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BMJ Open Diabetes Research & Care logoLink to BMJ Open Diabetes Research & Care
. 2016 Apr 19;4(1):e000190. doi: 10.1136/bmjdrc-2015-000190

Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial

Yukiko Matsushima 1,2,3, Yumie Takeshita 1,2,3, Yuki Kita 1,3, Toshiki Otoda 1,3, Ken-ichiro Kato 1,3, Hitomi Toyama-Wakakuri 1,3, Hiroshi Akahori 3, Akiko Shimizu 3, Erika Hamaguchi 3, Yasuyuki Nishimura 3, Takehiro Kanamori 1,3, Shuichi Kaneko 2, Toshinari Takamura 1,2,3
PMCID: PMC4838664  PMID: 27110370

Abstract

Purpose

A step-up strategy for diet therapy and/or single oral antihyperglycemic agent (OHA) regimens has not yet been established. The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in patients with type 2 diabetes with inadequate glycemic control while on diet therapy and/or treatment with a single OHA.

Methods

In this multicenter, randomized, open-label, parallel-group trial, a total of 260 patients with inadequately controlled type 2 diabetes (HbA1c levels >6.9%) were randomly assigned to receive either sitagliptin (50 mg, once daily) or voglibose (0.6 mg, thrice daily) for 12 weeks. The primary end point was HbA1c levels.

Results

Patients receiving sitagliptin showed a significantly greater decrease in HbA1c levels (−0.78±0.69%) compared with those receiving voglibose (−0.30±0.78%). Sitagliptin treatment also lowered serum alkaline phosphatase levels and increased serum creatinine, uric acid, cystatin-C and homeostasis model assessment-β values. Voglibose increased low-density lipoprotein-cholesterol levels and altered serum levels of several fatty acids, and increased Δ-5 desaturase activity. Both drugs increased serum adiponectin. The incidence of adverse events (AEs) was significantly lower in the sitagliptin group, due to the decreased incidence of gastrointestinal AEs.

Conclusions

Sitagliptin shows superior antihyperglycemic effects compared with voglibose as a first-line or second-line therapy. However, both agents possess unique pleiotropic effects that lead to reduced cardiovascular risk in Japanese people with type 2 diabetes.

Trial registration number

UMIN 000003503.

Keywords: Drug Therapy, Fatty Acid Desaturase(s), A1C

Key messages.

  • This study directly compared a hemoglobin A1c and the pleiotropic effects of sitagliptin with voglibose added to concurrent treatment in Japanese patients with type 2 diabetes who could not achieve adequate glycemic control through diet therapy or a single OHA. Compared to voglibose, sitagliptin was superior to voglibose in lowering Hb1Ac levels in monotherapy and in combination therapy.

  • Sitagliptin, but not voglibose, might impair renal function. Sitagliptin significantly increased serum Cre and cys-C decreased estimated glomerular filtration rate average.

  • Sitagliptin significantly decreased polyunsaturated fatty acids, especially ω6 fatty acids, whereas voglibose altered serum levels of many kinds of fatty acids. Voglibose, but not sitagliptin, increased Δ-5 desaturase activity. Both sitagliptin and voglibose exert significant unique pleiotropic effects on surrogate cardiovascular risks.

Introduction

Recent large-scale clinical trials have suggested that intensive antidiabetic therapies that cause unnecessary hyperinsulinemia do not achieve satisfactory cardiovascular outcomes in people with type 2 diabetes, as they may lead to hypoglycemia and weight gain.1 To avoid these problems, incretin-based agents that do not provoke unnecessary hyperinsulinemia have been developed, and are generally used as second- or third-line therapies, in addition to metformin, in Western countries.2 However, to date, limited clinical evidence is available regarding incretin-based agents as first-line or second-line antihyperglycemic therapies.

Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), which subsequently prevents enzymatic inactivation of endogenous glucagon-like peptide-1 (GLP-1)3 and thus improves glycemic control in type 2 diabetes. Sitagliptin has proven effective both as a monotherapy and in combination with other oral antihyperglycemic agents,4 5 although it is thought to be more effective in Asian patients than in Caucasian patients.6 However, the majority of studies on sitagliptin monotherapy and combination therapy are based on non-Japanese patients, and its pleiotropic effects have not been investigated extensively, especially in Japanese patients.

Voglibose is an α-glucosidase inhibitor widely used to improve postprandial hyperglycemia. The antidiabetic actions of voglibose may be mediated, at least in part, by endogenous incretins because an α-glucosidase inhibitor may increase GLP-1 levels both by inhibiting DPP-4 activity7 and by delaying intestinal absorption of a meal.8 However, the differences between sitagliptin and voglibose are unknown from the perspective of understanding pleiotropic effects.

The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in Japanese patients with type 2 diabetes who were unable to achieve adequate glycemic control via diet therapy and/or OHA monotherapy. Notably, dynamic randomization was used to adjust for demographic differences between the groups.

Research design and methods

Overview

This was a randomized, parallel-group study conducted on Japanese patients. The study was designed in accordance with the principles stated in the Declaration of Helsinki, and the protocol was reviewed and approved by the appropriate institutional review board for each study site. All patients provided written informed consent before participation.

A total of 260 type 2 diabetes patients who were unable to achieve adequate glycemic control via diet therapy and/or OHA monotherapy were recruited from 19 centers in Japan between May 2011 and August 2012. Type 2 diabetes was diagnosed according to WHO criteria, based on a 2 h plasma glucose value of >11.1 mmol/L.9 Inadequate disease control was defined as having a Hb1Ac level >6.9%. The trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (registration number UMIN000003503).

Patient eligibility

Participants were eligible if they were at least 20 years old, had type 2 diabetes mellitus, poorly controlled diabetes (HbA1c levels >6.9% within 12 weeks before screening), and had been treated with diet therapy and/or a single OHA, such as sulfonylurea (SU), biguanide (BG) or thiazolidinedione (TZD) class drugs, for 12 weeks or longer.

Exclusion criteria were: (1) hypersensitivity or a contraindication to sitagliptin or voglibose; (2) history of type 1 diabetes; (3) history of ketoacidosis; (4) having experienced symptoms of hypoglycemia; (5) treatment with sitagliptin or voglibose within 12 weeks before screening; (6) treatment with insulin within 12 weeks before screening; (7) concomitant corticosteroid therapy; (8) poorly controlled or unstable diabetes (the state with ketoacidosis or with an increase in HbA1c >3% in the 12 weeks before screening); (9) alanine aminotransferase and/or aspartate aminotransferase levels more than 2.5-fold the upper limit of normal; (10) poorly controlled hypertension or systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg; (11) presence of a severe health problem not suitable for the study; (12) pregnancy or breastfeeding; or (13) inability to participate in the study due to psychiatric or psychosocial status as assessed by the investigators.

Efficacy endpoints

A computer-generated randomization sequence was used to assign participants in a 1:1 ratio to either the sitagliptin or voglibose treatment group. Dynamic randomization was used to adjust for demographic differences (age, previous treatment for type 2 diabetes and HbA1c level) between the groups. In this active-comparator, parallel-group trial, eligible patients received either sitagliptin or voglibose in addition to their previous treatment for 12 weeks. Sitagliptin (Merck & Co, Inc, New Jersey, USA) was initiated and maintained at 50 mg once daily. Voglibose (Takeda Pharmaceutical Company Limited, Osaka, Japan) was initiated and maintained at 0.6 mg (0.2 mg with each meal). Other medications were unchanged during the study period.

The primary efficacy end point was the change in Hb1Ac levels from baseline over the 12-week period. Secondary end points recorded at baseline and week 12 included: fasting plasma glucose (FPG); serum creatinine (Cre); uric acid; alkaline phosphatase (ALP), bone alkaline phosphatase (BAP), cystatin-C (cys-C), 1,5-anhydroglucitol (1,5-AG), fasting serum insulin (IRI), fasting serum proinsulin, fasting C-peptide immunoreactivity (CPR), factors related to fasting lipid profile (including small dense low-density lipoprotein, low-density lipoprotein-cholesterol, adiponectin, tumour necrosis factor α (TNF-α) and leptin); blood pressure; and physical measures (waist circumference, body mass index (BMI)). The estimated glomerular filtration rates based on serum Cre (eGFRcreat) and serum cys-C (eGFRcys), and the average estimated glomerular filtration rate (eGFRaverage), were calculated using the following formulas: eGFRcreat=194×Cr−1.094×Age−0.287 (males) or 194×Cr−1.094×Age−0.287×0.739 (females); eGFRcys=(104×Cystatin C−1.019×0.996age)−8 (males) or (104×Cystatin C−1.019×0.996age×0.929)−8 (females); eGFRaverage=((eGFRcreat+eGFRcys)/2).10 11 The homeostasis model assessment of insulin resistance (HOMA-IR) was used as a conventional index for insulin resistance and was calculated as (IRI (U/mL)×FPG (mmol/L))/22.5).12 To assess basic insulin secretion by β cells, CPR index (CPI), homeostasis model assessment-β (HOMA-β), secretory unit of islet in transplantation index (SUIT index) and quantitative insulin sensitivity check index (QUICKI), were calculated as follows: CPI=(100×fasting CPR (ng/mL))/ FPG (mg/dL)),13 HOMA-β=(IRI (IU/L)×20/(FPG(mg/dL)−63)),14 SUIT index=(1500×CPR (ng/mL)/(FPG (mg/dL)−63))15 and QUICKI=(1/(log IRI(IU/L)+log FPG (mg/dL)).16

Serum fatty acid levels were measured as a secondary outcome. A serum sample (approximately 0.2 mL) and 2 mL of a chloroform-methanol solution (2:1) were placed in a Pyrex centrifuge tube, homogenized with a Polytron homogenizer (PCU-2-110; KINEMATICA GmbH, Switzerland) and centrifuged at 3000 rpm for 10 min. An aliquot of the chloroform-methanol extract was transferred to another Pyrex tube and dried under a stream of nitrogen gas. The dried sample was dissolved in 100 µL of 0.4 M potassium methoxide methanol/14% boron trifluoride-methanol solution, and the fatty acid concentrations were measured at SRL Inc (Tokyo, Japan), using a gas chromatograph (Shimizu GC 17A, Kyoto, Japan). Desaturase activities were estimated as follows: Δ-5 desaturase, C20:4ω6/C20:3ω6; Δ-6 desaturase, 18:3ω-6/18:2ω-6.17

Medication adherence and adverse events were monitored throughout the study, and were rated by investigators for intensity and relationship to study drug.

Statistical analysis

The sample size required to detect a −0.6% change in HbA1c levels in the sitagliptin group, and a −0.4% change in the voglibose group, with a power of 80% (α=0.05, one-tailed; β=0.20) and standardized effect size of 0.6, was 112 participants in each group. Taking into account a dropout rate of 15%, we aimed to recruit 260 participants. All analyses used the full analysis set, which included all patients who received at least one dose of study drug and for whom data were available at baseline and from at least one postrandomization time point. Missing data were replaced by the last observed value of each variable in this analysis. Data were expressed as the mean±SD. The Statistical Package for the Social Sciences (SPSS) V.22.0 (SPSS Inc, Chicago, Illinois, USA) was used for the statistical analyses. Parameters were analyzed using the Wilcoxon signed-rank test in the internal group comparison, the χ2 test or the Mann-Whitney U-test, or the Kruskal-Wallis test, in the intergroup comparison. Associations between variables were assessed using Spearman's rank correlation coefficient. Multiple regression analysis was carried out to determine independent factors for changes in HbA1c by sitagliptin or voglibose. p Values <0.05 were considered statistically significant.

Results

Patient characteristics

A total of 260 patients were screened and randomly assigned to either the sitagliptin or voglibose regimen, and 241 participants (mean age, 63.2±12.7 years; mean BMI, 25.0±4.5 kg/m2) were enrolled in this study (table 1). Nineteen patients were removed after randomisation before the intervention because they withdrew consent (n=17) or did not meet inclusion criteria (n=2; see online supplementary figure S1). No participants took EPA or docosahexaenoic acid (DHA) before or during the study and other subject medications remained unchanged during the study period. One hundred and sixteen patients received diet therapy, 61 patients received SU, 57 patients received BG and seven patients received TZD. FPG and HbA1c levels were 154.7±35.1 mg/dL and 7.9±0.9%, respectively. Baseline demographics and disease characteristics of the two groups did not differ significantly (table 1). The serum TNF-α levels at baseline included two outliers in the sitagliptin group. The median was similar in the two groups (Sitagliptin versus Voglibose, 1.20 vs 1.10 (pg/mL)) and there was no significant difference in the Mann-Whitney U test (p=0.166).

Table 1.

Characteristic of the study participants

All (n=241) Sitagliptin (n=120) Voglibose (n=121) p Value
Male/Female 143/98 72/48 71/50 0.603
Age (years) 63.2±12.7 63.2±13.8 63.2±11.6 0.699
Medication adherence rate (≥80%/<80%) 193/48 99/21 94/27 0.420
Combination therapy (Diet/SU/BG/TZD) 116/61/57/7 59/29/29/3 57/32/28/4 0.953
Body weight (kg) 64.8±14.4 63.8±13.6 65.8±15.1 0.515
BMI (kg/m2) 25.0±4.5 25.0±4.5 25.1±4.5 0.984
Waist circumference (cm) 89.9±11.1 88.7±10.5 91.0±11.7 0.162
Systolic BP (mm Hg) 130.8±17.7 130.0±16.8 131.6±18.5 0.413
FPG (mg/dL) 154.7±35.1 156.3±35.1 153.2±35.2 0.347
HbA1c (%) 7.9±0.9 7.9±1.0 7.8±0.8 0.935
1.5AG (μg/mL) 6.9±4.8 6.5±4.2 7.4±5.3 0.429
BUN (mg/dL) 15.1±4.5 14.9±4.1 15.2±4.9 0.886
s-Cre (mg/dL) 0.72±0.23 0.70±0.19 0.74±0.27 0.870
AST (IU/L) 26±14 26±13 26±16 0.823
ALT (IU/L) 31±25 32±25 30±25 0.522
γ-GTP (IU/L) 46±53 44±49 49±57 0.072
TC (mg/dL) 188.4±33.0 185.1±33.4 191.6.±32.4 0.130
TG (mg/dL) 140.1±93.6 136.0±83.1 144.2±103.1 0.899
HDL-C (mg/dL) 53.8±16.7 52.7±15.4 54.9±18.0 0.250
LDL-C (mg/dL) 106.2±28.1 105.0±29.6 107.5±26.5 0.234
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Data are expressed as means±SD. p Value for the intergroup comparison.

AG, anhydroglucitol; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BG, biguanide; BMI, body mass index; BP, blood pressure; BUN, blood urea nitrogen; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL-c, low-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol; s-Cre, serum creatinine; SU, sulfonylurea; TC, total cholesterol; TG, triglyceride; TZD, thiazolidinedione; γ-GTP, γ-glutamyl transpeptidase.

Supplementary data

bmjdrc-2015-000190supp.pdf (280.8KB, pdf)

Clinical outcomes

Compared to baseline, FPG and HbA1c levels decreased significantly in both groups at the end of the study (table 2). Sitagliptin was superior to voglibose in lowering HbA1c levels (−0.78±0.69 vs −0.30±0.78%, respectively) and FPG concentrations (−16.2±26.4 vs −4.4±38.7 mg/dL, respectively) relative to baseline. There was no significant difference of medication adherence between the groups (table 1). In addition, in the stratified analysis on good (≧80%) and poor (<80%) adherence, adherence rate did not affect these results (see online supplementary table S1).

Table 2.

Changes in the characteristics of patients between baseline and 12 weeks

Sitagliptin
 Voglibose
Parameter n Baseline 12-week p Value* n Baseline 12-week p Value* p Value†
Body weight (kg) 120 63.8±13.6 63.7±13.3 0.842 120 65.8±15.2 65.3±15.1 0.025 0.126
BMI 118 24.9±4.5 24.9±4.4 0.777 119 25.1±4.5 24.9±4.4 0.024 0.086
Waist (cm) 116 88.7±10.5 88.2±10.0 0.195 120 91.0±11.7 90.0±11.1 0.013 0.363
SBP (mm Hg) 120 130.0±16.8 129.5±17.1 0.998 121 131.6±18.5 128.9±16.7 0.067 0.265
DBP (mm Hg) 120 76.0±12.1 75.4±12.1 0.576 121 75.1±12.9 74.4±12.5 0.689 0.918
WBC (/mm3) 120 5815±1362 6057±1590 0.050 119 5985±1762 5940±1975 0.315 0.037
Neutrophils (/mm3) 108 3279±1015 3570±1096 0.008 107 3485±1313 3431±1587 0.193 0.007
Eosinophils (/mm3) 105 156±120 151±120 0.000 105 163±108 164±114 0.821 0.074
Basophils (/mm3) 105 30±23 31±23 0.359 105 32±21 34±28 0.864 0.247
Lymphocytes (/mm3) 105 1951±607 1866±586 0.007 105 2041±723 2023±766 0.772 0.023
Monocytes (/mm3) 105 323±113 345±122 0.004 105 339±139 340±150 0.270 0.009
PLT (104/mm3) 120 21.0±5.5 20.8±5.6 0.281 119 21.8±6.0 21.3±5.8 0.084 0.574
RBC (103/mm3) 120 458.4±43.7 459.2±45.4 0.723 119 454.1±52.1 457.2±50.3 0.124 0.612
Hb (g/mL) 120 13.9±1.6 14.0±1.8 0.943 119 13.9±1.6 14.0±1.5 0.548 0.882
Ht (%) 120 41.6±4.1 41.7±4.4 0.565 119 41.3±4.2 41.8±4.0 0.030 0.399
AST (IU/L) 120 26±13 26±13 0.554 120 26±16 25±11 0.961 0.776
ALT (IU/L) 120 32±25 30±21 0.459 120 30±26 30±20 0.505 0.309
ALP (IU/L) 120 236±71 226±76 0.000 118 237±91 236±101 0.168 0.074
BAP (μg /L) 116 12.6±5.6 12.3±5.6 0.140 116 12.7±5.5 12.5±4.9 0.832 0.186
γ-GTP (IU/L) 120 44±50 49.2±87.6 0.836 119 49±57 47±51 0.011 0.051
CK (IU/L) 117 105.5±71.6 105.2±68.0 0.920 116 109.2±59.5 107.4±54.5 0.552 0.720
BUN (mg/dL) 120 14.9±4.1 15.0±4.6 0.838 120 15.3±4.9 14.5±4.9 0.041 0.166
Cr (mg/dL) 120 0.71±0.19 0.74±0.19 0.000 120 0.74±0.27 0.76±0.27 0.129 0.199
UA (mg/dL) 119 5.08±1.14 5.30±1.24 0.001 120 5.13±1.40 5.28±1.40 0.073 0.328
Cystatin C (mg/L) 114 0.82±0.18 0.85±0.19 0.001 112 0.86±0.23 0.86±0.23 0.177 0.087
eGFRcreat (mL/min/1.73 m2) 120 85.0±28.4 80.6±26.5 0.000 120 80.4±24.1 78.3±23.4 0.069 0.203
eGFRcys (mL/min/1.73 m2) 114 91.1±23.2 91.1±29.3 0.969 112 87.9±25.0 88.5±22.9 0.626 0.132
eGFRaverage (mL/min/1.73 m2) 114 88.0±23.3 85.6±24.6 0.006 111 83.7±22.2 83.4±20.8 0.687 0.053
TC (mg/dL) 120 185.1±33.4 184.9±39.0 0.910 118 191.6±32.4 193.6±40.8 0.066 0.272
HDL-C (mg /dL) 118 52.7±15.4 52.3±14.8 0.873 118 54.9±18.0 54.8±18.3 0.739 0.712
Triglyceride (mg/dL) 120 136.0±83.1 129.8±85.5 0.098 120 144.2±103.2 129.3±79.0 0.015 0.450
LDL-C (mg/dL) 118 104.9±29.6 106.5±34.1 0.499 117 107.5±26.5 112.7±36.5 0.001 0.026
sdLDL (mg/dL) 118 36.8±15.4 34.9±15.1 0.134 120 38.0±16.6 38.3±17.6 0.831 0.220
IRI (IU/L) 116 8.46±8.20 8.69±9.37 0.342 118 14.1±65.1 14.2±69.5 0.028 0.039
CPR (ng/mL) 118 2.10±0.88 2.04±0.84 0.421 120 2.08±1.03 2.05±1.13 0.634 0.715
HMW adiponectin (μg/dL) 118 3.17±2.30 3.50±2.57 0.000 120 3.53±3.65 3.74±3.53 0.000 0.161
Hypersensitive TNF-α (pg/mL) 118 3.11±12.47 2.23±5.21 0.079 120 1.42±1.87 1.55±1.83 0.000 0.538
Leptin (ng/mL) 118 8.26±6.90 8.27±7.17 0.561 120 9.02±9.28 8.21±6.59 0.694 0.540
HOMA-IR 115 3.30±3.44 2.98±3.02 0.056 117 5.21±23.02 5.52±29.02 0.003 0.443
HOMA-β 115 36.0±32.8 47.2±57.6 0.000 117 63.7±299.6 59.5±237.4 0.408 0.002
SUIT index 117 39.5±30.4 45.9±28.3 0.000 118 38.0±22.1 40.9±23.8 0.004 0.047
CPI 117 1.41±0.67 1.52±0.71 0.001 118 1.38±0.68 1.43±0.78 0.080 0.207
QUICKI 112 0.34±0.04 0.34±0.04 0.093 116 0.34±0.05 0.34±0.05 0.090 0.784
Proinsulin (pM) 112 26.9±17.2 22.5±14.3 0.000 104 26.5±17.9 25.3±17.4 0.036 0.328
Proinsulin/Insulin Ratio 101 0.70±0.67 0.54±0.33 0.000 91 0.63±0.39 0.65±0.49 0.698 0.015
HbA1c (%) 120 7.94±1.03 7.15±0.88 0.000 121 7.86±0.78 7.56±1.02 0.000 0.000
1,5AG (μg/mL) 109 6.45±4.16 10.55±5.96 0.000 105 7.43±5.29 12.6±8.12 0.000 0.047
FPG (mg/dL) 119 156.3±35.1 140.0±31.7 0.000 119 153.2±35.2 148.0±43.0 0.001 0.006
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Data are expressed as means±SD.

*p Value for the intragroup comparison (baseline vs 12 weeks).

†p Value for the intergroup comparison (difference in changes from baseline between groups).

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BAP, bone alkaline phosphatase; BMI, body mass index; BUN, blood urea nitrogen; CK, creatinine kinase; CPI, CPR index; CPR, C-peptide immunoreactivity; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; Hb, hemoglobin; HDL-c, low-density lipoprotein cholesterol; HMW, high molecular weight; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment-β; IRI, fasting serum insulin; LDL-C, low-density lipoprotein-cholesterol; PLT, platelet; QUICKI, quantitative insulin sensitivity check index; RBC, red blood cell; SBP, systolic blood pressure; sdLDL, small dense low-density lipoprotein; SUIT, secretory unit of islet in transplantation index; TC, total cholesterol; TNF-α, tumour necrosis factor α; UA, uric acid; WBC, white blood cell count.

Both agents significantly increased 1,5-AG concentrations, but voglibose was superior to sitagliptin in this regard. Sitagliptin, but not voglibose, increased indices for insulin secretion such as HOMA-β, SUIT and CPI. Both agents lowered proinsulin levels and both agents exerted marked effects on the insulin sensitivity index, QUICKI.

Sitagliptin significantly reduced the counts of lymphocytes (p=0.007) and significantly increased the counts of neutrophils (p=0.008) at week 12, whereas voglibose had no effect on them (table 2). Sitagliptin significantly lowered ALP levels from 236±71 IU/L at baseline to 226±76 IU/L at week 12 (p=0.000) without changing bone alkaline phosphatase (BAP), whereas voglibose had no effect on ALP levels. Both agents were almost neutral in their effects on liver enzymes, except that voglibose treatment decreased γ-GTP levels from 49±57 IU/L at baseline to 47±51 IU/L at week 12 (p=0.011). Sitagliptin, but not voglibose, increased serum Cre, uric acid and cys-C. Both agents lowered serum triglyceride levels, whereas voglibose, but not sitagliptin, significantly increased LDL-C. Voglibose significantly increased TNF-α levels, whereas sitagliptin, rather, tended to decrease TNF-α levels. Both agents significantly increased adiponectin levels. In stratified analyses on each concomitant therapy, there was no significant difference in glycemic parameters (see online supplementary figure S2). SU significantly increased neutrophils and decreased diastolic blood pressure compared to BG in the sitagliptin group (data not shown).

Factors predicting the effects of sitagliptin and voglibose are shown in table 3. In the sitagliptin group, there was a significant correlation between ΔHbA1c and baseline levels of 1,5-AG (rs=0.338, p=0.000), HbA1c (rs=–0.589, p=0.000) and adiponectin (r=0.223, p=0.015; table 3). There was no predicting factor in the voglibose group. In a multiple regression analysis, only baseline HbA1c was the independent factor of ΔHbA1c in the sitagiptin group (β=−0525, p=0.000, adjusted R2=0.268).

Table 3.

Factors associated with a change in HbA1c

Sitagliptin
 Voglibose
rs p Value rs p Value
Baseline
Body weight (kg) −0.051 0.577 −0.082 0.374
Body mass index −0.142 0.126 −0.08 0.390
Fasting plasma glucose (mg/dL) −0.113 0.222 0.107 0.246
1,5 AG (%) 0.338 0.000 −0.034 0.714
HbA1c (%) −0.589 0.000 −0.121 0.185
Total cholesterol (mg/dL) 0.050 0.588 0.009 0.948
Fasting serum insulin (IU/L) −0.092 0.328 −0.079 0.392
CPR (ng/mL) −0.101 0.275 −0.004 0.965
HMW adiponectin (µg/mL) 0.223 0.015 0.137 0.137
CPI −0.048 0.609 −0.038 0.684
HOMAIR −0.128 0.171 0.114 0.222
HOMA-β −0.016 0.861 0.033 0.722
EPA (ng/mL) −0.064 0.490 0.062 0.502
DHA (ng/mL) −0.077 0.118 −0.078 0.396
Change from baseline
 ΔFPG 0.386 0.000 0.421 0.000
 ΔBW 0.212 0.020 0.047 0.609
 ΔBMI 0.206 0.025 0.058 0.533
 ΔALP 0.269 0.003 0.187 0.042
 ΔTC 0.231 0.011 −0.062 0.502
 ΔLDLC 0.266 0.004 0.151 0.103
 ΔTG 0.084 0.362 −0.152 0.098
 ΔHMW adiponectin −0.310 0.001 −0.346 0.000
 ΔHOMA-IR 0.233 0.012 0.105 0.262
 ΔHOMA-β −0.304 0.001 −0.222 0.016
 ΔSUIT index −0.377 0.000 −0.261 0.004
 ΔQUICKI −0.185 0.047 −0.175 0.060
 ΔCPI −0.235 0.011 −0.156 0.091
 ΔProinsulin insulin ratio 0.199 0.046 0.177 0.094
 ΔEPA −0.010 0.914 −0.062 0.502
 ΔDHA 0.073 0.430 −0.065 0.482
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AG, anhydroglucitol; ALP, alkaline phosphatase; BMI, body mass index; BW, body weight; CPR, C-peptide immunoreactivity; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment-β; HMW, high molecular weight; LDLC, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.

Changes in fatty acid composition in serum lipids

Sitagliptin, but not voglibose, significantly decreased serum levels of total polyunsaturated fatty acids, including linoleic acid and total ω6 fatty acids. Voglibose, but not sitagliptin, significantly decreased total saturated fatty acids (including palmitic acid and stearic acid), total monounsaturated fatty acids (including palmitoleic acid and oleic acid) and some polyunsaturated fatty acids (such as γ-linolenic acid, 5,8,11-eicosatrienoic acid, dihomo-γ-linolenic acid, docosatetraenoic acid and docosapentaenoic acid). Voglibose significantly decreased the activity of Δ-6 desaturase and increased that of Δ-5 desaturase (table 4). No correlation was observed between ΔHbA1c and eicosapentaenoic acid (EPA) levels at baseline in the sitagliptin group (table 3).

Table 4.

Changes in plasma fatty acid composition between baseline and 12 weeks

Sitagliptin
 Voglibose
Parameter n Baseline 12-week p Value* n Baseline 12-week p Value* p Value†
Lauric acid C12:0 (ng/mL) 118 2.3±2.2 2.3±2.3 0.555 120 2.5±2.1 2.2±2.3 0.139 0.592
Myristic acid C14:0 (ng/mL) 118 29.9±18.9 28.5±19.3 0.147 120 33.1±23.0 30.0±22.8 0.012 0.356
Palmitic acid C16:0 (ng/mL) 118 746.7±259.6 709.8±254.1 0.019 120 796.9±268.7 747.9±265.4 0.001 0.494
Palmitoleic acid C16:1ω7 (ng/mL) 118 80.3±46.2 77.0±51.6 0.130 120 89.7±51.6 82.0±53.7 0.000 0.049
Stearic acid C18:0 (ng/mL) 118 214.7±53.6 212.0±28.7 0.532 120 224.2±57.7 218.2±61.8 0.033 0.291
Oleic acid C18:1ω9 (ng/mL) 118 656.2±236.6 653.2±260.1 0.799 120 714.9±295.4 671.7±268.3 0.049 0.194
Linoleic acid C18:2ω6 (ng/mL) 118 774.4±182.1 736.3±188.6 0.021 120 798.6±208.2 807.2±244.4 0.902 0.143
γ-linolenic acid C18:3ω6 (ng/mL) 118 11.4±6.5 10.8±6.0 0.941 120 11.9±6.9 10.2±5.5 0.000 0.023
α-Linolenic acid C18:3ω3 (ng/mL) 118 27.6±12.5 25.9±11.1 0.010 120 27.3±15.0 27.2±16.3 0.331 0.164
Arachidic acid C20:0 (ng/mL) 118 7.2±1.3 7.3±1.6 0.876 120 7.6±1.6 7.7±1.7 0.935 0.935
Eicosenoic acid C20:1ω9 (ng/mL) 118 5.5±2.0 5.3±2.2 0.562 120 6.1±6.8 6.3±6.9 0.306 0.274
Eicosadienoic acid C20:2ω6 (ng/mL) 118 5.9±1.8 5.9±2.0 0.599 120 6.3±2.0 6.3±21 0.764 0.929
5-8-11Eicosatrienoic acid C20:3ω9 (ng/mL) 118 2.2±1.4 2.2±1.6 0.549 120 2.8±2.6 2.5±2.4 0.008 0.116
Dihomo-γ-linolenic acid C20:3ω6 (ng/mL) 118 38.8±13.2 39.7±16.4 0.260 120 42.4±15.5 39.9±12.7 0.005 0.010
Arachidonic acid C20:4ω6 (ng/mL) 118 173.2±48.7 172.0±51.3 0.706 120 184.5±46.5 183.5±44.6 0.691 0.898
Eicosapentaenoic acid C20:5ω3 (ng/mL) 118 80.6±48.3 79.7±43.5 0.884 120 81.2±70.0 85.5±78.4 0.659 0.955
Behenic acid C22:0 (ng/mL) 118 17.9±3.3 17.9±3.6 0.838 120 32.1±3.7 19.1±4.3 0.465 0.651
Erucic acid C22:1ω9 (ng/mL) 118 1.6±0.8 1.6±0.7 0.613 120 1.8±0.9 1.7±0.9 0.768 0.291
Docosatetraenoic acid C22:4ω6 (ng/mL) 118 5.2±2.2 5.1±2.6 0.248 120 5.5±2.3 5.1±1.9 0.011 0.306
Docosapentaenoic acid C22:5ω3 (ng/mL) 118 25.2±10.0 24.3±9.4 0.399 120 25.8±13.1 24.0±13.5 0.004 0.955
Lignoceric acid C24:0 (ng/mL) 118 16.3±2.8 16.3±3.3 0.775 120 17.5±3.4 17.8±3.9 0.423 0.598
Docosahexaenoic acid C22:6ω3 (ng/mL) 118 175.2±65.3 169.5±58.7 0.305 120 175.2±94.5 167.7±96.1 0.095 0.531
Nervonic acid C24:1ω9 (ng/mL) 118 34.8±7.5 34.5±7.5 0.357 120 37.0±8.2 37.7±8.0 0.028 0.028
EPA+DHA (ng/mL) 118 255.9±107.5 249.2±92.6 0.536 120 256.3±160.3 253.1±169.4 0.436 0.782
EPA/AA ratio 118 0.49±0.31 0.49±0.30 0.705 120 0.44±0.32 0.044±0.32 0.435 0.895
Total ω3 fatty acids (ng/mL) 118 308.7±121.9 299.0±105.3 0.370 120 309.4±181.0 304.3±191.6 0.308 0.735
Total ω6 fatty acids (ng/mL) 118 1008.7±224.8 969.8±237.7 0.024 120 1049.2±238.2 1052.3±273.9 0.684 0.239
Total ω9 fatty acids (ng/mL) 118 700.2±239.2 696.8±263.6 0.794 120 762.6±300.8 720.0±272.5 0.053 0.210
ω3/ω6 ratio 118 0.32±0.13 0.32±0.11 0.236 120 0.30±0.14 0.30±0.14 0.409 0.151
Total saturated fatty acids (ng/mL) 118 1034.9±330.7 994.1±330.3 0.050 120 1101.1±346.5 1043.0±348.1 0.002 0.515
Monounsaturated fatty acids (ng/mL) 118 778.3±276.8 771.7±305.2 0.762 120 854.3±346.8 799.5±306.6 0.020 0.132
Polyunsaturated fatty acids (ng/mL) 118 1319.5±277.3 1270.9±289.2 0.014 120 1361.4±336.2 1359.0±384.4 0.562 0.233
δ-5desaturase (20:4 ω6/20:3 ω6) 118 4.73±1.42 4.72±1.62 0.595 120 4.78±1.77 4.97±1.64 0.014 0.031
δ-6desaturase (18:3 ω6/18:2 ω6) 118 0.015±0.008 0.015±0.007 0.321 120 0.016±0.01 0.014±0.009 0.009 0.007
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Data are expressed as means±SD.

*p Value for the intragroup comparison (baseline vs 12 weeks).

†p Value for the intergroup comparison (difference in changes from baseline between groups).

AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.

Adverse events

The incidence of AEs was significantly lower in the sitagliptin group. This difference was attributable to the decreased incidence of gastrointestinal AEs, such as heartburn, abdominal pain, constipation, loose stool, diarrhea, meteorism and flatulence. Most AEs were mild or moderate but one patient in the voglibose group discontinued the treatment due to diarrhea. The incidence of hypoglycemia was low and similar in both groups. All incidences of hypoglycemia in this study were mild or moderate in severity, but one patient in the sitagliptin group discontinued the treatment due to hypoglycemia. Four serious adverse events (SAEs)—inguinal hernia, heart failure, pancreatitis and urinary tract infection—occurred in the voglibose group, but were considered not related to the study. Due to these SAEs, three patients discontinued the agents (see online supplementary table S2).

Discussion

This study directly compared HbA1c and the pleiotropic effects of sitagliptin with voglibose added to concurrent treatment in Japanese patients with type 2 diabetes who could not achieve adequate glycemic control through diet therapy or a single OHA. The novelty of the present study is as follows: First, dynamic randomization is methodologically novel. It is useful to adjust for demographic differences between each group. In this open-label, randomized, parallel-group study with dynamic allocation, we compared sitagliptin with voglibose, not only as a monotherapy, but also as an add-on therapy to SU, BG or TZD. Second, pleiotropic effects of sitagliptin and voglibose include previously yet-recognized findings.

Regarding the primary endpoint, sitagliptin was superior to voglibose in lowering HbA1c levels in monotherapy and in combination with each concurrent agent. A similar reduction in HbA1c was also observed in previous 12-week studies.18–20

Regarding the secondary end points, sitagliptin and voglibose exerted unique pleiotropic effects in the present study. Sitagliptin, but not voglibose, significantly increased the markers of β-cell function (HOMA-β and proinsulin/insulin ratio). Preclinical studies have shown that GLP-1 stimulates β-cell differentiation and proliferation, inhibits apoptosis of β-cells,21 22 and stimulates β-cell neogenesis and survival in streptozotocin-treated rats.23 In fact, several reviews have indicated that DPP-4 inhibitors consistently improve markers of β-cell function in type 2 diabetes patients.20 24 25 A decrease in the fasting proinsulin-to-insulin ratio, consistent with improved β-cell function, was observed in association with sitagliptin treatment in a previous study.26

Sitagliptin compared with voglibose significantly reduced the counts of lymphocytes and increased those of neutrophils in the present study, as observed in the previous study.27 DPP-4 is highly expressed by T-cells, especially CD4+ T-cells. Sitagliptin decreases CD4+ T-cells in a glucose-independent manner.27 Whether DPP-4 inhibitors suppress immunity by reducing the number of circulating CD4+ T-cells should be examined in future. Sitagliptin significantly increased serum levels of Cre, cys-C and uric acid, and decreased eGFRcreat, whereas voglibose had no effect on these parameters in the present study. These results might relate to the Na-diuretic action of GLP-1,28 although we observed no reduction in blood pressure in the present study. Therefore, it is possible that sitagliptin impairs renal function. In fact, during a much longer, 54-week study, it was found that 18.8% of patients in the sitagliptin group with moderate renal insufficiency at baseline transitioned to severe renal insufficiency status over the course of the study.29 On the other hand, in our study, deterioration of eGFRcys was not observed. After 12 weeks, sitagliptin, but not voglibose, decreased ALP levels relative to baseline without affecting BAP levels. Although it is not certain whether this sitagliptin-mediated decrease in ALP is related to bone metabolism, the decrease in ALP from baseline significantly correlated with a decrease in HbA1c levels, as observed in previous studies.30 31

Both sitagliptin and voglibose significantly increased plasma adiponectin levels, as stated in previous reports.32 33 There was a negative correlation between ΔHbA1c and Δadiponectin (table 3), suggesting that glycemic control at least partly contributes to the increase in adiponectin levels. The increased adiponectin levels might improve endothelial function and likely yield anti-atherosclerotic effects.34 In addition, baseline levels of adiponectin were negatively correlated with ΔHbA1c only in the sitagliptin group, suggesting that adiponectin level might be a predictive maker for the effect of sitagliptin in glycemic control. Serum EPA concentrations are reported to be associated with the glucose-lowering effect of DPP-IV inhibitors in Japanese patients with type 2 diabetes.35 However, in our study, baseline EPA levels were not correlated with the change in HbA1c in the sitagliptin group (table 3). On the other hand, sitagliptin significantly decreased polyunsaturated fatty acids, especially ω6 fatty acids, whereas voglibose altered serum levels of many kinds of fatty acids, unlike in a previous study with acarbose.36 Notably, voglibose, but not sitagliptin, increased Δ-5 desaturase activity. Several cross-sectional studies showed that the Δ-5 desaturase activity index, which refers to the ratio of arachidonic acids to dihomo-γ-linolenic acids, is positively associated with insulin sensitivity37 38 and the onset of newly diagnosed type 2 diabetes,39 and is negatively associated with several metabolic risk factors in patients with metabolic syndrome.40 High Δ-5 desaturase activity was associated with reduced coronary heart disease risk.41 Conversely, voglibose decreased Δ-6 desaturase activity. Δ-6 desaturase activity was associated with an increased probability of metabolic syndrome.40 These findings suggest the possibility that voglibose, rather than sitagliptin, might reduce coronary heart disease risk by altering fatty acids profiling. However, as a limitation, because the present 3-month, open-label study was designed to compare the antihyperglycemic effects of sitagliptin and voglibose, the study duration may be insufficient to evaluate some of the pleiotropic effects. In the subgroup analysis, concomitant antidiabetic agents did not affect the results in glycemic parameters.

In summary, we showed that sitagliptin is superior to voglibose in terms of improving glycemic control as a first/second-line therapy in Japanese people with type 2 diabetes. However, both agents exert unique pleiotropic effects on surrogate cardiovascular risks, which suggests a theoretical basis for potential benefits through combined therapy. A large-scale clinical trial on cardiovascular events is required to test this hypothesis.

Footnotes

Collaborators: Clinical Centres for the ERA-DM study Chapter 1 group: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science (Kanazawa, Ishikawa), Municipal Tsuruga Hospital (Tsuruga, Fukui), Koshino Hospital (Kanazawa, Ishikawa), Ishida Hospital (Kanazawa, Ishikawa), Handa Medical Clinic (Kanazawa, Ishikawa), Yumie Takeshita, MD PhD, Toshinari Takamura, MD PhD, Toshiki Otoda, MD PhD; Ken-ichiro Kato MD, Hitomi Wakakuri, MD, Masayuki Yamada, MD, Hirofumi Misu, MD PhD, Shuichi Kaneko, MD PhD, Tsuguhito Ota, MD PhD, Takehiro Kanamori, MD, Yukiko Matsushima (coordinator), Shima Kitakata (coordinator); Public Hakui Hospital (Hakui, Ishikawa), Toshiki Otoda, MD PhD; Japanese Red Cross Kanazawa Hospital (Kanazawa, Ishikawa), Erika Hamaguchi, MD PhD, Yasuyuki Nishimura, MD PhD; Toyama City Hospital (Toyama, Toyama), Akiko Shimizu, MD PhD; Public Central Hospital of Matto Ishikawa (Matto, Ishikawa), Yuki Kita, MD PhD, Kozo Kawai, MD PhD; Kahoku Central Hospital (Kahoku, Ishikawa), Kensuke Mouri, MD; Fukui Saiseikai Hospital (Fukui, Fukui), Kosuke R Shima, MD, Yukihiro Bando, MD PhD; Kanazawa Municipal Hospital (Kanazawa, Ishikawa), Nobuhiko Koike, MD PhD.

Contributors: TT is the guarantor of this study and, as such, had full access to all of the data, and takes responsibility for the integrity and accuracy of the data and the analysis. YM designed the study, analysed and interpreted the data, and wrote the manuscript. YT designed the study, recruited the patients, collected clinical information, analysed and interpreted the data, and wrote the manuscript. YK, TO, KK, HT-W, HA, AS, EH, YN and TK collected clinical information. SK initiated and organized the study. All the authors have read and approved the final manuscript.

Funding: This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Research grants from ONO Pharmaceutical Co, Ltd (to TT and SK).

Competing interests: None declared.

Patient consent: Obtained.

Ethics approval: Kanazawa University Hospital Institutional Review Board.

Provenance and peer review: Not commissioned; externally peer reviewed.

References

  • 1.Ray KK, Seshasai SRK, Wijesuriya S et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–72. 10.1016/S0140-6736(09)60697-8 [DOI] [PubMed] [Google Scholar]
  • 2.Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–79. 10.2337/dc12-0413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kirby M, Yu DMT, O'Connor S et al. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond) 2010;118:31–41. 10.1042/CS20090047 [DOI] [PubMed] [Google Scholar]
  • 4.Karasik A, Aschner P, Katzeff H et al. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008;24:489–96. 10.1185/030079908X261069 [DOI] [PubMed] [Google Scholar]
  • 5.Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006;49:2564–71. 10.1007/s00125-006-0416-z [DOI] [PubMed] [Google Scholar]
  • 6.Iwamoto Y, Taniguchi T, Nonaka K et al. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J 2010;57:383–94. 10.1507/endocrj.K09E-272 [DOI] [PubMed] [Google Scholar]
  • 7.Moritoh Y, Takeuchi K, Hazama M. Chronic Administration of Voglibose, an α-Glucosidase Inhibitor, Increases Active Glucagon-Like Peptide-1 Levels by Increasing Its Secretion and Decreasing Dipeptidyl Peptidase-4 Activity in ob/ob Mice. J Pharmacol Exp Ther 2009;329:669–76. 10.1124/jpet.108.148056 [DOI] [PubMed] [Google Scholar]
  • 8.Ranganath LMV. Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect. Diabet Med 1998;15:120–4. [DOI] [PubMed] [Google Scholar]
  • 9.[No authors listed] Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–97. 10.2337/diacare.20.7.1183 [DOI] [PubMed] [Google Scholar]
  • 10.Japanese Society of Nephrology, ed. Clinical practice guidebook for diagnosis and treatment of chronic kidney disease 2012. Tokyo: Tokyo-igakusha, 2012. [PubMed] [Google Scholar]
  • 11.Horio M. [Development of evaluation of kidney function and classification of chronic kidney disease (CKD)—including CKD clinical practice guide 2012]. Rinsho Byori 2013;61:616–21. [PubMed] [Google Scholar]
  • 12.Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004;27:1487–95. 10.2337/diacare.27.6.1487 [DOI] [PubMed] [Google Scholar]
  • 13.Iwata M, Maeda S, Kamura Y et al. Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals. Diabetes Care 2012;35:1763–70. 10.2337/dc11-2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–19. 10.1007/BF00280883 [DOI] [PubMed] [Google Scholar]
  • 15.Yamada Y, Fukuda K, Fujimoto S et al. SUIT, secretory units of islets in transplantation: an index for therapeutic management of islet transplanted patients and its application to type 2 diabetes. Diabetes Res Clin Pract 2006;74:222–6. 10.1016/j.diabres.2006.03.030 [DOI] [PubMed] [Google Scholar]
  • 16.Katz A. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402–10. 10.1210/jcem.85.7.6661 [DOI] [PubMed] [Google Scholar]
  • 17.Corpeleijn E, Feskens EJM, Jansen EHJM et al. Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study. Diabetologia 2006;49:2392–401. 10.1007/s00125-006-0383-4 [DOI] [PubMed] [Google Scholar]
  • 18.Nonaka K, Kakikawa T, Sato A et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2008;79:291–8. 10.1016/j.diabres.2007.08.021 [DOI] [PubMed] [Google Scholar]
  • 19.Iwamoto Y, Tajima N, Kadowaki T et al. Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial. Diabetes Obes Metab 2010;12:613–22. 10.1111/j.1463-1326.2010.01197.x [DOI] [PubMed] [Google Scholar]
  • 20.Cai X, Han X, Luo Y et al. Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on β-cell function in Asian and Caucasian type 2 diabetes mellitus patients: a meta-analysis. J Diabetes 2015;7:347–59. 10.1111/1753-0407.12196 [DOI] [PubMed] [Google Scholar]
  • 21.Holst JJ, Deacon CF. Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr Opin Pharmacol 2004;4:589–96. 10.1016/j.coph.2004.08.005 [DOI] [PubMed] [Google Scholar]
  • 22.Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199–206. 10.1152/ajpendo.00545.2003 [DOI] [PubMed] [Google Scholar]
  • 23.Pospisilik JA, Martin J, Doty T et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003;52:741–50. 10.2337/diabetes.52.3.741 [DOI] [PubMed] [Google Scholar]
  • 24.Gerich J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract 2010;90:131–40. 10.1016/j.diabres.2010.07.006 [DOI] [PubMed] [Google Scholar]
  • 25.Pratley RE, Schweizer A, Rosenstock J et al. Robust improvements in fasting and prandial measures of beta-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database. Diabetes, Obes Metab 2008;10:931–8. 10.1111/j.1463-1326.2007.00835.x [DOI] [PubMed] [Google Scholar]
  • 26.Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29: 2638–43. 10.2337/dc06-0706 [DOI] [PubMed] [Google Scholar]
  • 27.Aso Y, Fukushima M, Sagara M et al. Sitagliptin, a DPP-4 inhibitor, alters the subsets of circulating CD4+ T cells in patients with type 2 diabetes. Diabetes Res Clin Pract 2015;110:250–6. 10.1016/j.diabres.2015.10.012 [DOI] [PubMed] [Google Scholar]
  • 28.Kubota A, Maeda H, Kanamori A et al. Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients. J Clin Med Res 2012;4:309–13. 10.4021/jocmr1061w [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Arjona Ferreira JC, Marre M, Barzilai N et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care 2013;36:1067–73. 10.2337/dc12-1365 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632–7. 10.2337/dc06-0703 [DOI] [PubMed] [Google Scholar]
  • 31.Seo C, Sakamoto M, Nishimura R et al. Comparison of glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose: a continuous glucose monitoring-based pilot study. Diabetes Technol Ther 2013;15:378–85. 10.1089/dia.2012.0262 [DOI] [PubMed] [Google Scholar]
  • 32.Kubota Y, Miyamoto M, Takagi G et al. The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci 2012;27:1364–70. 10.3346/jkms.2012.27.11.1364 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Fujitaka K, Otani H, Jo F et al. Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome. Endocr J 2011;58:425–32. 10.1507/endocrj.K10E-327 [DOI] [PubMed] [Google Scholar]
  • 34.Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol 2014;13:103 10.1186/1475-2840-13-103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Senmaru T, Fukui M, Kobayashi K et al. Dipeptidyl-peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations. J Diabetes Investig 2012;3:498–502. 10.1111/j.2040-1124.2012.00220.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Inoue I, Shinoda Y, Nakano T et al. Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance. Metab Clin Exp 2006;55:946–52. 10.1016/j.metabol.2006.03.002 [DOI] [PubMed] [Google Scholar]
  • 37.Vessby B, Gustafsson I-B, Tengblad S et al. Desaturation and elongation of Fatty acids and insulin action. Ann N Y Acad Sci 2002;967:183–95. 10.1111/j.1749-6632.2002.tb04275.x [DOI] [PubMed] [Google Scholar]
  • 38.Warensjö E, Rosell M, Hellenius M-L et al. Associations between estimated fatty acid desaturase activities in serum lipids and adipose tissue in humans: links to obesity and insulin resistance. Lipids Health Dis 2009;8:37 10.1186/1476-511X-8-37 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Kröger J, Schulze MB. Recent insights into the relation of Δ5 desaturase and Δ6 desaturase activity to the development of type 2 diabetes. Curr Opin Lipidol 2012;23:4–10. 10.1097/MOL.0b013e32834d2dc5 [DOI] [PubMed] [Google Scholar]
  • 40.Mayneris-Perxachs J, Guerendiain M, Castellote AI et al. Plasma fatty acid composition, estimated desaturase activities, and their relation with the metabolic syndrome in a population at high risk of cardiovascular disease. Clin Nutr 2014;33:90–7. 10.1016/j.clnu.2013.03.001 [DOI] [PubMed] [Google Scholar]
  • 41.Lu Y, Vaarhorst A, Merry AHH et al. Markers of endogenous desaturase activity and risk of coronary heart disease in the CAREMA cohort study. PLoS ONE 2012;7:e41681 10.1371/journal.pone.0041681 [DOI] [PMC free article] [PubMed] [Google Scholar]

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