0.094
−0.129±0.220
−0.001±0.222
−0.127 (−0.693 to 0.439)
0.655
SBP (mmHg)
12 mo
−0.757±1.221
1.121±1.238
−1.878 (−4.968 to 1.213)
0.233
−1.483±2.754
−2.863±2.677
1.381 (−5.621 to 8.382)
0.695
24 mo
0.142±1.392
0.316±1.385
−0.174 (−3.679 to 3.331)
0.922
1.730±2.862
0.432±2.698
1.298 (−5.787 to 8.382)
0.716
DBP (mmHg)
12 mo
−0.821±0.879
1.148±0.894
−1.970 (−4.199 to 0.260)
0.083
−2.062±1.673
−0.502±1.641
−1.560 (−5.882 to 2.762)
0.474
24 mo
−0.230±0.905
−0.213±0.904
−0.016 (−2.302 to 2.269)
0.989
2.965±1.808
−0.386±1.723
3.351 (−1.216 to 7.918)
0.148
HbA1c (%)
12 mo
−0.364±0.049
−0.258±0.049
−0.107 (−0.230 to 0.017)
0.090
−0.498±0.069
−0.413±0.067
−0.085 (−0.260 to 0.090)
0.337
24 mo
−0.363±0.054
−0.217±0.054
−0.146 (−0.282 to −0.010)
0.035
−0.390±0.112
−0.215±0.103
−0.175 (−0.450 to 0.101)
0.210
FPG (mg/dL)
12 mo
−5.041±3.020
−6.896±2.945
1.854 (−5.590 to 9.299)
0.624
−4.451±5.343
−7.961±5.152
3.510 (−9.977 to 16.998)
0.605
24 mo
−6.306±3.083
−5.283±2.994
−1.023 (−8.747 to 6.702)
0.795
−7.595±5.938
−9.174±5.689
1.579 (−13.422 to 16.580)
0.834
Non-HDL cholesterol (mg/dL)
12 mo
−2.700±2.061
0.114±2.065
−2.814 (−7.969 to 2.341)
0.284
5.642±3.506
1.305±3.552
4.337 (−4.462 to 13.136)
0.329
24 mo
−1.207±2.193
0.146±2.223
−1.353 (−6.914 to 4.209)
0.632
−3.986±4.287
−1.179±3.994
−2.806 (−13.142 to 7.529)
0.589
Serum creatinine (mg/dL)
12 mo
0.020±0.009
0.007±0.009
0.014 (−0.008 to 0.035)
0.212
0.010±0.023
0.003±0.023
0.006 (−0.052 to 0.065)
0.828
24 mo
0.047±0.014
0.036±0.014
0.011 (−0.023 to 0.045)
0.540
0.026±0.038
0.023±0.035
0.004 (−0.090 to 0.097)
0.938
eGFR (mL/min/1.73m2)
12 mo
−1.967±0.770
−0.779±0.787
−1.187 (−3.143 to 0.768)
0.233
−1.040±1.224
−0.265±1.207
−0.774 (−3.899 to 2.350)
0.623
24 mo
−3.637±0.838
−3.391±0.847
−0.247 (−2.375 to 1.881)
0.820
−1.934±1.946
−0.128±1.797
−1.805 (−6.585 to 2.975)
0.453
Mean CCA IMT (mm)
12 mo
0.001±0.008
−0.004±0.008
0.005 (−0.015 to 0.024)
0.655
−0.022±0.018
−0.001±0.019
−0.021 (−0.066 to 0.024)
0.349
24 mo
0.008±0.007
0.011±0.007
−0.003 (−0.022 to 0.015)
0.718
−0.013±0.015
−0.007±0.015
−0.007 (−0.043 to 0.030)
0.724
Mean bulb IMT (mm)
12 mo
0.056±0.037
0.082±0.037
−0.026 (−0.118 to 0.066)
0.583
0.057±0.079
−0.021±0.091
0.078 (−0.113 to 0.270)
0.412
24 mo
0.060±0.036
0.063±0.036
−0.003 (−0.093 to 0.087)
0.945
0.056±0.070
−0.026±0.068
0.082 (−0.088 to 0.252)
0.335
Mean ICA IMT (mm)
12 mo
0.112±0.041
0.134±0.040
−0.023 (−0.126 to 0.081)
0.666
0.078±0.099
0.010±0.105
0.068 (−0.165 to 0.302)
0.557
24 mo
−0.024±0.031
0.079±0.030
−0.104 (−0.182 to −0.026)
0.009
0.062±0.058
−0.002±0.051
0.064 (−0.069 to 0.196)
0.337
Max CCA IMT (mm)
12 mo
0.002±0.013
−0.015±0.013
0.018 (−0.014 to 0.049)
0.278
0.000±0.027
−0.003±0.029
0.003 (−0.065 to 0.071)
0.937
24 mo
0.015±0.013
0.011±0.013
0.004 (−0.029 to 0.036)
0.816
0.015±0.024
−0.022±0.023
0.037 (−0.022 to 0.096)
0.217
Max bulb IMT (mm)
12 mo
0.006±0.051
0.051±0.051
−0.046 (−0.171 to 0.080)
0.473
−0.058±0.108
−0.246±0.121
0.188 (−0.068 to 0.445)
0.146
24 mo
0.079±0.049
0.080±0.049
0.000 (−0.122 to 0.121)
0.996
0.059±0.097
−0.108±0.093
0.167 (−0.062 to 0.396)
0.149
Max ICA IMT (mm)
12 mo
0.121±0.054
0.137±0.052
−0.016 (−0.149 to 0.118)
0.816
0.101±0.131
0.034±0.136
0.067 (−0.239 to 0.373)
0.659
24 mo
−0.019±0.043
0.123±0.043
−0.142 (−0.252 to −0.033)
0.011
0.073±0.090
0.026±0.077
0.047 (−0.155 to 0.249)
0.641
Plaque area (mm2)
12 mo
0.281±0.810
0.644±0.678
−0.363 (−2.271 to 1.545)
0.707
3.158±3.381
−0.353±4.695
3.511 (−2.935 to 9.957)
0.267
24 mo
0.814±0.619
−0.361±0.569
1.175 (−0.334 to 2.684)
0.126
−0.840±1.739
−2.331±1.452
1.491 (−2.062 to 5.045)
0.401
Plaque gray scale median
12 mo
8.507±5.327
9.815±4.424
−1.308 (−13.856 to 11.239)
0.837
10.639±8.156
8.802±11.599
1.837 (−13.740 to 17.415)
0.807
24 mo
−1.662±2.738
3.617±2.518
−5.280 (−11.967 to 1.407)
0.121
−1.755±5.505
−2.805±4.532
1.050 (−10.193 to 12.293)
0.851
Abbreviation: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.


### 3.3. Effect of Sitagliptin on the Ultrasonic Tissue Characteristics of the Carotid Wall in Subgroups

There were no significant differences in the GSM-Plaque between the two treatment groups in each subgroup at baseline and 24 months (Tables1–3).


### 3.4. Antidiabetic and Other Medications in Subgroups during the Study

There were no significant differences in the baseline frequency of noninvestigational drugs except glinide between the treatment groups in each subgroup. In each conventional group, the additional use of sulfonylureas, metformin,α-glucosidase inhibitor, and thiazolidinedione increased during the 24 mo observation period. However, with the exception of metformin, there was no increase in drug use in each sitagliptin group (Table 4).Table 4
Frequency of the use of antidiabetic and other agents.
Variable
Time point
Anemia (NO)
Anemia (YES)
Sitagliptin group
Conventional
P
Sitagliptin group
Conventional
P
Sulfonylurea
Baseline
50 (28.6%)
42 (25.0%)
0.455
5 (11.4%)
10 (20.0%)
0.254
12 mo
35 (21.3%)
55 (35.3%)
0.006
4 (10.8%)
11 (25.0%)
0.102
24 mo
32 (20.8%)
51 (34.2%)
0.009
3 (8.6%)
10 (23.3%)
0.083
Metformin
Baseline
24 (13.7%)
19 (11.3%)
0.501
8 (18.2%)
13 (26.0%)
0.364
12 mo
30 (18.3%)
50 (32.1%)
0.004
8 (21.6%)
18 (40.9%)
0.064
24 mo
34 (22.1%)
50 (33.6%)
0.026
9 (25.7%)
18 (41.9%)
0.136
α-Glucosidase inhibitor
Baseline
57 (32.6%)
46 (27.4%)
0.294
14 (31.8%)
20 (40.0%)
0.410
12 mo
42 (25.6%)
61 (39.1%)
0.010
11 (29.7%)
23 (52.3%)
0.041
24 mo
35 (22.7%)
58 (38.9%)
0.002
10 (28.6%)
23 (53.5%)
0.027
Thiazolidinedione
Baseline
35 (20.0%)
36 (21.4%)
0.744
17 (38.6%)
17 (34.0%)
0.641
12 mo
25 (15.2%)
45 (28.8%)
0.003
13 (35.1%)
19 (43.2%)
0.461
24 mo
24 (15.6%)
47 (31.5%)
0.001
11 (31.4%)
15 (34.9%)
0.747
Glinide
Baseline
5 (2.9%)
15 (8.9%)
0.016
2 (4.5%)
4 (8.0%)
0.494
12 mo
1 (0.6%)
21 (13.5%)
0.0001
3 (8.1%)
4 (9.1%)
0.875
24 mo
1 (0.6%)
17 (11.4%)
0.0001
2 (5.7%)
4 (9.3%)
0.554
Statin
Baseline
133 (76.0%)
125 (74.4%)
0.732
33 (75.0%)
36 (72.0%)
0.743
12 mo
122 (74.4%)
113 (72.4%)
0.692
26 (70.3%)
30 (68.2%)
0.839
24 mo
114 (74.0%)
106 (71.1%)
0.573
25 (71.4%)
29 (67.4%)
0.704
Fibrate
Baseline
1 (0.6%)
3 (1.8%)
0.295
1 (2.3%)
0 (0.0%)
0.284
12 mo
1 (0.6%)
3 (1.9%)
0.291
1 (2.7%)
0 (0.0%)
0.273
24 mo
1 (0.6%)
3 (2.0%)
0.298
1 (2.9%)
0 (0.0%)
0.265
Angiotensin II receptor blocker
Baseline
98 (56.0%)
84 (50.0%)
0.266
31 (70.5%)
27 (54.0%)
0.102
12 mo
90 (54.9%)
80 (51.3%)
0.519
27 (73.0%)
24 (54.5%)
0.087
24 mo
87 (56.5%)
76 (51.0%)
0.338
27 (77.1%)
23 (53.5%)
0.030
Angiotensin-converting enzyme inhibitor
Baseline
20 (11.4%)
25 (14.9%)
0.344
6 (13.6%)
11 (22.0%)
0.293
12 mo
20 (12.2%)
23 (14.7%)
0.504
3 (8.1%)
9 (20.5%)
0.119
24 mo
16 (10.4%)
21 (14.1%)
0.325
3 (8.6%)
10 (23.3%)
0.083
Number of patients in the NO anemia subgroup = baseline: 175 (Sita), 168 (Con); 12 months: 164 (Sita), 156 (Con); 24 months: 154 (Sita), 149 (Con). Number of patients in the anemia subgroup = baseline: 44 (Sita), 50 (Con); 12 months: 37 (Sita), 44 (Con); 24 months: 35 (Sita), 43 (Con). Data are expressed as number (%).


## 3.1. Baseline Characteristics of Study Subjects

The baseline demographic and clinical characteristics of the 442 study participants (222 subjects in the sitagliptin group and 220 in the conventional treatment group) have been previously reported. There were no significant differences in terms of the clinical parameters between the two groups. In thispost hoc analysis, we compared the baseline demographics and clinical variables in subgroups (Table 1). As shown by the baseline hemoglobin distribution in Figure 1, the hemoglobin concentrations of male and female nonanemic patients were 14.642±1.030g/DL and 13.366±0.807g/DL, respectively. And the hemoglobin concentrations of male and female anemic patients were 11.944±0.732g/DL and 10.988±1.018g/DL, respectively. The baseline variables were similar between treatment groups, except more prevalent prior to chronic heart failure in patients treated with conventional in the anemic subgroup. The average body mass index, diastolic blood pressure, fasting plasma glucose, and prevalence of dyslipidemia were modestly higher in the nonanemic subgroup. Baseline HbA1c levels in the two subgroups were around 7.0%. No significant difference in CIMT parameters between the treatment groups in each subgroup.Table 1
Baseline clinical characteristics of the study population.
Variable
Anemia (NO,n=343)
P
Anemia (YES,n=94)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
Mean age (years)
68.18±8.87
68.16±9.34
0.982
73.95±8.27
73.56±6.95
0.802
Gender (male),n (%)
118 (67.4%)
114 (67.9%)
0.932
25 (56.8%)
36 (72.0%)
0.124
BMI (kg/m2)
25.55±4.14
25.25±4.05
0.504
24.24±3.83
23.75±3.54
0.521
Dyslipidemia (%)
132 (75.4%)
117 (69.6%)
0.230
28 (63.6%)
30 (60.0%)
0.717
Cerebral infarction (%)
16 (9.1%)
17 (10.1%)
0.759
4 (9.1%)
8 (16.0%)
0.317
Myocardial infarction (%)
34 (19.4%)
38 (22.6%)
0.468
10 (22.7%)
17 (34.0%)
0.228
PCI (%)
42 (24.0%)
50 (29.8%)
0.229
16 (36.4%)
19 (38.0%)
0.870
CABG (%)
16 (9.1%)
11 (6.5%)
0.372
3 (6.8%)
5 (10.0%)
0.581
Chronic heart failure (%)
14 (8.0%)
16 (9.5%)
0.618
1 (2.3%)
10 (20.0%)
0.008
Arrhythmia (%)
28 (16.0%)
23 (13.7%)
0.548
4 (9.1%)
9 (18.0%)
0.212
Stroke (%)
21 (12.0%)
21 (12.5%)
0.888
5 (11.4%)
9 (18.0%)
0.367
SBP (mmHg)
130.19±15.76
128.08±15.73
0.215
130.18±14.87
131.02±19.10
0.812
DBP (mmHg)
73.50±10.65
72.81±11.20
0.560
70.36±10.70
68.06±11.80
0.327
HbA1c (%)
6.99±0.69
6.96±0.54
0.652
6.80±0.36
6.95±0.59
0.138
FPG (mg/dL)
140.15±43.86
137.31±35.10
0.520
130.52±32.32
126.06±42.18
0.579
Non-HDL cholesterol (mg/dL)
126.16±29.02
125.99±31.19
0.958
107.12±28.32
103.34±24.23
0.494
Serum creatinine (mg/dL)
0.83±0.21
0.82±0.22
0.937
0.97±0.29
0.97±0.27
0.997
eGFR (mL/min/1.73m2)
68.85±16.66
69.64±17.55
0.671
56.83±17.57
58.58±16.23
0.617
Mean CCA IMT (mm)
0.819±0.146
0.816±0.161
0.860
0.833±0.222
0.904±0.255
0.673
Mean bulb IMT (mm)
1.060±0.381
1.129±0.451
0.182
1.330±0.550
1.173±0.352
0.154
Mean ICA IMT (mm)
0.782±0.279
0.772±0.319
0.780
0.799±0.246
0.816±0.268
0.793
Max CCA IMT (mm)
1.037±0.197
1.047±0.215
0.659
1.132±0.316
1.185±0.370
0.463
Max bulb IMT (mm)
1.522±0.570
1.603±0.677
0.286
1.865±0.843
1.741±0.537
0.459
Max ICA IMT (mm)
1.059±0.375
1.039±0.440
0.700
1.057±0.333
1.135±0.397
0.399
Plaque area (mm2)
11.083±7.311
11.283±6.656
0.837
12.903±7.992
13.085±14.233
0.955
Plaque gray scale median
52.335±23.765
51.094±18.747
0.675
44.525±15.908
55.956±28.407
0.077
Abbreviation: BMI: body mass index; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; HDL: high-density lipoprotein; eGFR: estimated glomerular filtration rate; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.Figure 1
Distribution of the baseline hemoglobin concentrations across the entire cohort of male and female patients. (a) and (b) indicate the number of male and female nonanemic patients, respectively. While (c) and (d) indicate the number of male and female anemic patients, respectively.
(a)
(b)
(c)
(d)


## 3.2. Effect of Sitagliptin on Metabolic Factors and Carotid IMT in Subgroups

The effects of sitagliptin on metabolic factors and CIMT have been previously reported. In conclusion, sitagliptin treatment has a more effective hypoglycemic effect than conventional treatment. In thispost hoc analysis of the PROLOGUE study, we also found a similar result. The changes in HbA1c at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.146 mm (95% CI −0.282 to −0.010), p=0.035]. However, regarding blood pressure, non-HDL cholesterol, serum creatinine, and estimated glomerular filtration rate (eGFR), there was no significance between treatment group differences in changes from baseline to 24 months. As shown in Figure 2, hemoglobin concentration was slightly higher in patients treated with sitagliptin than in patients treated with conventional in the anemic subgroup (11.981±0.180g/DL and 11.473±0.178g/DL, p=0.027). The treatment group difference in baseline-adjusted mean CCA-IMT at 24 months was −0.003 mm (95% CI −0.022 to 0.015, p=0.718) in the nonanemic subgroup and − 0.007 mm (95% CI −0.043 to 0.030, p=0.724) in the anemic subgroup (Tables 2 and 3). Although there were no significant differences in the other CIMT parameters between the treatment groups in the anemic subgroup, the changes in mean and max ICA-IMT at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.104 mm (95% CI −0.182 to −0.026), p=0.009 and −0.142 mm (−0.252 to −0.033), p=0.011, respectively].Figure 2
Time course of hemoglobin concentration of anemic and nonanemic subgroups during treatment. Graph shows sex-, age- and baseline-adjusted mean (±standard error) at 12 and 24 months. Hemoglobin at 12 months shows a significant difference in the anemic subgroup.∗p=0.027 vs. conventional subgroup.Table 2
Baseline-adjusted mean and group difference between treatment groups.
Variable
Time point
Anemia (NO,n=343)
Anemia (YES,n=94)
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
BMI (kg/m2)
12 mo
25.289±0.099
25.154±0.101
0.135 (−0.118 to 0.388)
0.294
24.104±0.191
24.294±0.193
−0.190 (−0.669 to 0.290)
0.433
24 mo
25.112±0.124
25.382±0.128
−0.270 (−0.585 to 0.046)
0.094
24.154±0.220
24.281±0.222
−0.127 (−0.693 to 0.439)
0.655
SBP (mmHg)
12 mo
128.561±1.221
130.439±1.238
−1.878 (−4.968 to 1.213)
0.233
129.517±2.754
128.137±2.677
1.381 (−5.621 to 8.382)
0.695
24 mo
129.209±1.392
129.383±1.385
−0.174 (−3.679 to 3.331)
0.922
132.486±2.862
131.188±2.698
1.298 (−5.787 to 8.382)
0.716
DBP (mmHg)
12 mo
72.438±0.879
74.408±0.894
−1.970 (−4.199 to 0.260)
0.083
68.025±1.673
69.585±1.641
−1.560 (−5.882 to 2.762)
0.474
24 mo
72.801±0.905
72.817±0.904
−0.016 (−2.302 to 2.269)
0.989
72.786±1.808
69.435±1.723
3.351 (−1.216 to 7.918)
0.148
HbA1c (%)
12 mo
6.604±0.049
6.711±0.049
−0.107 (−0.230 to 0.017)
0.090
6.386±0.069
6.471±0.067
−0.085 (−0.260 to 0.090)
0.337
24 mo
6.575±0.054
6.721±0.054
−0.146 (−0.282 to −0.010)
0.035
6.513±0.112
6.687±0.103
−0.175 (−0.450 to 0.101)
0.210
FPG (mg/dL)
12 mo
132.904±3.020
131.049±2.945
1.854 (−5.590 to 9.299)
0.624
122.157±5.343
118.647±5.152
3.510 (−9.977 to 16.998)
0.605
24 mo
129.971±3.083
130.994±2.994
−1.023 (−8.747 to 6.702)
0.795
118.844±5.938
117.265±5.689
1.579 (−13.422 to 16.580)
0.834
Non-HDL cholesterol (mg/dL)
12 mo
124.406±2.061
127.221±2.065
−2.814 (−7.969 to 2.341)
0.284
110.024±3.506
105.687±3.552
4.337 (−4.462 to 13.136)
0.329
24 mo
125.432±2.193
126.784±2.223
−1.353 (−6.914 to 4.209)
0.632
101.153±4.287
103.960±3.994
−2.806 (−13.142 to 7.529)
0.589
Serum creatinine (mg/dL)
12 mo
0.840±0.009
0.826±0.009
0.014 (−0.008 to 0.035)
0.212
0.981±0.023
0.975±0.023
0.006 (−0.052 to 0.065)
0.828
24 mo
0.861±0.014
0.850±0.014
0.011 (−0.023 to 0.045)
0.540
1.002±0.038
0.999±0.035
0.004 (−0.090 to 0.097)
0.938
eGFR (mL/min/1.73m2)
12 mo
67.663±0.770
68.850±0.787
−1.187 (−3.143 to 0.768)
0.233
57.007±1.224
57.781±1.207
−0.774 (−3.899 to 2.350)
0.623
24 mo
66.450±0.838
66.696±0.847
−0.247 (−2.375 to 1.881)
0.820
55.854±1.946
57.659±1.797
−1.805 (−6.585 to 2.975)
0.453
Mean CCA IMT (mm)
12 mo
0.812±0.008
0.808±0.008
0.005 (−0.015 to 0.024)
0.655
0.877±0.018
0.898±0.019
−0.021 (−0.066 to 0.024)
0.349
24 mo
0.819±0.007
0.823±0.007
−0.003 (−0.022 to 0.015)
0.718
0.894±0.015
0.900±0.015
−0.007 (−0.043 to 0.030)
0.724
Mean bulb IMT (mm)
12 mo
1.145±0.037
1.171±0.037
−0.026 (−0.118 to 0.066)
0.583
1.299±0.079
1.221±0.091
0.078 (−0.113 to 0.270)
0.412
24 mo
1.164±0.036
1.167±0.036
−0.003 (−0.093 to 0.087)
0.945
1.308±0.070
1.226±0.068
0.082 (−0.088 to 0.252)
0.335
Mean ICA IMT (mm)
12 mo
0.908±0.041
0.931±0.040
−0.023 (−0.126 to 0.081)
0.666
0.909±0.099
0.840±0.105
0.068 (−0.165 to 0.302)
0.557
24 mo
0.740±0.031
0.844±0.030
−0.104 (−0.182 to −0.026)
0.009
0.878±0.058
0.814±0.051
0.064 (−0.069 to 0.196)
0.337
Max CCA IMT (mm)
12 mo
1.035±0.013
1.017±0.013
0.018 (−0.014 to 0.049)
0.278
1.157±0.027
1.154±0.029
0.003 (−0.065 to 0.071)
0.937
24 mo
1.046±0.013
1.042±0.013
0.004 (−0.029 to 0.036)
0.816
1.182±0.024
1.145±0.023
0.037 (−0.022 to 0.096)
0.217
Max bulb IMT (mm)
12 mo
1.560±0.051
1.606±0.051
−0.046 (−0.171 to 0.080)
0.473
1.704±0.108
1.516±0.121
0.188 (−0.068 to 0.445)
0.146
24 mo
1.656±0.049
1.656±0.049
0.000 (−0.122 to 0.121)
0.996
1.831±0.097
1.664±0.093
0.167 (−0.062 to 0.396)
0.149
Max ICA IMT (mm)
12 mo
1.207±0.054
1.223±0.052
−0.016 (−0.149 to 0.118)
0.816
1.232±0.131
1.165±0.136
0.067 (−0.239 to 0.373)
0.659
24 mo
1.012±0.043
1.154±0.043
−0.142 (−0.252 to −0.033)
0.011
1.176±0.090
1.129±0.077
0.047 (−0.155 to 0.249)
0.641
Plaque area (mm2)
12 mo
12.141±0.810
12.504±0.678
−0.363 (−2.271 to 1.545)
0.707
17.922±3.381
14.411±4.695
3.511 (−2.935 to 9.957)
0.267
24 mo
11.743±0.619
10.568±0.569
1.175 (−0.334 to 2.684)
0.126
13.401±1.739
11.910±1.452
1.491 (−2.062 to 5.045)
0.401
Plaque gray scale median
12 mo
60.939±5.327
62.247±4.424
−1.308 (−13.856 to 11.239)
0.837
57.477±8.156
55.640±11.599
1.837 (−13.740 to 17.415)
0.807
24 mo
49.202±2.738
54.482±2.518
−5.280 (−11.967 to 1.407)
0.121
49.298±5.505
48.248±4.532
1.050 (−10.193 to 12.293)
0.851
Abbreviation: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.Table 3
Changes in baseline-adjusted mean and group difference between treatment groups.
Variable
Time point
Anemia (NO,n=343)
Anemia (YES,n=94)
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Baseline-adjustedmean±SE
Group difference in baseline-adjusted mean (95% CI)
P
Sitagliptin group (n=175)
Conventional (n=168)
Sitagliptin group (n=44)
Conventional (n=50)
BMI (kg/m2)
12 mo
−0.019±0.099
−0.154±0.101
0.135 (−0.118 to 0.388)
0.294
−0.102±0.191
0.087±0.193
−0.190 (−0.669 to 0.290)
0.433
24 mo
−0.381±0.124
−0.112±0.128
−0.270 (−0.585 to 0.046)
0.094
−0.129±0.220
−0.001±0.222
−0.127 (−0.693 to 0.439)
0.655
SBP (mmHg)
12 mo
−0.757±1.221
1.121±1.238
−1.878 (−4.968 to 1.213)
0.233
−1.483±2.754
−2.863±2.677
1.381 (−5.621 to 8.382)
0.695
24 mo
0.142±1.392
0.316±1.385
−0.174 (−3.679 to 3.331)
0.922
1.730±2.862
0.432±2.698
1.298 (−5.787 to 8.382)
0.716
DBP (mmHg)
12 mo
−0.821±0.879
1.148±0.894
−1.970 (−4.199 to 0.260)
0.083
−2.062±1.673
−0.502±1.641
−1.560 (−5.882 to 2.762)
0.474
24 mo
−0.230±0.905
−0.213±0.904
−0.016 (−2.302 to 2.269)
0.989
2.965±1.808
−0.386±1.723
3.351 (−1.216 to 7.918)
0.148
HbA1c (%)
12 mo
−0.364±0.049
−0.258±0.049
−0.107 (−0.230 to 0.017)
0.090
−0.498±0.069
−0.413±0.067
−0.085 (−0.260 to 0.090)
0.337
24 mo
−0.363±0.054
−0.217±0.054
−0.146 (−0.282 to −0.010)
0.035
−0.390±0.112
−0.215±0.103
−0.175 (−0.450 to 0.101)
0.210
FPG (mg/dL)
12 mo
−5.041±3.020
−6.896±2.945
1.854 (−5.590 to 9.299)
0.624
−4.451±5.343
−7.961±5.152
3.510 (−9.977 to 16.998)
0.605
24 mo
−6.306±3.083
−5.283±2.994
−1.023 (−8.747 to 6.702)
0.795
−7.595±5.938
−9.174±5.689
1.579 (−13.422 to 16.580)
0.834
Non-HDL cholesterol (mg/dL)
12 mo
−2.700±2.061
0.114±2.065
−2.814 (−7.969 to 2.341)
0.284
5.642±3.506
1.305±3.552
4.337 (−4.462 to 13.136)
0.329
24 mo
−1.207±2.193
0.146±2.223
−1.353 (−6.914 to 4.209)
0.632
−3.986±4.287
−1.179±3.994
−2.806 (−13.142 to 7.529)
0.589
Serum creatinine (mg/dL)
12 mo
0.020±0.009
0.007±0.009
0.014 (−0.008 to 0.035)
0.212
0.010±0.023
0.003±0.023
0.006 (−0.052 to 0.065)
0.828
24 mo
0.047±0.014
0.036±0.014
0.011 (−0.023 to 0.045)
0.540
0.026±0.038
0.023±0.035
0.004 (−0.090 to 0.097)
0.938
eGFR (mL/min/1.73m2)
12 mo
−1.967±0.770
−0.779±0.787
−1.187 (−3.143 to 0.768)
0.233
−1.040±1.224
−0.265±1.207
−0.774 (−3.899 to 2.350)
0.623
24 mo
−3.637±0.838
−3.391±0.847
−0.247 (−2.375 to 1.881)
0.820
−1.934±1.946
−0.128±1.797
−1.805 (−6.585 to 2.975)
0.453
Mean CCA IMT (mm)
12 mo
0.001±0.008
−0.004±0.008
0.005 (−0.015 to 0.024)
0.655
−0.022±0.018
−0.001±0.019
−0.021 (−0.066 to 0.024)
0.349
24 mo
0.008±0.007
0.011±0.007
−0.003 (−0.022 to 0.015)
0.718
−0.013±0.015
−0.007±0.015
−0.007 (−0.043 to 0.030)
0.724
Mean bulb IMT (mm)
12 mo
0.056±0.037
0.082±0.037
−0.026 (−0.118 to 0.066)
0.583
0.057±0.079
−0.021±0.091
0.078 (−0.113 to 0.270)
0.412
24 mo
0.060±0.036
0.063±0.036
−0.003 (−0.093 to 0.087)
0.945
0.056±0.070
−0.026±0.068
0.082 (−0.088 to 0.252)
0.335
Mean ICA IMT (mm)
12 mo
0.112±0.041
0.134±0.040
−0.023 (−0.126 to 0.081)
0.666
0.078±0.099
0.010±0.105
0.068 (−0.165 to 0.302)
0.557
24 mo
−0.024±0.031
0.079±0.030
−0.104 (−0.182 to −0.026)
0.009
0.062±0.058
−0.002±0.051
0.064 (−0.069 to 0.196)
0.337
Max CCA IMT (mm)
12 mo
0.002±0.013
−0.015±0.013
0.018 (−0.014 to 0.049)
0.278
0.000±0.027
−0.003±0.029
0.003 (−0.065 to 0.071)
0.937
24 mo
0.015±0.013
0.011±0.013
0.004 (−0.029 to 0.036)
0.816
0.015±0.024
−0.022±0.023
0.037 (−0.022 to 0.096)
0.217
Max bulb IMT (mm)
12 mo
0.006±0.051
0.051±0.051
−0.046 (−0.171 to 0.080)
0.473
−0.058±0.108
−0.246±0.121
0.188 (−0.068 to 0.445)
0.146
24 mo
0.079±0.049
0.080±0.049
0.000 (−0.122 to 0.121)
0.996
0.059±0.097
−0.108±0.093
0.167 (−0.062 to 0.396)
0.149
Max ICA IMT (mm)
12 mo
0.121±0.054
0.137±0.052
−0.016 (−0.149 to 0.118)
0.816
0.101±0.131
0.034±0.136
0.067 (−0.239 to 0.373)
0.659
24 mo
−0.019±0.043
0.123±0.043
−0.142 (−0.252 to −0.033)
0.011
0.073±0.090
0.026±0.077
0.047 (−0.155 to 0.249)
0.641
Plaque area (mm2)
12 mo
0.281±0.810
0.644±0.678
−0.363 (−2.271 to 1.545)
0.707
3.158±3.381
−0.353±4.695
3.511 (−2.935 to 9.957)
0.267
24 mo
0.814±0.619
−0.361±0.569
1.175 (−0.334 to 2.684)
0.126
−0.840±1.739
−2.331±1.452
1.491 (−2.062 to 5.045)
0.401
Plaque gray scale median
12 mo
8.507±5.327
9.815±4.424
−1.308 (−13.856 to 11.239)
0.837
10.639±8.156
8.802±11.599
1.837 (−13.740 to 17.415)
0.807
24 mo
−1.662±2.738
3.617±2.518
−5.280 (−11.967 to 1.407)
0.121
−1.755±5.505
−2.805±4.532
1.050 (−10.193 to 12.293)
0.851
Abbreviation: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; CCA: common carotid artery; IMT: intima-media thickness; ICA: internal carotid artery.


## 3.3. Effect of Sitagliptin on the Ultrasonic Tissue Characteristics of the Carotid Wall in Subgroups

There were no significant differences in the GSM-Plaque between the two treatment groups in each subgroup at baseline and 24 months (Tables1–3).


## 3.4. Antidiabetic and Other Medications in Subgroups during the Study

There were no significant differences in the baseline frequency of noninvestigational drugs except glinide between the treatment groups in each subgroup. In each conventional group, the additional use of sulfonylureas, metformin,α-glucosidase inhibitor, and thiazolidinedione increased during the 24 mo observation period. However, with the exception of metformin, there was no increase in drug use in each sitagliptin group (Table 4).Table 4
Frequency of the use of antidiabetic and other agents.
Variable
Time point
Anemia (NO)
Anemia (YES)
Sitagliptin group
Conventional
P
Sitagliptin group
Conventional
P
Sulfonylurea
Baseline
50 (28.6%)
42 (25.0%)
0.455
5 (11.4%)
10 (20.0%)
0.254
12 mo
35 (21.3%)
55 (35.3%)
0.006
4 (10.8%)
11 (25.0%)
0.102
24 mo
32 (20.8%)
51 (34.2%)
0.009
3 (8.6%)
10 (23.3%)
0.083
Metformin
Baseline
24 (13.7%)
19 (11.3%)
0.501
8 (18.2%)
13 (26.0%)
0.364
12 mo
30 (18.3%)
50 (32.1%)
0.004
8 (21.6%)
18 (40.9%)
0.064
24 mo
34 (22.1%)
50 (33.6%)
0.026
9 (25.7%)
18 (41.9%)
0.136
α-Glucosidase inhibitor
Baseline
57 (32.6%)
46 (27.4%)
0.294
14 (31.8%)
20 (40.0%)
0.410
12 mo
42 (25.6%)
61 (39.1%)
0.010
11 (29.7%)
23 (52.3%)
0.041
24 mo
35 (22.7%)
58 (38.9%)
0.002
10 (28.6%)
23 (53.5%)
0.027
Thiazolidinedione
Baseline
35 (20.0%)
36 (21.4%)
0.744
17 (38.6%)
17 (34.0%)
0.641
12 mo
25 (15.2%)
45 (28.8%)
0.003
13 (35.1%)
19 (43.2%)
0.461
24 mo
24 (15.6%)
47 (31.5%)
0.001
11 (31.4%)
15 (34.9%)
0.747
Glinide
Baseline
5 (2.9%)
15 (8.9%)
0.016
2 (4.5%)
4 (8.0%)
0.494
12 mo
1 (0.6%)
21 (13.5%)
0.0001
3 (8.1%)
4 (9.1%)
0.875
24 mo
1 (0.6%)
17 (11.4%)
0.0001
2 (5.7%)
4 (9.3%)
0.554
Statin
Baseline
133 (76.0%)
125 (74.4%)
0.732
33 (75.0%)
36 (72.0%)
0.743
12 mo
122 (74.4%)
113 (72.4%)
0.692
26 (70.3%)
30 (68.2%)
0.839
24 mo
114 (74.0%)
106 (71.1%)
0.573
25 (71.4%)
29 (67.4%)
0.704
Fibrate
Baseline
1 (0.6%)
3 (1.8%)
0.295
1 (2.3%)
0 (0.0%)
0.284
12 mo
1 (0.6%)
3 (1.9%)
0.291
1 (2.7%)
0 (0.0%)
0.273
24 mo
1 (0.6%)
3 (2.0%)
0.298
1 (2.9%)
0 (0.0%)
0.265
Angiotensin II receptor blocker
Baseline
98 (56.0%)
84 (50.0%)
0.266
31 (70.5%)
27 (54.0%)
0.102
12 mo
90 (54.9%)
80 (51.3%)
0.519
27 (73.0%)
24 (54.5%)
0.087
24 mo
87 (56.5%)
76 (51.0%)
0.338
27 (77.1%)
23 (53.5%)
0.030
Angiotensin-converting enzyme inhibitor
Baseline
20 (11.4%)
25 (14.9%)
0.344
6 (13.6%)
11 (22.0%)
0.293
12 mo
20 (12.2%)
23 (14.7%)
0.504
3 (8.1%)
9 (20.5%)
0.119
24 mo
16 (10.4%)
21 (14.1%)
0.325
3 (8.6%)
10 (23.3%)
0.083
Number of patients in the NO anemia subgroup = baseline: 175 (Sita), 168 (Con); 12 months: 164 (Sita), 156 (Con); 24 months: 154 (Sita), 149 (Con). Number of patients in the anemia subgroup = baseline: 44 (Sita), 50 (Con); 12 months: 37 (Sita), 44 (Con); 24 months: 35 (Sita), 43 (Con). Data are expressed as number (%).


## 4. Discussion

The present study, a subgroup analysis using data obtained from the PROLOGUE study showed that sitagliptin treatment significantly inhibited the progression of mean and max ICA-IMT after 24 months observation period in the nonanemic subgroup, while the conventional treatment did not affect the ICA-IMT. But in the anemic subgroup, there was no significant difference in changes with CIMT between sitagliptin and conventional treatment groups. Although there was no significant difference in CCA-IMT between the treatment group in each subgroup, this analysis shows that sitagliptin treatment more effectively inhibited the progression of CIMT than conventional treatment in nonanemic T2DM patients. However, patients with T2DM and anemic do not seem to benefit from sitagliptin treatment.Although anemia is a common complication in diabetic patients, it is often overlooked. And the relationship between anemia and ICA-IMT in patients undergoing sitagliptin treatment has not been described. This may be an important issue. Anemia is a strong risk factor for death in people with diabetes due to CVD [32–34]. Although many previous clinical studies have shown that there is a correlation between hemoglobin levels and subclinical atherosclerotic markers in patients with CVD or hypertension, however, the studies in patients with T2DM are rare. Therefore, elucidating the effect of hemoglobin levels on the development of atherosclerosis in patients with diabetes mellitus has great clinical significance. In the PROLOGUE study population, 21.3% of participants had baseline anemia events. If patients with T2DM and anemia benefit from sitagliptin treatment, that is important from a public health standpoint, as its use could slow ICA-IMT progression in nearly one-fourth of the T2DM patients with anemia.The etiology of anemia in patients with diabetes has been previously reported and is considered to be multifactorial. In addition to diabetic nephropathy, the inflammation, nutritional deficiency, and hormone changes are all causes of anemia. Renal tubules are the main sites for the production of erythropoietin [38]. Systemic inflammation, reduced red cell survival, functional erythropoietin deficiency, and erythropoietin resistance caused by renal tubular dysfunction in patients with diabetes may lead to insufficient erythropoietin response [31, 39, 40]. In addition, absolute or relative (functional) iron deficiency is also a major cause of anemia in diabetes. In general, relative iron deficiency is more common and is closely related to the upregulation of inflammatory cytokines and impaired tissue responsiveness to erythropoietin. Previous studies have shown a link between anemia and CVD in diabetic patients. Even mild anemia can lead to serious complications in CVD, such as myocardial infarction [41, 42]. According to physiological theories, anemia affects tissue perfusion and oxygenation by a reduction in the oxygen-carrying ability of blood due to decreases in hemoglobin concentration and the change of blood apparent viscosity resulting from low hematocrit [43]. And blood viscosity can affect systemic vascular resistance, which leads to cardiovascular hemodynamics changes. Moreover, anemia has been suggested to be directly involved in tissue protection and regulation of cardiovascular homeostasis by affecting the atypical functions of erythrocytes. Erythrocytes are an important part of blood antioxidant capacity. Anemia significantly weakened the antioxidant system [44]. The activation of erythropoiesis can lead to the decrease of oxidative stress, which in turn prevents atherosclerotic progression [45]. Atherosclerosis is one of the main factors contributing to an increase of CIMT [46]. Anemia may lead to endothelial dysfunction and decrease the level of nitric oxide (NO) by reducing endothelial shear stress, which in turn accelerates atherosclerosis by increasing the oxidation of low-density lipoprotein (LDL) [47–50]. Ganidagli et al. found that the patient (LH group) with the highest hemoglobin variability had the highest CIMT (LN: 0.601 mm, LH: 0.744 mm, NH: 0.604 mm, p<0.001) [51]. Dogan and Citak found that low levels of hemoglobin were associated with increased CIMT in children with β-thalassemia major [52]. These findings support that changes in hemoglobin levels may lead to arterial remodeling. In the post hoc analysis, we also found that the baseline CIMT parameters of the anemic subgroup were higher than those of the nonanemic subgroup.Our results suggest that patients with diabetes may be more significant to see the benefits of sitagliptin treatment before the development of anemia. For patients with anemia, it may be difficult to see the benefit of sitagliptin treatment. There is biologic plausibility of the findings that patients with T2DM and nonanemia can benefit from sitagliptin treatment. Anemia is associated with increased progression of atherosclerosis, increased carotid artery intimal-medial thickness, and cardiac hypertrophy [53]. The pathophysiological process of atherosclerosis in patients with anemia may be more advanced. These patients may not be able to benefit from sitagliptin treatment. In addition, the control of blood glucose helps to improve the tissue characteristics of carotid artery plaque. Although the decrease in HbA1c levels in the anemic subgroup was greater in the sitagliptin group than that in the conventional group, we consider that most patients have achieved relatively good blood glucose control and strict management of risk factors. Therefore, the progression of CIMT may be partially affected by anemia, although the additional effect of sitagliptin on the progression of CIMT was not shown in patients with risk factors for anemia. As an adjunct treatment for statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, it seems to have a unique or additive antiatherosclerotic effects in T2DM patients without anemia. Previous studies have confirmed that statins and angiotensin-converting enzyme inhibitors can reduce the development of atherosclerosis in T2DM patients [54, 55]. The T2DM patients without anemia risk factors should choose more appropriate drugs for prevention and treatment. Furthermore, we speculate that a higher frequency of the use of angiotensin II receptor blocker and thiazolidinedione in anemia subgroup may be part of the reason for this result. Because the inhibitory effect of angiotensin II receptor blocker and thiazolidinedione on CIMT has also been confirmed [56, 57], this may mask or diminish the effectiveness of investigational drugs. In the PROLOGUE study, patients inevitably took other drugs, and it was difficult to rule out their effects. However, we reiterate that the real intention of the present study as an exploratory subgroup analysis is to explore whether sitagliptin can have an additional effect on the CIMT process. Our subgroup study did not find that sitagliptin slowed the progression of CIMT in patients with T2DM and anemia. The precise reasons are not clear. Tanaka et al. pointed out that T2DM patients with or without previous CV events were recruited in the PROLOGUE study [58], while other studies investigating the effects of DPP-4 inhibitors only recruited T2DM patients without events [24, 25].Our study has the following limitations. First, it is a post hoc subanalysis using data obtained from the PROLOGUE study. The analysis was not part of the original statistical plan. Therefore, the result needs to be treated with caution. Second, other noninvestigational drugs such as antidiabetic, antihyperlipidemic, and antihypertensive may influence the CIMT progression, although the baseline drug therapies were almost matched in this post hoc analysis. Third, the sample size may not be sufficient to detect significant differences in CIMT variables between treatment groups in the anemia subgroup. In order to confirm our findings, it is necessary to design a prespecified study with a large sample size.


## 5. Conclusions

In this post hoc study of PROLOGUE study data, the patients with T2DM and nonanemia can obtain better antiatherosclerotic effects in the sitagliptin treatment group compared with the conventional group. Since this finding may be attributed to sampling variability, therefore, it would be premature to conclude that sitagliptin treatment significantly inhibited CIMT progression. Further research is needed.



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*Source: 8143835-2020-05-11.xml*