Sitagliptin attenuates the progression of coronary atherosclerosis in patients with coronary disease and type 2 diabetes

Atherosclerosis 300 (2020) 10–18

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Sitagliptin attenuates the progression of coronary atherosclerosis in patients with coronary disease and type 2 diabetes

T

Bo Lia,1, Yan-Rong Luob,1, Feng Tianc, Yun-Dai Chenc,∗, Jin-Wen Tiana, Yu Dingc, Mei Zhuc, Jing-Wei Lic, Ying-Qian Zhangc, Wei-Ming Shid a

Department of Cardiology, Chinese Hainan Hospital of PLA General Hospital, Sanya, Hainan Province, China Department of Radiation Oncology, Chinese PLA General Hospital, Beijing, China c Department of Cardiology, Chinese PLA General Hospital, Beijing, China d Department of Cardiology, Fukang Hospital of T.C.M, Fukang, Xinjiang Province, China b

HIGHLIGHTS

a dipeptidyl peptidase 4 (DPP-4) inhibitor, have anti-atherogenic effects both in an animal model and clinical setting. • Sitagliptin, 18 months, sitagliptin attenuated the progression of coronary atherosclerosis in patients with coronary disease and type 2 diabetes independent of the effect on • Atglycaemic control evaluated with three-dimension quantitative coronary angiography (3D-QCA) analysis. • This study may have important implications for defining the optimal strategy for management of patients with type 2 diabetes and coronary atherosclerosis. ARTICLE INFO

ABSTRACT

Keywords: Sitagliptin Dipeptidyl peptidase 4 inhibitor Glucagon-like peptide 1 Atherosclerosis Diabetes

Background and aims: Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for ASCVD, the aim of this study was to investigate the effects of a dipeptidyl peptidase-4 inhibitor, sitagliptin, on prevention of progression of coronary atherosclerosis assessed by three-dimensional quantitative coronary angiography (3DQCA) in T2DM patients with coronary artery disease (CAD). Methods: This was a prospective, randomized, double-center, open-label, blinded end point, controlled 18month study in patients with CAD and T2DM. A total of 149 patients, who had at least 1 atherosclerotic plaque with 20%–80% luminal narrowing in a coronary artery, and had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to sitagliptin group (n = 74) or control group (n = 75). Atherosclerosis progression was measured by repeat 3D-QCA examination in 88 patients at study completion. The primary outcome was changes in percent atheroma volume (PAV) from baseline to study completion measured by 3D-QCA. Secondary outcomes included change in 3D-QCA-derived total atheroma volume (TAV) and late lumen loss (LLL). Results: The primary outcome of PAV increased of 1.69% (95%CL, −0.8%–4.2%) with sitagliptin and 5.12% (95%CL, 3.49%–6.74%) with the conventional treatment (p = 0.023). The secondary outcome of change in TAV in patients treated with sitagliptin increased of 6.45 mm3 (95%CL,-2.46 to 6.36 mm3) and 9.45 mm3 (95%CL,4.52 to 10.14 mm3) with conventional treatment (p = 0.023), however, no significant difference between groups was observed (p = 0.175). Patients treated with sitagliptin had similar LLL as compared with conventional antidiabetics (−0.06, 95%CL, −0.22 to 0.03 vs. −0.08, −0.23 to −0.03 mm, p = 0.689). Conclusions: In patients with type 2 diabetes and coronary artery disease, treatment with sitagliptin resulted in a significantly lower rate of progression of coronary atherosclerosis compared with conventional treatment.

1. Introduction Type

2

diabetes

mellitus

(T2DM)

increases

the

risk

for

atherosclerosis and cardiovascular disease, which is one of the major causes of morbidity and mortality in these patients [1,2]. Atherosclerosis is one of the major pathological manifestations of diabetic

Corresponding author. E-mail address: [email protected] (Y.-D. Chen). 1 These authors contributed equally to this work. ∗

https://doi.org/10.1016/j.atherosclerosis.2020.03.015 Received 27 November 2019; Received in revised form 1 March 2020; Accepted 18 March 2020 Available online 21 March 2020 0021-9150/ © 2020 Elsevier B.V. All rights reserved.

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vascular complications, which leads to narrowing of arterial walls due to the plague progression. Epidemiological studies have shown that the mortality caused by T2DM is equivalent to that resulting from coronary artery disease (CAD) [3,4]. Given the high incidence of T2DM, the management of its macrovascular complications continues to draw serious concern for healthcare systems around the world. Good glycemic control, which is the principal treatment goals of diabetes therapy, significantly reduces the risk of diabetes-related vascular complications among patients with type 2 diabetes [5,6]. However, intensive glucose control, which is one of the principal treatment goals of diabetes therapy, does not seem to be beneficial in controlling the macrovascular complications of this disease compared with standard therapy [5,7,8]. Few antidiabetic agents have the ability to reduce the progression of coronary atherosclerosis independent of glucose levels control [9]. Dipeptidyl peptidase 4 (DPP-4) inhibitor, sitagliptin, a new class of oral hypoglycemic agents, inhibits the degradation of active glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin tropic polypeptide and increases their biological effects [10,11]. Incretin hormones, such as glucagon-like peptide-1 (GLP-1), have been shown to have extra-pancreatic effects beyond glycemic control, including antiatherosclerotic properties [12,13]. Sitagliptin has also been shown to have anti-atherogenic effects both in an animal model and clinical setting [14–18]. However, two large-scale clinical trials of other DPP-4 inhibitors failed to reduce major adverse cardiovascular events but did raise safety concerns regarding a possible elevated risk of hospitalization for heart failure [19,20]. In the TECOS trial, the rates of hospitalization for heart failure did not increased in the sitagliptin group compared to placebo, but sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome [21]. So, whether sitagliptin has an anti-atherosclerosis effect among patients with T2DM in the clinical setting remains unclear. We designed this trial to determine the effect of sitagliptin compared with acarbose, which is widely used but is a distinctly different class of oral hypoglycemic agents, on the rate of progression of coronary atherosclerosis in patients with T2DM and coexisting coronary artery disease. Three-dimension quantitative coronary angiography (3D-QCA) was used as the evaluated procedure because this imaging modality is considered an accurate and reliable approach compared to the conventional QCA.

pressure > 170 mmHg or diastolic blood pressure > 100 mmHg); renal insufficiency (serum creatinine 1.5 mg/dL for men or 1.4 mg/dL for women); and active liver disease. Each of these exclusion criteria was selected to exclude patients who might not complete a full 18 months of treatment after randomization. All diabetic medications, including insulin, were permitted during the study except for GLP-1 analogue or other DPP-4 inhibitors. An independent committee blinded to treatment assignment centrally adjudicated adverse cardiovascular events. 2.2. Management of glycemia and follow-up Patients were randomized using a blocked randomization procedure (computerized random numbers) in a 1:1 ratio to either the sitagliptin (100 mg/d) group or the control group receiving conventional treatment consisting of the initial drug acarbose (50 mg, tid) other than DPP-4 inhibitors. At the time of randomization, the doses of other oral antidiabetic drugs were reduced by 50% and were discontinued during a visit 1 month later. Open-label metformin (maximal total daily dose, 2550 mg) and insulin or both was added after the first 3 months if needed to maintain a hemoglobin A1C at 7% with the use of a glycemic titration algorithm designed to provide comparable glycemic control between treatment groups. No study drugs were reduced before study drugs in the event of hypoglycemia requiring dose reductions. Unless informed consent was formally withdrawn, all patients were followed until 18 months from randomization, and the clinical status was ascertained regardless of whether they continued to take study medication. All patients in the two groups were administered atorvastatin (atorvastatin calcium; Pfizer, New York, NY, USA) 20 mg and aspirin 100 mg daily for 18 months. The addition of other DPP-4 inhibitors, GLP-1 analogues or sodiumglucose cotransporter 2 (SGLT2) inhibitors was banned both in the sitagliptin and control group. The use of antihyperlipidemic and antihypertensive drugs was allowed during the study. Non-study drugs were reduced before study drugs in the event of hypoglycemia requiring dose reductions. Unless informed consent was formally withdrawn, all patients were followed until 18 months from randomization, and clinical status was ascertained regardless of whether they continued to take the study medication. All major adverse cardiovascular and cerebrovascular events (MACCE, defined as death/myocardial infarction/ repeat revascularization) during the follow-up period were recorded and adjudicated by physicians not involved in the trial.

2. Patients and methods 2.1. Ethics statement The present study was conducted in accordance with the Declaration of Helsinki and the guidelines of the Ethics Committee of Chinese PLA (People's Liberty Army) General Hospital, Beijing, China. The experimental protocol was approved by the Ethics Committee of Chinese PLA (People's Liberty Army) General Hospital, Beijing, China. This trial was registered at https://Clinicaltrial.com as NCT02655757. The clinical study was a prospective, randomized, double-center, open-label, blinded end point, controlled 18-month trial. A total of 149 patients from two centers, who were aged 30–80 years, with established type 2 diabetes mellitus,s and who had clinically indicated coronary angiography or percutaneous coronary intervention (PCI) between February 2016 and January 2017, were recruited. Patients were included if they had at least 1 atherosclerotic plaque with at least 20% luminal narrowing in a coronary artery that had not undergone any intervention and if their diabetes mellitus was treated with either lifestyle approaches (with a hemoglobin A1C > 7% and < 10%) or oral agents comprising 1 oral agent at any dose or 2 oral agents, in which case each was prescribed at 50% of its maximal dose (with a hemoglobin A1C > 6.5% and≤8.5%). Exclusion criteria were as follows: ST-segment elevation myocardial infarction in the prior 30 days; coronary artery bypass graft surgery; severe valvular heart disease; left ventricular ejection fraction < 40%; any heart failure (New York Heart Association class I to IV); uncontrolled hypertension (systolic blood

2.3. Primary outcomes The primary outcome was change in percent atheroma volume (PAV) from baseline to study completion measured by repeat threedimension quantitative coronary angiography (3D-QCA). Secondary outcomes included change in total atheroma volume (TAV) and late lumen loss (LLL). All measurements were performed in-segment and on the 5-mm proximal and distal target lesion margins. 2.4. 3D-QCA examination and measurement Baseline and second follow-up CAG were performed in all patients after the administration of 200 g of intracoronary nitroglycerin. The coronary lesion chosen for the study was obtained with same coronary angiography angulations when the follow-up CAG was performed. Offline angiograms were reviewed separately by two independent observers blinded to all clinical data in the core laboratory (PLA general hospital, Beijing, China). 3D angiographic reconstruction and quantitative analysis were performed using 3D-QCA software package (QAngio XA 3D Research Edition 1.0; Medis Specials bv, Leiden, The Netherlands) according to standard protocols [22]. The process comprised the following major steps as shown in Fig. 1: (1) two image sequences acquired at two arbitrary angiographic views with projection 11

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Fig. 1. Examples of 3-dimensional quantitative coronary angiographic analyses of coronary artery stenosis. The 2 selected views in baseline (A and B: two image sequences acquired with projection angles at least 25° apart; C: three-dimensional reconstruction). The 2 selected views of the same target vessel segment in final follow-up coronary angiogram examinations (D and E: two image sequences acquired with projection angles at least 25° apart; F: three-dimensional reconstruction). p, proximal diameter; m, minimal lumen diameter; d, distal diameter.

target number of patients that should achieve the primary end point. Nakayama et al. [23] reported previously that change in coronary plague volume was −6.7 ± 5.9 mm3 in the pioglitazone group and 2.3 ± 6.2 mm3 in the control group. The sample size required in this study is 45 patients in each group to achieve 80% power using a 2-sided 2-sample t-test at a significance level of 5%, according to the assumption that the change in PAV in patients receiving sitagliptin are likely to be similar to those receiving pioglitazone as reported in that study. However, the rate of the patient drop out was more than 20% than previous studies [9,24], we altered the sample size to 70 patients which will be a feasible number of enrollments.

angles at least 25° apart were loaded. (2) Properly contrast-filled enddiastolic frames were selected from these sequences (3) One to three anatomical markers (e.g. bifurcations). were identified as reference points in the two views for the automated correction of angiographic system distortions. (4) The lumen of the interrogated vessel segment was automatically delineated using an extensively validated edge detection algorithm (5) The lumen and reference surface (i.e. the normal lumen if there were no obstruction present). were reconstructed in three dimensions and the relevant QCA parameters were derived. Minimal lumen diameter, percent diameter stenosis, minimal lumen area, percent area stenosis, reference volume, lumen volume, and intraluminal atheroma plaque volume were measured at baseline and follow-up CAG. The primary outcome, change (end of treatment minus baseline) in PAV, was calculated as follows: PAV= (intraluminal atheroma plaque volume/reference volume) × 100. The secondary outcomes included change in intraluminal atheroma plaque volume (TAV) in the 10-mm subsegment of the coronary artery with the largest plaque volume at baseline (the most diseased segment) and late lumen loss (LLL) defined as the difference between the baseline and the 18month follow up.

3. Results 3.1. Participants A total of 149 patients, who had at least 1 atherosclerotic plaque with 20%–80% luminal narrowing in a coronary artery, and had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to sitagliptin (n = 75) and control (n = 74) group. Evaluable baseline and follow-up coronary angiogram examinations were available in 88 patients (59.1%), 44 in the sitagliptin group and 44 in the control group. All the final 3D-QCA follow-up dropouts, which were not significantly different between two groups, were due to poor compliance (31 sitagliptin, 30 control). The final clinical follow-up at 18 months was available in 149 patients. The disposition of patients in the trial is shown in Fig. 2. Baseline clinical characteristics, including potential risk factors for coronary atherosclerosis, were compared between treatment groups in Table 1. As shown in Table 1, baseline clinical characteristics, including potential risk factors for coronary atherosclerosis, were comparable between the groups. A high percentage of patients received concomitant medications of established value in prevention of coronary atherosclerosis disease. All the patients were receiving atorvastatin for lipid-lowering and aspirin for antiplatelet therapy. Approximately 50% of patients who needed dual antiplatelet therapy were taking clopidogrel or ticagrelor, additionally. Greater than 40% of patients were receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, more than 40% were

2.5. Statistical methods Group data of normally distributed continuous variables are expressed as mean ± SD or median and interquartile range if non-normally distributed. Differences between 2 variables were tested using unpaired Student's t tests or Mann-Whitney U tests. 3D-QCA efficacy parameters were analyzed using analysis of covariance and reported as least square means and 95% CIs using a linear model that included treatment group, pooled center, and baseline values as covariates. The primary outcome, change in PAV was also analyzed by groups at the end of treatment period with an ANCOVA model, adjusting the final change for the baseline ones. All p values are 2-sided and not adjusted for multiple testing. A p value < 0.05 was considered statistically significant. All analyses were performed using SPSS version 19.0 (IBM, Armonk, NY, USA). for Windows. For the primary efficacy parameter, change in PAV, no similar studies have examined the effect of DPP-4 inhibitors on coronary atherosclerosis assessed using 3D-QCA. Therefore, it is difficult to set a 12

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Fig. 2. Disposition of participants through the trial. Table 1 Baseline demographic characteristics and medications at the time of randomization.

Age, mean (SD), y Male, n (%) Weight, mean (SD), kg BMIa, mean (SD) Duration of T2DM, median (IQRd), mo Smoking, n (%) Hypertension, n (%) Dyslipidemia, n (%) Prior myocardial infarction, n (%) Medication use, n (%) Aspirin Other antiplatelet ACEb inhibitor or ARBc Statin β-blocker Nitrates Glucose-lowering agents, n (%) Metformin Sulfonylurea Glinides Thiazolidinediones Any insulin a b c d

Sitagliptin group (n = 75)

Control group (n = 74)

p

60.55 ± 9.54 55 (73.33) 71.21 ± 11.72 25.05 ± 3.72 76 (60–120) 29 (38.67) 53 (70.67) 12 (16.00) 12 (16.0)

59.65 ± 10.30 59 (79.73) 71.95 ± 9.53 24.91 ± 3.13 119 (60–121) 35 (47.30) 61 (82.43) 15 (20.27) 19 (25.0)

0.697 0.618 0.676 0.808 0.135 0.287 0.09 0.269 0.053

75 51 49 75 42 34

74 52 43 74 47 32

> 0.99 0.764 0.364 > 0.99 0.350 0.797

(100) (68.00) (65.33) (100) (56.00) (45.33)

49 (65.91) 9 (12.0) 2 (2.6) 1 (1.3) 20 (26.67)

(100) (70.27) (58.11) (100) (63.51) (43.24)

54 (72.97) 13 (17.57) 9 (12.16) 4 (5.4) 30 (40.54)

0.313 0.467 0.057 0.355 0.073

BMI = Body mass index. ACE = Angiotensin-converting enzyme. ARB = Angiotensin receptor blocker. IQR = Interquartile range.

receiving a β-blocker. Laboratory values, body weight, and blood pressures for the 88 patients who finished the endpoint CAG examinations at both baseline and follow-up are shown in Table 2. At baseline, in the sitagliptin groups, mean HbA1c concentration was 8.2% slightly higher than the control group 7.9%, but statistically insignificant. Also, there were no significant differences in fasting plasma glucose and insulin level between the two groups. Blood cholesterol level (include HDL-C, LDL-C),

high-sensitivity C reactive protein, NT-proBNP, serum creatinine and blood pressure were comparable in both groups at baseline. Characteristics were similar in the 88 patients who completed the final 3DQCA follow-up and the 61 patients who did not (Supplementary data). Patients were followed for a mean of 18.1 months (SD, 2.6 months). Although compared with the control group (73.2 ± 8.6), patients in the sitagliptin group had greater mean weight loss (68.7 ± 10.3, p = 0.03) at final follow-up; there were no significant median weight 13

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Table 2 Baseline and final visit vital signs and laboratory values in participants completing the trial.

Baseline HbA1ca, mean (SD), % FBGb, mean (SD), mmol/L TCc, mean (SD), mmol/L LDLd-C, M(IQR), mmol/L HDLe-C, mean (SD), mmol/L hs-CRPf, M(IQR), mmol/ml NT-proBNPg, M(IQR), pg/ml Scrh, M(IQR), μmol/L Blood pressure, mean (SD), mmHg Systolic Diastolic Weight, mean (SD), kg eGFRi M(IQR), ml/min1.73 m2 Final visit HbA1c, M (IQR), % FBG, M (IQR), mmol/L TC, mean (SD), mmol/L LDL-C, mean (SD), mmol/L HDL-C, mean (SD), mmol/L hs-CRP, M (IQR), mg/ml NT-proBNP, M (IQR), pg/ml Scr, M (IQR), μmol/L Blood pressure, mean (SD), mmHg Systolic Diastolic Weight, mean (SD), kg eGFR, M(IQR), ml/min1.73 m2 Change from baseline HbA1c, M (95% CL), % FBG, M (95% CL), mmol/L Total cholesterol, M (95% CL), mmol/L LDL-C, M (95% CL), mmol/L HDL-C, M (95% CL), mmol/L hs-CRP, M (95% CL), (mg/ml) NT-proBNP, M (95% CL), (pg/ml) Scr, M (95% CL), μmol/L Blood pressure, M(95% CL), mmHg Systolic Diastolic Weight, M (IQR), kg eGFR, M (IQR), ml/min1.73 m2 a b c d e f g h i

Sitagliptin group (n = 44)

Control group (n = 44)

p

8.15 ± 1.50 8.52 ± 1.22 4.33 ± 0.95 3.01 (2.23,3.71) 0.98 ± 0.22 0.77 (0.32,1.17) 145.0 (79.63,337.25) 71.3 (63.45,79.78)

7.89 ± 0.91 8.36 ± 1.09 4.38 ± 0.68 2.86 (2.23,3.43) 0.94 ± 0.24 1.00 (0.76,1.35) 139.5 (68.33,283.7) 70.4 (60.63,82.26)

0.325 0.516 0.291 0.285 0.356 0.059 0.305 0.964

135 ± 20 76 ± 13 69.4 ± 10.6 91.8 (79.94,101.71)

132 ± 19 74 ± 11 73 ± 9.8 93.69 (81.81,102.58)

0.477 0.491 0.086 0.509

6.95 (6.53,7.15) 6.78 (6.37,7.25) 3.55 ± 0.59 2.46 ± 0.49 1.05 ± 0.30 0.34 (0.15,0.94) 146.45 (74.86,268.51) 71.75 (65.9,82.38)

6.92 (6.61,7.10) 6.82 (6.28,7.20) 3.82 ± 0.81 2.47 ± 0.61 1.02 ± 0.23 0.53 (0.25,0.99) 129.72 (62.91,188.42) 75.34 (67.53,88.36)

0.920 0.950 0.084 0.915 0.593 0.270 0.263 0.314

130 ± 12 75 ± 8 69.4 ± 11.5 90.14 (67.89,99.88)

129 ± 13 73 ± 9 73.3 ± 9.8 90.81 (68.33,99.67)

0.708 0.464 0.086 0.918

−1.18 (-1.89 to −0.90) −1.57 (-2.05 to −1.23) −0.58 (-1.07 to −0.49) −0.39 (-0.93 to −0.38) 0.05 (-0.04 to 0.17) −0.23 (-0.61 to −0.22) −11.2 (-248.5 to .16.5) −0.15 (-3.47 to 6.46)

−0.9 (-1.31 to −0.78) −1.6 (-1.94 to −0.93) −0.48 (-0.78 to −0.36) −0.36 (-0.63 to −0.2) 0.07 (0–0.16) −0.16 (-0.64 to −0.26) −7.73 (-250 to 137.17) 1.79 (-7.32 to 40.77)

0.585 0.867 0.496 0.225 0.742 0.993 0.289 0.278

0 (-9.3 to −0.34) −1 (-4.31 to 2.31) 0 (-1.64 to 0.19) −0.64 (-9.43,2.56)

−2.5 (-7.1 to 1.34) 0 (-4.15 to 2.97) 0 (-0.9 to 0.56) −3.09 (-9.57,1.20)

0.802 0.828 0.370 0.372

HbA1c = Hemoglobin A1C. FBG=Fasting blood glucose. TC = Total cholesterol. LDL = Low-density lipoprotein. HDL=High-density lipoprotein. hs-CRP = High-sensitivity C-reactive protein. NT-proBNP = N terminal pro B type natriuretic peptide. Scr = Serum creatinine. eGFR = Estimating glomerular filtration rate, calculated with MDRDⅡ [25].

Table 3 Clinical endpoints in all randomized patients.

Composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for myocardial ischemia All-cause death Cardiovascular death Non-fatal MIa Non-fatal stroke Hospitalization for unstable angina Hospitalization for congestive heart failure Coronary revascularization

Values are number of patients with an event (%). a MI = Myocardial infarction. 14

Sitagliptin group (n = 75)

Control group (n = 74)

p

7 (15.91)

8 (18.18)

0.792

0 0 1 0 6 0 6

0 0 0 0 8 0 8

> 0.99 > 0.99 > 0.99 > 0.99 0.780 > 0.99 0.780

(0.0) (0.0) (2.27) (0.0) (13.63) (0.0) (13.63)

(0.0) (0.0) (0.0) (0.0) (18.18) (0.0) (18.18)

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Table 4 Baseline, follow-up, and change from baseline in 3D-QCA end points.

Baseline RVDa, mean (SD), (mm) MLDb, mean (SD), (mm) PAVc, mean (SD), (%) TAVd, M (IQR), (mm3) Final visit RVD, mean (SD), (mm) MLD, mean (SD), (mm) PAV, mean (SD), (%) TAV, mean (SD), (mm3) Change from baseline PAV, mean (95% CL), (%) TAV, M (95% CL), (mm3) LLLe, M (95% CL), (mm) a b c d e

Sitagliptin group (n = 44)

Control group (n = 44)

p

2.46 ± 0.58 1.49 ± 0.34 50.81 ± 11.81 74.75 (47.90,95.30)

2.52 ± 0.31 1.43 ± 0.29 51.58 ± 10.93 79.45 (50.33,97.85)

0.553 0.402 0.754 0.590

2.44 ± 0.53 1.37 ± 0.33 52.5 ± 11.92 75.41 ± 22.55

2.50 ± 0.35 1.30 ± 0.23 56.69 ± 8.42 83.26 ± 25.96

0.516 0.256 0.060 0.134

1.69 (-0.8 to 4.2) 6.45 (-2.46 to 6.36) −0.06 (-0.22 to 0.03)

5.12 (3.49–6.74) 9.45 (4.52–10.14) −0.08 (-0.23,-0.03)

0.023 0.175 0.689

RVD = Reference vessel diameter. MLD = Minimal lumen diameter. PAV=Percent atheroma volume. TAV = Total atheroma volume. LLL = Late lumen loss.

changes from baseline between the two groups (p = 0.37). Both types of treatment significantly reduced HbA1c levels to below 7%, and the difference was no significant in patients in sitagliptin group (median, 6.95%) compared to the control group (median, 6.92; p = 0.92). The reduction from baseline in HbA1c levels was 1.18% (median) in the sitagliptin group and 0.9% (median) in the control group (p = 0.59).

Similarly, there were no significant differences in the value and changes in HDL-C, LDL-C, high-sensitivity C reactive protein, NT-proBNP, serum creatinine and blood pressure at final follow-up visit and from baseline (Table 2). Incidence of MACE included cardiovascular and non-cardiovascular death, non-fatal myocardial infarction and stroke, hospitalization for

Fig. 3. Effect of sitagliptin on the primary outcome of change in PAV according to predefined subgroups. p values reflect the test for an interaction between the subgroups. a Median values are shown in parentheses. b BMI= Body mass index, calculated as weight in kilograms divided by height in meters squared; c SBP= Systolic blood pressure; d HbA1c = Hemoglobin A1c; e HDL-C=High-density lipoprotein cholesterol; f LDLC = Low-density lipoprotein cholesterol; g TG = Triglyceride; h hs-CRP=High sensitive C-reactive protein. 15

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unstable angina or congestive heart failure, and coronary revascularization at final clinical follow-up, showed no significantly change (p = 0.79) in patients allocated to the sitagliptin group (1 non-fatal myocardial infarction, and 6 hospitalizations for unstable angina) compared with the control group (8 hospitalizations for unstable angina in the control group) Table 3.

the coronary artery plaque volumes reliably [36,37]. When absolute lumen dimensions are measured, QCA requires calibration, which can increase measurement variability and introduce the so-called out-ofplane magnification error [38]. When the vessel of interest is not aligned in the same plane as the calibration object, lumen size can be overestimated or underestimated depending on the assessed position. Another important limitation in the assumption of circular cross-sections might lead to inaccurate assessments of lumen dimensions for non-circular lesions. To address the limitations in conventional QCA, 3D-QCA has recently been developed to overcome the limitations of conventional QCA, and allows the fusion of 2 or more angiographic views to enable 3D reconstruction of the coronary artery without the need of additional invasive imaging. By restoring vascular structures in natural shape, 3D QCA was able to resolve some of these limitations, e.g., the vessel foreshortening and out-of-plane magnification errors, and reveal more details in the arterial cross-sections [39]. Several studies utilizing in vivo phantoms and stents to assess the accuracy of 3DQCA techniques have shown good correspondence of measurement [40–43]. In addition, 3D-QCA was used to evaluate the atherosclerotic progression in our previous study, which showed validity in coronary plague assessment [22]. In this study, the addition of sitagliptin to conventional glycemic control had a definite glucose-lowering effect amounting to about 1.18% HbA1c decrease over 18 months from baseline, which was similar to conventional treatment (0.9%) under our effort to achieve an optimal glycemic target by adjusting the oral hypoglycemic agents’ dosage. Thus, the differences in coronary PAV progression could not be explained by the difference in HbA1c, suggesting that these changes in the coronary artery could be independent of the glucose lowering effects. Although the exact mechanism by which DPP-4 inhibitors attenuate the progression of coronary artery atherosclerosis remains uncertain at present, there are several potential explanations. Antihypertensive effects by enhancing GLP-1 signaling with sitagliptin or GLP-1 receptor agonists may reduce risk of atherosclerosis in a mouse study [44]. Clinical studies showed that blood pressure in patients with T2DM, who use GLP-1 receptor agonists, was reduced significantly [45,46]. In addition, both animal and clinical studies have found that GLP-1 analogues and DPP-4 inhibitors can improve blood lipid metabolism, reduce serum cholesterol and triglyceride levels, and then slow down the progression of atherosclerosis [47–49]. However, in this study, all patients who completed secondary coronary angiogram follow-up received optimal treatment for blood pressure and nearly 100% of patients received atorvastatin for lipid-lowering therapy. Average LDL-C levels and blood pressure during treatment were below the current guideline targets. So, the potential beneficial effects on blood pressure and lipid level of sitagliptin cannot explain the differences in change in coronary PAV between the two treatment groups in this study. Previous animal studies demonstrated that treatment with DPP-4 inhibitors decreased the levels of various markers of inflammation and macrophage infiltration in atherosclerotic plaques [16,50,51]. A clinical study also showed GLP-1 analogues exenatide was associated with improved hs-CRP in patients with type 2 diabetes versus glimepiride [52]. However, in this study, addition of sitagliptin to conventional glycemic control did not improve serum hs-CRP, a marker of inflammation, compared to the control group. Some other mechanisms could potentially contribute to reduced atherosclerosis. The prespecified subgroup analyses suggesting an effect of sitagliptin on 3D-QCA derived PAV in participants with an age below 60 years raise the possibility of some anti-atherosclerotic effects in this subgroup but should be viewed as hypothesis generating because of the many subgroups tested. Although DPP-4 inhibitors sitagliptin attenuates the progression of coronary artery atherosclerosis as measured by the primary 3D-QCA analysis end point of PAV compared with the control group, sitagliptin failed to reduce the secondary outcome of TAV and LLL in this 18 month trial. The absence of a significant effect of

3.2. Coronary angiograms results Table 4 summarizes the results for the primary and secondary 3DQCA efficacy parameters. During the course of the study, the primary outcome, change in PAV, increased of 1.69% (95% CI, −0.8%–4.2%) in the sitagliptin group and 5.12% (95% CI, 3.49%–6.74%, between groups, p = 0.02) in the control group. A secondary end outcome, change in plague volume, increased of 6.45 mm3 (95%CI, −2.46 to 6.36 mm3) in the sitagliptin group and 9.45 mm3 (95%CI, 4.52–10.14 mm3, between groups, p = 0.175) in the control group. Another secondary endpoint of LLL showed a reduction for the sitagliptin group compared with the control group: −0.06 mm (95%CI, −0.22 to 0.03 mm) vs. −0.08 mm (95% CI, −0.23 to −0.03 mm) that did not reach statistical significance (p = 0.69). When analyzed according to prespecified subgroups (Fig. 3), an interaction between treatment allocation and age was noted (p = 0.01) such that sitagliptin attenuated the PAV more than acarbose in the control group patients under the age of 60 years (i.e., 7.54% decrease versus 0.08% in patients younger than 60 years). Analysis of the primary end point adjusting for baseline differences in age did not significantly alter the results (F = 5.54, between groups, p = 0.021), and change in PAV, increased of 1.7% (95% CI,-0.30%–3.7%) in the sitagliptin group and 5.1% (95% CI, 3.1%–7.1%) in the control group. 4. Discussion This is the first clinical study to demonstrate that sitagliptin significantly attenuates the progression of coronary artery atherosclerosis compared with conventional treatment in patients with type 2 diabetes mellitus and coronary artery disease evaluated by three-dimensional quantitative coronary angiography. Atherosclerosis in patients with diabetes is particularly aggressive, characterized by higher cardiovascular event rates and a greater severity of coronary obstructive disease [26]. The optimal treatment strategy for patients with coronary artery disease and type 2 diabetes mellitus was not only simply lowering blood glucose level but preventing the major vascular events [27,28]. Since the introduction of DPP-4 inhibitors, many in vivo studies have demonstrated these classes of oral hypoglycemic agents had effects on the prevention of atherosclerosis progression independent of glucosereducing effects [15,29,30]. Moreover, several clinical studies assessed the effects of DPP-4 inhibitors on carotid intima-media thickness (IMT) in T2DM and found that sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment [17,18]. In this study, we further demonstrated DPP-4 inhibitors sitagliptin could stabilize coronary atherosclerosis plaque assessed by 3D-QCA analysis in patients with diabetes. In the current study, all patients received evidence-based secondary prevention therapies for coronary artery disease including lipid-lowering therapy by satin. Average LDL-C levels and blood pressures during treatment were below the current guideline targets. HbA1c levels were consistent with good diabetes management (≤7.0%). Thus, sitagliptin showed the ability to further reduce disease progression on a background of contemporary medical therapy. Over the past years, quantitative coronary analysis (QCA) has been chosen for angiographic assessment of coronary lumen narrowing as a means to detect atherosclerotic progression [31–35]. However, QC, which shows only the outline of lumen, may underestimate lesion severity when QCA is used to assess disease progression and cannot assess 16

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sitagliptin on TAV of target lesions in this study may be due to the relatively short observation time and small sample size. Three largerscale prospective randomized clinical studies [19–21] showed that the use of DPP-4 inhibitors did not increase nor decrease the CVD event rate among patients with T2DM compared with placebo. Similarly, there were no observed differences in major cardiovascular morbidity or mortality in the current trial, although the trial was not powered to assess clinical outcomes. Therefore, a larger-scale prospective clinical trial with a longer observation period is required to assess the major cardiovascular events of DPP-4 inhibitors. Recently, a new class of hypoglycemic agents, sodium-glucose cotransporter-2 inhibitors (SGLT2i), has been developed and demonstrated that have moderate benefits on atherosclerotic major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death) that seem confined to patients with established atherosclerotic cardiovascular disease [53]. The mechanism explaining the cardiac benefits with SGLT-2 inhibitors also seems independent of the glucose lowering effects [54], which are thought to have parallels with DPP-4 inhibitors. We recognize that the current study has limitations. The high withdrawal rate (40.9%) of follow-up coronary angiogram examinations in this trial, which was similar to previous studies [9,24] may be attributed to the difficulty of maintaining patient compliance on second coronary invasive examination. In this study, even though there were no significant differences between the area under the ROC curve (AUC) of 3D-QCA MLA,MLD, and IVUS MLA [55], 3D-QCA measurement for assessing plaque burden and composition may be less accurate than IVUS mainly because of practical constraints, including trial costs. In recent years, IVUS or optical coherence tomography (OCT) has been widely used as an intravascular imaging technology to determine the morphology of the plaque, which is more important than luminal stenosis [56]. However, despite these limitations, this analysis is unique in focusing on the progression of coronary artery atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease with angiographically documented CAD. In conclusion, sitagliptin significantly attenuates the progression of coronary artery atherosclerosis compared with conventional treatment in patients with type 2 diabetes mellitus and coronary artery disease. Although our finding may have important implications for defining the optimal strategy for management of patients with type 2 diabetes and coronary atherosclerosis, a large-scale prospective trial is required to establish the usefulness of DPP-4 inhibitors in the primary prevention of CAD in patients with T2DM.

Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. Acknowledgments The authors thank all the clinical staff and members who participated in this trial (Ming-Zhi Shen, Jue-Lin Deng, Feng-Qi Wang, Department of Cardiovascular Medicine, Chinese Hainan hospital of PLA General Hospital; and Yu-Tao Guo, Jing Jin, Department of Cardiovascular Medicine, Chinese PLA General Hospital) for their assistance with the execution and completion of the clinical trial. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.atherosclerosis.2020.03.015. References [1] S.M. Haffner, S. Lehto, T. Ronnemaa, et al., Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, N. Engl. J. Med. 339 (1998) 229–234. [2] R. Huxley, F. Barzi, M. Woodward, Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies, BMJ 332 (2006) 73–78. [3] L. Whiteley, S. Padmanabhan, D. Hole, et al., Should diabetes be considered a coronary heart disease risk equivalent?: results from 25 years of follow-up in the Renfrew and Paisley survey, Diabetes Care 28 (2005) 1588–1593. [4] Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III), Jama 285 (2001) 2486–2497. [5] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group, Lancet 352 (1998) 837–853. [6] R.R. Holman, S.K. Paul, M.A. Bethel, et al., 10-year follow-up of intensive glucose control in type 2 diabetes, N. Engl. J. Med. 359 (2008) 1577–1589. [7] Action to Control Cardiovascular Risk in Diabetes Study, G, H.C. Gerstein, M.E. Miller, et al., Effects of intensive glucose lowering in type 2 diabetes, N. Engl. J. Med. 358 (2008) 2545–2559. [8] F. Giorgino, P.D. Home, J. Tuomilehto, Glucose control and vascular outcomes in type 2 diabetes: is the picture clear? Diabetes Care 39 (Suppl 2) (2016) S187–S195. [9] S.E. Nissen, S.J. Nicholls, K. Wolski, et al., Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial, J. Am. Med. Assoc. 299 (2008) 1561–1573. [10] L.J. Scott, Sitagliptin: a review in type 2 diabetes, Drugs 77 (2017) 209–224. [11] G. Waldrop, J. Zhong, M. Peters, et al., Incretin-based therapy for diabetes: what a cardiologist needs to know, J. Am. Coll. Cardiol. 67 (2016) 1488–1496. [12] J. Sivertsen, J. Rosenmeier, J.J. Holst, et al., The effect of glucagon-like peptide 1 on cardiovascular risk, Nat. Rev. Cardiol. 9 (2012) 209–222. [13] S.G. Chrysant, G.S. Chrysant, Clinical implications of cardiovascular preventing pleiotropic effects of dipeptidyl peptidase-4 inhibitors, Am. J. Cardiol. 109 (2012) 1681–1685. [14] N.N. Ta, C.A. Schuyler, Y. Li, et al., DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice, J. Cardiovasc. Pharmacol. 58 (2011) 157–166. [15] Z. Shah, T. Kampfrath, J.A. Deiuliis, et al., Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis, Circulation 124 (2011) 2338–2349. [16] J. Matsubara, S. Sugiyama, K. Sugamura, et al., A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice, J. Am. Coll. Cardiol. 59 (2012) 265–276. [17] S. Ishikawa, M. Shimano, M. Watarai, et al., Impact of sitagliptin on carotid intimamedia thickness in patients with coronary artery disease and impaired glucose tolerance or mild diabetes mellitus, Am. J. Cardiol. 114 (2014) 384–388. [18] T. Mita, N. Katakami, T. Shiraiwa, et al., Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the sitagliptin preventive study of intima-media thickness evaluation (SPIKE): a randomized controlled trial, Diabetes Care 39 (2016) 455–464. [19] B.M. Scirica, D.L. Bhatt, E. Braunwald, et al., Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N. Engl. J. Med. 369 (2013) 1317–1326. [20] W.B. White, C.P. Cannon, S.R. Heller, et al., Alogliptin after acute coronary syndrome in patients with type 2 diabetes, N. Engl. J. Med. 369 (2013) 1327–1335. [21] J.B. Green, M.A. Bethel, P.W. Armstrong, et al., Effect of sitagliptin on

Financial support This study was supported by clinical support fund grant number 2017FC-TSYS-3039 from the Chinese PLA General Hospital. In addition, this work was supported by the Chinese Cardiovascular AssociationV.G. fund (2017-CCA-VG-027). The drug sitagliptin was provided freely by Merck Sharp & Dohme Italia SPA. CRediT authorship contribution statement Bo Li: Conceptualization, Methodology, Supervision, Funding acquisition, Project administration, Writing - original draft, Writing - review & editing, Visualization. Yan-Rong Luo: Writing - original draft, Writing - review & editing, Visualization. Feng Tian: Software, Validation, Formal analysis. Yun-Dai Chen: Conceptualization, Methodology, Supervision, Funding acquisition, Project administration, Writing - original draft, Writing - review & editing, Visualization. JinWen Tian: Software, Validation, Formal analysis. Yu Ding: Software, Validation, Formal analysis. Mei Zhu: Investigation, Resources, Data curation. Jing-Wei Li: Investigation, Resources, Data curation. YingQian Zhang: Investigation, Resources, Data curation. Wei-Ming Shi: Investigation, Resources, Data curation. 17

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