DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study

  • Kazufumi Nakamura1Email author,

    Affiliated with

    • Hiroki Oe1,

      Affiliated with

      • Hajime Kihara2,

        Affiliated with

        • Kenei Shimada3,

          Affiliated with

          • Shota Fukuda4,

            Affiliated with

            • Kyoko Watanabe5,

              Affiliated with

              • Tsutomu Takagi6,

                Affiliated with

                • Kei Yunoki1,

                  Affiliated with

                  • Toru Miyoshi1,

                    Affiliated with

                    • Kumiko Hirata7,

                      Affiliated with

                      • Junichi Yoshikawa8 and

                        Affiliated with

                        • Hiroshi Ito1Email author

                          Affiliated with

                          Cardiovascular Diabetology201413:110

                          DOI: 10.1186/s12933-014-0110-2

                          Received: 13 December 2013

                          Accepted: 29 June 2014

                          Published: 30 July 2014

                          Abstract

                          Background

                          Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes.

                          Methods

                          We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events.

                          Results

                          ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1).

                          Conclusions

                          Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events.

                          Trial registration

                          registered at http://​www.​umin.​ac.​jp/​ctrj/​ under UMIN000003951

                          Keywords

                          Dipeptidyl peptidase 4 (DPP-4) inhibitors Alpha glucosidase inhibitor Endothelial function Flow-mediated dilatation CD34

                          Introduction

                          Postprandial hyperglycemia (PPH) plays a major role in cardiovascular complications in patients with type 2 diabetes [1] and impaired glucose tolerance (IGT) [2]. PPH is one of the main factors leading to endothelial dysfunction, which is an early event in the pathogenesis of atherosclerosis [3],[4].

                          Alpha glucosidase inhibitor (GI) prevents the digestion of carbohydrates including starch and table sugar, attenuates postprandial hyperglycemia [5] and delays the development of type 2 diabetes in patients with IGT [6]. Miglitol, an alpha GI, improves endothelial dysfunction assessed by the response of forearm blood flow to reactive hyperemia and flow-mediated dilatation (FMD) in patients with type 2 diabetes and coronary artery disease [7],[8]. Acarbose, an alpha GI, improves postprandial endothelial dysfunction in patients with type 2 diabetes [9],[10] and reduces the risk of cardiovascular events in patients with type 2 diabetes [11] and IGT [12],[13].

                          Dipeptidyl peptidase 4 (DPP-4) inhibitor enhances endogenous incretin action and promotes glucose-dependent insulin secretion. Thus, DPP-4 inhibitor attenuates postprandial hyperglycemia [14]. Furthermore, glucagon-like peptide-1 (GLP-1), an incretin, induces an endothelial-dependent relaxation via NO-dependent action [15] and improves endothelial dysfunction in patients with type 2 diabetes [16], and sitagliptin, a DPP-4 inhibitor, protects endothelial function in spontaneously hypertensive rats through a GLP-1-dependent mechanism [17]. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated and has been controversial [18],[19].

                          We conducted a randomized prospective multicenter study to compare the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function assessed by FMD in patients with type 2 diabetes.

                          Liao et al. reported that number of circulating endothelial progenitor cells (EPCs) in patients with type 2 diabetes was significantly lower than that in the healthy subjects, treatment with metformin significantly increased EPCs and the EPCs number was related to endothelial function assessed by FMD [20]. Fadini et al. reported that sitagliptin increased circulating EPCs in type 2 diabetic patients [21]. We also compared the effects of sitagliptin and voglibose on number of circulating EPCs assessed by measurement of CD34, a maker of EPCs [22], postive cells in patients with type 2 diabetes in this study.

                          DPP-4 inhibitors have anti-inflammatory and anti-oxidative effects [23]-[25]. Ishibashi et al. reported that linagliptin inhibited the generation of reactive oxygen species induced by advanced glycation end products (AGEs) in endothelial cells [23]. Matsubara et al. reported that sitagliptin improves endothelial dysfunction in association with ant-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes [24]. Shiraki et al. reported that GLP-1 reduced TNF-α-induced oxidative stress in endothelial cells [25]. We also measured levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP) and pentraxin-3 (PTX-3), and oxidative stress markers, including malondialdehyde-modified low-density lipoprotein (MDA-LDL) and urine 8-hydroxy-2’-deoxyguanosine (8-OHdG).

                          The primary endpoint in this study was a sitagliptin- or voglibose-induced change in FMD (ΔFMD) from baseline to the end of follow-up. Secondary efficacy measures included changes in HbA1c, gastric inhibitory peptide (GIP), GLP-1, C-peptide, CD34, lipid profile, adiponectin, oxidative stress markers including MDA-LDL and urine 8-OHdG, inflammatory markers including hs-CRP and PTX-3, and estimated glomerular filtration rate (eGFR) and any adverse events.

                          Methods

                          Study populations

                          We conducted a randomized prospective multicenter study in patients with type 2 diabetes who did not achieve the treatment goal with diet, exercise, sulfonylurea, metformin or pioglitazone treatment. We recruited 66 patients (men and women) who were from 20 to 85 years of age. Thirty-one patients received the sitagliptin (50 mg/day) treatment and 35 patients, the voglibose (0.6 mg/day) treatment. The doses of the two drugs used in this study are recommended therapeutic doses for Japanese [26],[27] and the doses are covered by the Japanese National Health Insurance. The exclusion criteria were as follows: treatment with insulin, alpha GI or glinide, type 1 diabetes, HbA1c ≥ 9.0%, systolic blood pressure ≥ 160 mmHg and serum creatinine ≥ 1.5 mg/dL at baseline. The study protocol was approved by the Ethics Committee of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and written informed consent was obtained from all patients before any study procedure was undertaken.

                          Study protocol

                          The patients were followed for at least 8 weeks to confirm that they did not achieve the treatment goal with diet, exercise, sulfonylurea, metformin or pioglitazone treatment. The patients were prospectively randomly assigned to additional treatment with either sitagliptin (50 mg/day) or voglibose (0.6 mg/day) for 12 weeks (Figure 1). The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of the treatment. Blood and urine tests were also performed at baseline and at the end of the study. The patients’ antihypertensive, antihyperlipidemic and antidiabetic drugs were not changed and anti-oxidant drugs, including vitamin C and E, were not added throughout the study period.
                          http://static-content.springer.com/image/art%3A10.1186%2Fs12933-014-0110-2/MediaObjects/12933_2014_Article_110_Fig1_HTML.jpg
                          Figure 1

                          Study protocol. The patients were followed for at least 8 weeks to confirm that they did not achieve the treatment goal. The patients were prospectively, randomly assigned to additional treatment with either sitagliptin (50 mg/day) or voglibose (0.6 mg/day) for 12 weeks. Measurements of flow-mediated dilatation (FMD) of the brachial artery and blood and urine tests were performed in the fasting state at baseline and after 12 weeks of treatment.

                          Measurements of biochemical parameters

                          The following parameters were measured at baseline and after 12 weeks of treatment: complete blood count, liver function test including measurement of AST, ALT and LDH, renal function test including measurement of BUN, creatinine, Na, K and Cl, HbA1c, gastric inhibitory peptide (GIP), GLP-1, C-peptide, CD34, lipid profile including total cholesterol, triglyceride, and high-density lipoprotein (HDL-C), adiponectin, oxidative stress markers including MDA-LDL and urine 8-OHdG, inflammatory markers including hs-CRP and PTX-3, and estimated glomerular filtration rate (eGFR). HbA1c levels were measured using high-performance liquid chromatography. The number of CD34+ cells was determined by flow cytometry using FITC-labeled CD45 and phycoerythrin (PE)-labeled CD34 antibodies (BD Biosciences). eGFR (mL/min/1.73 m2) was determined by the modified Modification of Diet and Renal Disease study formula (MDRD) for Japanese: eGFR = 194 × (age-0.287) × (serum creatinine-1.094) × (0.739 if female) [28]. These measurements were performed by SRL Company, Ltd. (Tokyo, Japan).

                          Flow-mediated dilation (FMD)

                          Endothelium-dependent dilation was assessed as a parameter of vasodilation according to the guidelines for ultrasound assessment of FMD of the brachial artery in the fasting state [29]. Using a 10-MHz linear-array transducer probe (Unex Company Ltd., Nagoya, Japan), longitudinal images of the brachial artery at baseline were recorded with a stereotactic arm, and measurements of the artery diameter were made after supine rest for ≥5 min as previously described [30]-[32]. The diameter of the artery was measured from clear anterior (media-adventitia) and posterior (intima-media) interfaces, which were manually determined. Then, suprasystolic compression (50 mmHg higher than systolic blood pressure) was performed at the right forearm for 5 min, and measurements of the artery diameter were made continuously from 30 sec before to ≥2 min after cuff release. Maximum vasodilation was then evaluated from the change in artery diameter after the release of occlusion (%FMD). FMD is known to be affected by a wide range of biological, environmental, and methodological factors [33]. To quantify inter- and intra-observer reproducibility, baseline brachial diameter and FMD were measured by three individuals in Okayama University Hospital. Inter- and intra-observer coefficients were high (r > 0.90).

                          Statistical analysis

                          The results are expressed as mean ± SD. We assumed that FMD increased by 2% in sitagliptin group and decreased by 0.5% in voglibose group with a standard deviation of 3%. A minimum sample size of 24 participants in each group was required to detect statistical differences in FMD with a power of 80% and α error of 5%. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index (BMI). Differences in age, sex, BMI and abdominal girth were compared using Student’s t-test. The duration of diabetes was compared using the Wilcoxon rank sum test and categorical variables, using Fisher’s exact test. Differences in secondary efficacy measures between baseline and 12 weeks were compared using the paired Student’s t-test. Values of P < 0.05 were considered to be statistically significant.

                          Results

                          Baseline characteristics

                          Although 66 patients with type 2 diabetes were enrolled in this study between September 2010 and December 2011, 6 patients were excluded from this study (4 protocol violation at baseline and 2 withdrawal of consent). During the follow-up period, 5 patients with hypertension dropped out of the study due to change of concomitant antihypertensive drugs. The follow-up study was completed in 55 (83%) of the patients; 24 patients received the sitagliptin treatment and 31 patients, the voglibose treatment. The data collection was completed in July 2012. Baseline characteristics, including age, sex, BMI and the type of anti-diabetic medication are shown in Table 1. It has been reported that endothelium-dependent vasodilation assessed by FMD declines with advance of age [34],[35]. We recruited men and women who were from 20 to 85 years of age. The age range was quite wide in our study, but there was no significant difference in age or baseline FMD between the two groups (age, sitagliptin: 66.6 ± 11.9, >70 years: 12, median 69.5, range: 37 – 84 versus voglibose: 68.4 ± 9.2, >70 years: 14, median 70.0, range: 48 – 80 years old, P = 0.529, Table 1) (baseline FMD, sitagliptin: 5.41 ± 2.25 versus voglibose: 4.96 ± 2.16%, P = 0.450, Table 2). We did not exclude patients with severe dyslipidemia, but there were no significant differences in use of antihyperlipidemic drugs (Table 1) and baseline total cholesterol, triglyceride and HDL-C (Table 3) between the two groups. No patients died, developed cardiovascular events or were admitted to the hospital during the course of the study.
                          Table 1

                          Baseline clinical characteristics

                          Variables

                          Sitagliptin, n = 24

                          Voglibose, n = 31

                          P value

                          Age, y

                          66.6 ± 11.9

                          68.4 ± 9.2

                          0.529

                          Male

                          10 (41.7%)

                          18 (58.1%)

                          1.000

                          Diabetes duration, m

                          57.6 ± 41.2

                          41.9 ± 44.1

                          0.075

                          BMI, kg/m2

                          27.8 ± 3.5

                          25.7 ± 4.3

                          0.061

                          Abdominal girth, cm

                          91.4 ± 11.1

                          85.6 ± 17.4

                          0.303

                          Current smoking

                          5 (20.8%)

                          5 (16.1%)

                          0.475

                          Regular alcohol drinkers

                          4 (16.7%)

                          9 (29.0%)

                          0.349

                          Diabetic complication

                          1 (4.2%)

                          2 (6.5%)

                          1.000

                            Diabetic retinopathy

                          1 (4.2%)

                          0 (0%)

                          0.436

                            Diabetic nephropathy

                          0 (0%)

                          2 (6.5%)

                          0.499

                            Diabetic neuropathy

                          0 (0%)

                          0 (0%)

                          -

                          Hypertension

                          20 (83.3%)

                          25 (80.6%)

                          1.000

                          Hyperlipidemia

                          15 (62.5%)

                          18 (58.1%)

                          0.787

                          Hyperuricemia

                          4 (16.7%)

                          2 (6.5%)

                          0.387

                          Renal disturbance

                          3 (12.5%)

                          2 (3.2%)

                          0.307

                          Established Cardiovascular diseases

                          7 (29.2)

                          7 (22.6)

                          0.756

                            Cerebrovascular disease

                          4 (16.7%)

                          1 (3.2%)

                          0.156

                            Myocardial infarction

                          3 (12.5%)

                          5 (16.1%)

                          1.000

                            Peripheral artery disease

                          2 (8.3%)

                          1 (3.2%)

                          0.575

                          Antidiabetic drugs

                             

                            Pioglitazone

                          11 (45.8)

                          16 (51.6%)

                          0.787

                            Sulfonylurea

                          5 (20.8%)

                          3(9.7%)

                          0.276

                            Metformin

                          3 (12.5%)

                          0 (0%)

                          0.077

                          Antihypertensive drugs

                             

                            ARB

                          15 (62.5%)

                          19 (61.3%)

                          1.000

                            CCB

                          13 (54.2%)

                          18 (58.1%)

                          0.791

                            Diuretics

                          9 (37.5%)

                          10 (32.3%)

                          0.778

                            Others

                          11 (45.8%)

                          12 (38.7%)

                          0.783

                            ACE-I

                          1 (4.2%)

                          3 (9.7%)

                           

                            α-Blocker

                          4 (16.7%)

                          3 (9.7%)

                           

                            β-Blocker

                          3 (12.5%)

                          5 (16.1%)

                           

                            αβ-Blocker

                          1 (4.2%)

                          1 (3.2%)

                           

                            Aldosterone antagonist

                          2 (8.3%)

                          0 (0%)

                           

                          Antihyperlipidemic drugs

                          2 (8.3%)

                          0 (0%)

                           

                            Statins

                          12 (50.0%)

                          14 (45.2%)

                          0.789

                            Fibrate

                          2 (8.3%)

                          2 (6.5%)

                          1.000

                            Ezetimibe

                          3 (12.5%)

                          6 (19.4%)

                          0.716

                            Eicosapentaenoic acid

                          2 (8.3%)

                          3 (9.7%)

                          1.000

                          Antithrombogenic agents

                             

                            Antiplatelet agent

                          16 (66.7%)

                          17 (54.8%)

                          0.417

                            Anticoagulant agent

                          2 (8.3%)

                          0 (0.0%)

                          0.186

                          Others

                             

                            Nitrates

                          3 (12.5%)

                          0 (0%)

                          0.077

                            Allopurinol

                          1 (4.2%)

                          1 (3.2%)

                          1.000

                            Uricosuric agents

                          0 (0%)

                          1 (3.2%)

                          1.000

                          ARB: angiotensin receptor blocker, CCB: calcium channel blocker, ACE-I: Angiotensin-converting enzyme inhibitor. Data are expressed as mean ± SD or as a number (percentage).

                          Table 2

                          Changes in FMD (ΔFMD) in the sitagliptin and voglibose group

                          Variable

                          Sitagliptin

                          Voglibose

                          Between-group difference

                          n = 24

                          n = 31

                          FMD (%)

                             

                            Baseline at 0 W

                          5.41 ± 2.25

                          4.96 ± 2.16

                          P = 0.450

                            at 12 W

                          6.17 ± 2.00

                          5.94 ± 2.15

                          P = 0.692

                            ΔFMD:12 W-0 W

                          0.76 ± 2.42

                          0.98 ± 2.41

                          P = 0.729

                          Adjusted ΔFMD:12 W-0 W*

                          1.11

                          0.98

                          P = 0.8316

                            (95% CIs)

                          (0.07-2.16)

                          (0.04-1.91)

                          Values are means ± SD or the least square means (95% CI). *The least square means (95% CIs) were derived from ANCOVA adjusted for the baseline FMD, age, sex, current smoking, diabetes duration and BMI.

                          Table 3

                          Changes in secondary efficacy measures in the sitagliptin and voglibose groups

                           

                          Sitagliptin

                          Voglibose

                          Between-group difference

                          Variable

                          mean ± SD

                          P value

                          mean ± SD

                          P value

                          P value

                          HbA1C

                               

                            baseline at 0 W

                          7.04 ± 0.56

                           

                          6.94 ± 0.45

                            

                            at 12 W

                          6.65 ± 0.57

                           

                          6.59 ± 0.45

                            

                            12 W-0 W

                          −0.39 ± 0.60

                          0.0051

                          −0.35 ± 0.39

                          <0.0001

                          0.8021

                          GIP

                               

                            baseline at 0 W

                          289.92 ± 326.04

                           

                          214.21 ± 220.15

                            

                            at 12 W

                          246.50 ± 284.25

                           

                          258.41 ± 226.88

                            

                            12 W-0 W

                          −43.42 ± 190.10

                          0.3077

                          44.20 ± 198.54

                          0.2671

                          0.1323

                          GLP-1

                               

                            baseline at 0 W

                          5.71 ± 5.92

                           

                          6.65 ± 10.18

                            

                            at 12 W

                          8.25 ± 6.37

                           

                          6.66 ± 6.15

                            

                            12 W-0 W

                          2.54 ± 5.71

                          0.0611

                          0.00 ± 5.70

                          0.9973

                          0.1418

                          C-peptide

                               

                            baseline at 0 W

                          3.913 ± 2.567

                           

                          3.037 ± 1.629

                            

                            at 12 W

                          3.909 ± 2.410

                           

                          3.571 ± 2.710

                            

                            12 W-0 W

                          −0.003 ± 1.366

                          0.9906

                          0.534 ± 2.712

                          0.2977

                          0.3555

                          CD34

                               

                            baseline at 0 W

                          0.956 ± 0.563

                           

                          0.896 ± 0.622

                            

                            at 12 W

                          1.134 ± 0.615

                           

                          0.847 ± 0.470

                            

                            12 W-0 W

                          0.178 ± 0.379

                          0.0311

                          −0.050 ± 0.368

                          0.4656

                          0.0304

                          Total cholesterol

                               

                            baseline at 0 W

                          181.6 ± 28.8

                           

                          187.8 ± 38.9

                            

                            at 12 W

                          172.5 ± 28.2

                           

                          183.9 ± 46.6

                            

                            12 W-0 W

                          −9.0 ± 21.5

                          0.0509

                          −3.9 ± 30.0

                          0.4865

                          0.4807

                          Triglyceride

                               

                            baseline at 0 W

                          158.9 ± 131.1

                           

                          141.2 ± 68.4

                            

                            at 12 W

                          122.4 ± 60.9

                           

                          119.2 ± 51.9

                            

                            12 W-0 W

                          −36.5 ± 98.8

                          0.0837

                          −22.1 ± 52.0

                          0.0249

                          0.5217

                          HDL-C

                               

                            baseline at 0 W

                          56.4 ± 16.8

                           

                          53.8 ± 13.0

                            

                            at 12 W

                          57.5 ± 24.4

                           

                          50.3 ± 11.4

                            

                            12 W-0 W

                          1.0 ± 20.9

                          0.8096

                          −3.5 ± 8.3

                          0.0246

                          0.3223

                          adiponectin

                               

                            baseline at 0 W

                          13.80 ± 12.88

                           

                          15.15 ± 13.81

                            

                            at 12 W

                          13.11 ± 11.10

                           

                          14.09 ± 8.76

                            

                            12 W-0 W

                          −0.69 ± 2.71

                          0.2260

                          −1.06 ± 7.41

                          0.4413

                          0.8020

                          MDA-LDL

                               

                            baseline at 0 W

                          98.7 ± 32.0

                           

                          112.4 ± 44.3

                            

                            at 12 W

                          99.7 ± 44.5

                           

                          116.6 ± 49.7

                            

                            12 W-0 W

                          1.0 ± 33.8

                          0.8812

                          4.2 ± 45.0

                          0.6156

                          0.7787

                          8-OHdG

                               

                            baseline at 0 W

                          12.20 ± 6.55

                           

                          12.31 ± 8.88

                            

                            at 12 W

                          13.10 ± 7.39

                           

                          12.43 ± 15.46

                            

                            12 W-0 W

                          0.90 ± 7.30

                          0.5533

                          0.12 ± 17.29

                          0.9699

                          0.8252

                          hs-CRP

                               

                            baseline at 0 W

                          2194.4 ± 4079.1

                           

                          2052.2 ± 3816.2

                            

                            at 12 W

                          1202.0 ± 1424.2

                           

                          3322.7 ± 7813.6

                            

                            12 W-0 W

                          −992.4 ± 3609.6

                          0.1911

                          1270.5 ± 5592.1

                          0.2233

                          0.0783

                          PTX-3

                               

                            baseline at 0 W

                          1.606 ± 0.733

                           

                          2.461 ± 2.989

                            

                            at 12 W

                          1.491 ± 0.585

                           

                          1.848 ± 0.790

                            

                            12 W-0 W

                          −0.115 ± 0.462

                          0.2334

                          −0.613 ± 2.542

                          0.1967

                          0.3012

                          e-GFR

                               

                            baseline at 0 W

                          66.8 ± 20.8

                           

                          63.6 ± 20.8

                            

                            at 12 W

                          62.2 ± 17.8

                           

                          61.4 ± 19.9

                            

                            12 W-0 W

                          −4.6 ± 9.7

                          0.0301

                          −2.1 ± 7.7

                          0.1306

                          0.3007

                          GIP: gastric inhibitory peptide, GLP-1: glucagon-like peptide-1, HDL-C: high density lipoprotein cholesterol, MDA-LDL: malondialdehyde-modified low density lipoprotein, 8-OHdG: 8-hydroxy-2’-deoxyguanosine, hs-CRP: high-sensitivity C-reactive protein, PTX-3: pentraxin-3, e-GFR: estimated glomerular filtration rate. Data are expressed as mean ± SD.

                          The primary endpoint

                          Change in FMD (ΔFMD) was significantly improved after 12 weeks of treatment in both groups (sitagliptin: +1.11, 95% CI: 0.07-2.16 versus voglibose: +0.98, 95% CI: 0.04-1.91), and there was no significant difference in ΔFMD between the two groups (Table 2 and Figure 2).
                          http://static-content.springer.com/image/art%3A10.1186%2Fs12933-014-0110-2/MediaObjects/12933_2014_Article_110_Fig2_HTML.jpg
                          Figure 2

                          Adjusted changes in FMD (ΔFMD) in the sitagliptin and voglibose groups. Values are the least square means (95% CI). The least square means (95% CIs) were derived from ANCOVA adjusted for the baseline FMD, age, sex, current smoking, diabetes duration and BMI. ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups.

                          Secondary efficacy measures

                          There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups (Table 3). Sitagliptin tended to increase GLP-1 levels after 12 weeks of treatment (0 week: 5.71 ± 5.92 versus 12 weeks: 8.25 ± 6.37 pmol/L, P = 0.0611), but voglibose did not change the levels (0 week: 6.65 ± 10.18 versus 12 weeks: 6.66 ± 6.15 pmol/L, P = 0.9973). Compared with voglibose, sitagliptin significantly increased circulating CD34, a marker of positive endothelial progenitor cells (P < 0.05) (Table 3 and Figure 3).
                          http://static-content.springer.com/image/art%3A10.1186%2Fs12933-014-0110-2/MediaObjects/12933_2014_Article_110_Fig3_HTML.jpg
                          Figure 3

                          Changes in CD34 in the sitagliptin and voglibose groups. A. Circulating CD34 levels at 0 week and 12 weeks in the sitagliptin and voglibose groups. *P < 0.05 vs. 0 W, paired t-test. B. Change in CD34 from the baseline to the end of follow-up (ΔCD34). **P < 0.05, Student’s t-test.

                          Adverse events

                          Adverse events were observed in 5 patients in the voglibose group (Table 4). There were no serious side effects in either group.
                          Table 4

                          Adverse events

                          Events

                          Sitagliptin

                          Voglibose

                           

                          n = 29

                          n = 34

                          Diarrhea

                          0 (0%)

                          1 (2.9%)

                          Nausea

                          0 (0%)

                          1 (2.9%)

                          Edema

                          0 (0%)

                          2 (5.9%)

                          Abdominal fullness

                          0 (0%)

                          1 (2.9%)

                          Number of cases (%) is shown.

                          Discussion

                          In summary, ΔFMD was significantly improved after 12 weeks of treatment in both the sitagliptin and voglibose groups, and there was no significant difference in ΔFMD between the two groups.

                          Alpha GI improves postprandial endothelial dysfunction in patients with type 2 diabetes [9],[10]. We showed that not only voglibose, an alpha GI, but also sitagliptin, a DPP-4 inhibitor, improves endothelial function as assessed by FMD in patients with type 2 diabetes. The impact of a DPP-4 inhibitor on endothelial dysfunction in patients with type 2 diabetes is controversial. A recent study showed that sitagliptin improved endothelial dysfunction assessed by the reactive hyperemia arterial tonometry index (RHI) after 6 months of treatment in patients with diabetes and coronary artery disease [24]. We also showed that sitagliptin improved endothelial dysfunction assessed by another method, FMD. A prospective observational single arm trial also showed that the treatment with sitagliptin for 12 weeks increased FMD in patients with type 2 diabetes [36]. Here, we conducted a randomized prospective multicenter study in patients with type 2 diabetes and revealed improvement of FMD after the 12-week treatment with sitagliptin. In contrast, another short-term study showed that DPP-4 inhibitors, including sitagliptin or alogliptin, attenuated endothelial function as evaluated by FMD after 6 weeks of treatment in patients with diabetes [19]. Furthermore, voglibose, an alpha GI, did not affect FMD in the study. Therefore, short-term treatment with either DPP-4 inhibitors or alpha GI does not ameliorate endothelial dysfunction in patients with diabetes. Our study showed that 12-week treatment with either sitagliptin or voglibose ameliorated endothelial function. Thus, at least 12 weeks of treatment is needed to improve endothelial function.

                          The STOP-NIDDM trial showed that an alpha GI reduces the risk of cardiovascular events in patients with IGT [12]. DPP-4 inhibitors are also expected to have beneficial cardiovascular effects [37],[38]. However, two recent trials with DPP-4 inhibitors, SAVOR-TIMI 53 and EXAMINE trials, showed that saxagliptin and alogliptin did not increase or decrease ischemic events in patients with type 2 diabetes [39],[40]. These trials demonstrated the safety of DPP-4 inhibitors but did not demonstrate cardiovascular benefits. Patients at high risk patients for cardiovascular disease were enrolled in those studies. In the SAVOR-TIMI 53 trial, about 78% of the patients had established cardiovascular disease, and the EXAMINE trial consisted of patients with acute coronary syndrome. Mean HbA1c levels were about 8.0 in patients of those studies. Our study included relatively low-risk patients. Only about 25% of the patients in our study had established cardiovascular diseases. Mean HbA1c levels were about 7.0. ΔFMD was significantly improved after 12 weeks of treatment in both the sitagliptin and voglibose groups in our study. The clinical implication of this study is the demonstration of beneficial effects of both sitagliptin and voglibose on endothelial dysfunction in low-risk and mild-risk patients with type 2 diabetes. Therefore, sitagliptin and voglibose might have cardiovascular benefits in low-risk and mild-risk patients with type 2 diabetes. Further studies are needed to clarify the long-term benefits for cardiovascular disease [37].

                          Iwamoto et al. reported that once-daily sitagliptin monotherapy (50 mg/day) showed greater efficacy and better tolerability than did thrice-daily voglibose (0.6 mg/day) over 12 weeks in Japanese patients with type 2 diabetes [41], but there was no significant difference in changes in HbA1c between the sitagliptin (50 mg/day) and voglibose (0.6 mg/day) groups in our study. Mean HbA1c levels at baseline in the former study and our study were about 7.8 and 7.0, respectively. Lower HbA1c at baseline in our study might have had an influence on changes in HbA1c levels. Sitagliptin tended to increase GLP-1 levels after 12 weeks of treatment, but there was no significant difference in changes in GIP and GLP-1 between the two groups in this study. These results might be because of the small sample size.

                          Matsubara et al. reported that treatment with sitagliptin for 6 months improved endothelial dysfunction along with a decrease in hs-CRP in patients with coronary artery disease and uncontrolled diabetes [24]. Lipid profiles and eGFR did not change after treatment with sitagliptin in that study as well as in our study. Our study showed no significant difference in changes in hs-CRP after treatment with sitagliptin. Furthermore, Sakamoto et al. reported that sitagliptin improved blood pressure and lipid profiles in patients with type 2 diabetes [42]. These different results might be due to the small sample size, short-term treatment or study in low risk patients with type 2 diabetes.

                          Fadini et al. reported that sitagliptin increased circulating EPCs in type 2 diabetic patients with concomitant upregulation of stromal-derived factor-1α (SDF-1α) [21]. SDF-1α is a chemokine that stimulates bone marrow mobilization of EPCs and is one of the substrates of DPP-4. We also showed that sitagliptin significantly increased circulating CD34, but voglibose did not increase CD34. Therefore, this is an ancillary effect of sitagliptin and it is independent from blood glucose levels. Liao et al. reported that the number of EPCs was an independent risk factor for FMD [20]. Thus, this effect might be favorable for the preservation of endothelial function in the future. Further long-term studies are needed to clarify this point.

                          A recent study revealed that alogliptin, a DPP-4 inhibitor, did not increase the frequency of serious adverse events, including hypoglycemia, cancer, pancreatitis, and initiation of dialysis in patients with type 2 diabetes who had a recent acute coronary syndrome [40]. A pooled analysis of 25 randomized clinical trials did not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus [43]. Our study also showed that sitagliptin did not cause serious adverse events. Thus, DPP-4 inhibitors may be safe drugs for patients with type 2 diabetes.

                          Study limitations

                          The first limitation of this study was the small sizes of the groups. The second was heterogeneity of the population in this study. The age range was quite wide in our study. The third limitation was that our study was a short-term study. Our findings need to be confirmed in a large cohort of patients with type 2 diabetes and with a long period.

                          In conclusion, sitagliptin improves endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Furthermore, sitagliptin increases the level of circulating CD34. Sitagliptin has protective effects on endothelial function without adverse events. These effects have potential favorable cardiovascular implications for patients with type 2 diabetes.

                          Abbreviations

                          BMI: 

                          Body mass index

                          DPP-4: 

                          Dipeptidyl peptidase IV

                          eGFR: 

                          Estimated glomerular filtration rate

                          FMD: 

                          Flow-mediated dilatation

                          GIP: 

                          Gastric inhibitory peptide

                          GLP-1: 

                          Glucagon-like peptide-1

                          GI: 

                          Glucosidase inhibitor

                          hs-CRP: 

                          High-sensitivity C-reactive protein

                          8-OHdG: 

                          8-hydroxy-2’-deoxyguanosine

                          IGT: 

                          Impaired glucose tolerance

                          MDA-LDL: 

                          Malondialdehyde-modified low density lipoprotein

                          PTX-3: 

                          Pentraxin-3

                          PPH: 

                          Postprandial hyperglycemia

                          Declarations

                          Acknowledgements

                          This study was supported by Osaka Foundation for the prevention of cancer and cardiovascular diseases. The authors also thank the EDGE study investigators: Kazufumi Nakamura, MD; Hiroki Oe, MD; Kei Yunoki, MD; Toru Miyoshi, MD, Hiroshi Ito, MD (Okayama University, Okayama, Japan), Hajime Kihara, MD (Kihara Cardiovascular Clinic), Kenei Shimada, MD (Osaka City University of Medicine), Shota Fukuda, MD (Osaka Ekisaikai Hospital), Kyoko Watanabe, MD (Okayama Saiseikai Hospital), Tsutomu Takagi, MD (Takagi Cardiology Clinic), Kumiko Hirata, MD (Wakayama Medical University) and Junichi Yoshikawa, MD (Nishinomiya Watanabe Cardiovascular Center).

                          Authors’ Affiliations

                          (1)
                          Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
                          (2)
                          Department of Internal Medicine, Kihara Cardiovascular Clinic
                          (3)
                          Department of Internal Medicine and Cardiology, Osaka City University of Medicine
                          (4)
                          Department of Medicine, Osaka Ekisaikai Hospital
                          (5)
                          Department of Internal Medicine, Okayama Saiseikai General Hospital
                          (6)
                          Takagi Cardiology Clinic
                          (7)
                          Department of Cardiovascular Medicine, Wakayama Medical University
                          (8)
                          Nishinomiya Watanabe Cardiovascular Center

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                          © Nakamura et al.; licensee BioMed Central Ltd. 2014

                          This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

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