Open Access

Comparison of effects of sitagliptin and voglibose on left ventricular diastolic dysfunction in patients with type 2 diabetes: results of the 3D trial

  • Hiroki Oe1Email author,
  • Kazufumi Nakamura2,
  • Hajime Kihara3,
  • Kenei Shimada4,
  • Shota Fukuda5,
  • Tsutomu Takagi6,
  • Toru Miyoshi2,
  • Kumiko Hirata7,
  • Junichi Yoshikawa8,
  • Hiroshi Ito2Email author and
  • FESC, for Effect of a DPP-4 inhibitor on left ventricular diastolic dysfunction in patients with type 2 diabetes and diabetic cardiomyopathy (3D) study investigators.
Cardiovascular Diabetology201514:83

https://doi.org/10.1186/s12933-015-0242-z

Received: 20 February 2015

Accepted: 5 June 2015

Published: 19 June 2015

Abstract

Background

Left ventricular (LV) diastolic dysfunction is frequently observed in patients with type 2 diabetes. Dipeptidyl peptidase-4 inhibitor (DPP-4i) attenuates postprandial hyperglycemia (PPH) and may have cardio-protective effects. It remains unclear whether DPP-4i improves LV diastolic function in patients with type 2 diabetes, and, if so, it is attributable to the attenuation of PPH or to a direct cardiac effect of DPP-4i. We compared the effects of the DPP-4i, sitagliptin, and the alpha-glucosidase inhibitor, voglibose, on LV diastolic function in patients with type 2 diabetes.

Methods

We conducted a prospective, randomized, open-label, multicenter study of 100 diabetic patients with LV diastolic dysfunction. Patients received sitagliptin (50 mg/day) or voglibose (0.6 mg/day). The primary endpoints were changes in the e’ velocity and E/e’ ratio from baseline to 24 weeks later. The secondary efficacy measures included HbA1c, GLP-1, lipid profiles, oxidative stress markers and inflammatory markers.

Results

The study was completed with 40 patients in the sitagliptin group and 40 patients in the voglibose group. There were no significant changes in the e’ velocity and E/e’ ratio from baseline to 24 weeks later in both groups. However, analysis of covariance demonstrated that pioglitazone use is an independent factor associated with changes in the e’ and E/e’ ratio. Among patients not using pioglitazone, e’ increased and the E/e’ ratio decreased in both the sitagliptin and voglibose groups. GLP-1 level increased from baseline to 24 weeks later only in the sitagliptin group (4.8 ± 4.7 vs. 7.3 ± 5.5 pmol/L, p < 0.05). The reductions in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group (−0.7 ± 0.6 % vs. −0.3 ± 0.4, p < 0.005; −1.3 ± 3.2 kg vs. 0.4 ± 2.8 kg, p < 0.05, respectively). There were no changes in lipid profiles and inflammatory markers in both groups.

Conclusions

Our trial showed that sitagliptin reduces HbA1c levels more greatly than voglibose does, but that neither was associated with improvement in the echocardiographic parameters of LV diastolic function in patients with diabetes.

Trial registration

Registered at http://www.umin.ac.jp under UMIN000003784

Keywords

Dipeptidyl peptidase 4 (DPP-4) inhibitors Alpha-glucosidase inhibitor LV diastolic function

Background

Diabetes mellitus is a major risk factor for heart failure (HF), especially HF with preserved ejection fraction (HFPEF) development [1, 2]. Diabetes and HF commonly coexist, and together these conditions are associated with increased morbidity and mortality compared with either condition alone [37]. A recent study in Olmsted County, MN, USA, has shown that the prevalence of diabetes in HF patients has increased markedly over time (3.8 % per year) [8]. An angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) is effective in treating HF as well as reducing insulin resistance in patients with diabetes [9]. Other therapeutic strategies are lacking the same level of effectiveness. Studies have shown that elevated HbA1c is a marker of increased risk of developing HF and, therefore, poor glycemic control may be causally related to the development of HF [10, 11]. However, the optimal treatment of hyperglycemia in patients with diabetes to reduce the progression of HF has not been well studied.

Recent studies have shown that dipeptidyl peptidase-4 inhibitor (DPP-4i), which increases the circulating glucagon-like peptide-1 (GLP-1) level, attenuates postprandial hyperglycemia and may have cardio-protective effects [1214]. In a diabetic rat model, Shigeta et al. [15] demonstrated that DPP4 inhibition reverses left ventricular (LV) diastolic dysfunction via membrane-bound DPP4/stromal cell-derived factor-1α-dependent local actions on angiogenesis and circulating DPP4/GLP-1-mediated inotropic actions. Using HF-model rats, dos Santos et al. [16] reported that sitagliptin (40 mg/kg) administered for 6 weeks exhibited a significant improvement in cardiac contraction and reduction in LV end-diastolic pressure and chamber stiffness. Small pilot studies of GLP-1 have shown potential promise in the treatment of HF patients [17, 18]. However, it remains unknown whether DPP-4i improves LV diastolic function in patients with type 2 diabetes, and, if so, whether the effect is attributable to the attenuation of postprandial hyperglycemia or to the direct cardiac effect of DPP-4i.

Methods

We conducted a randomized, prospective, open-label, multicenter study to compare the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on LV diastolic function. The assessment was done by Doppler echocardiography in patients with type 2 diabetes at 13 sites between January 2011 and January 2013.

Study population

Our study population consisted of outpatients with type 2 diabetes from 20 to 85 years of age with LV diastolic dysfunction (LV ejection fraction >50 %, mitral annular early diastolic velocity (e’) <8 cm/s or the ratio of mitral inflow velocity to e’ velocity (E/e’ ratio) >15). These patients had not achieved the targets for glycemic control with diet, exercise, sulfonylurea, metformin or pioglitazone treatments. We recruited 100 patients with 50 receiving sitagliptin (50 mg/day) treatment and 50 voglibose (0.6 mg/day). The doses of the two drugs used in this study are the recommended therapeutic doses for Japanese patients who are covered by the Japanese National Health Insurance.

The exclusion criteria were: patients being treated with insulin, alpha GI or glinide; and/or exhibited any of the following: type 1 diabetes, HbA1c ≥9.0 % (75 mmol/mol), systolic blood pressure ≥160 mmHg and serum creatinine ≥1.5 mg/dL at baseline, myocardial infarction (MI) or stroke within the previous 24 weeks, significant LV hypertrophy at baseline (LV wall thickness ≥13 mm), atrial fibrillation at baseline, and significant valve diseases (more than or equal to moderately severe valve diseases). The study protocol was approved by the Ethics Committee of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and of each hospital. Written informed consent was obtained from all patients before any study procedure.

Study protocol

The patients were followed for at least 8 weeks to observe that the treatment goal by diet, exercise, sulfonylurea, metformin or pioglitazone was not being achieved. The patients were prospectively and randomly assigned to additional treatment with either sitagliptin (50 mg/day) or voglibose (0.6 mg/day) for at least 24 weeks (Fig. 1). We chose a stratified block randomization. Stratified block randomization was computer-generated and done by use of a web-based system (Nouvelle Place Inc. [http://www.n-place.co.jp/]). Patients were stratified according to age (≥ or < 65 years old), HbA1c (≥ or < 7 %), e’ (≥ or < 6.0 cm/s), and combined use of thiazolidinediones.
Fig. 1

The study’s workflow. Twenty patients were excluded including 6 who were lost to follow-up, 1 who declined to participate and 13 for protocol violation (not meeting inclusion criteria, 12 patients; LVEF < 50 %, 1; under medical treatment with high-dose sulfonylurea). The follow-up study was completed in 77 (77 %) of the patients; 38 received sitagliptin and 39 voglibose

Standard echocardiography was performed at the baseline and after 24 weeks of treatment. From the mitral flow velocity pattern, measurements were taken of peak velocities of E and A waves, the ratio of their peak velocities (E/A ratio) and deceleration time of the E wave. Spectral pulsed-wave Doppler tissue interrogation of longitudinal mitral annular velocity was recorded throughout the cardiac cycle at the septal annulus in the apical four-chamber view. The peaks of myocardial systolic apically directed velocity (s’) and early diastolic velocity (e’) were measured.

Additional exploratory analyses including changes in the chamber dimensions and LV ejection fraction were assessed. LV mass was measured by using the American Society of Echocardiography-recommended formula and the end-systolic left atrial volume was measured by using the ellipsoid model [19]. Both values were indexed with body surface area in m2. All echocardiographic studies were done when patients were clinically stable on treatment.

Measurements of biochemical parameters

The following parameters were measured at baseline and after 24 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 malondialdehyde-modified low density lipoprotein (MDA-LDL) and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG), inflammatory markers including high-sensitive C-reactive protein (hs-CRP) and pentraxin-3 (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 fluorescein isothiocyanate-labeled CD45 and phycoerythrin (PE)-labeled CD34 antibodies (BD Biosciences, Franklin Lakes, NJ, USA). 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). Brain natriuretic peptide (BNP) concentrations were measured using a commercially available specific radioimmunoassay for human BNP (Shiono RIA BNP assay kit, Shionogi Co., Ltd., Osaka, Japan), respectively. Antihypertensive, antihyperlipidemic and antidiabetic drugs were not changed and anti-oxidant drugs including vitamin C and E were not added throughout the study period.

Endpoints

The primary endpoints were changes in e’ and E/e’ ratio from baseline to the end of follow-up. The secondary efficacy measures included changes in glucose, HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers including MDA-LDL and 8-OHdG, inflammatory markers including hs-CRP and PTX-3 and eGFR, and any adverse events.

Statistical analysis

All of the results are expressed as mean ± SD or as proportions (%). We assumed that e’ increased by 1.0 cm/s in the sitagliptin group and 0.2 cm/s in the voglibose group with a standard deviation of 1.5 cm/s [20]. A minimum sample size of 57 participants in each group was required to detect statistical differences in e’ with a power of 80 % and α error of 5 %. The effects of sitagliptin and voglibose on LV diastolic function were compared using a paired t-test. Differences in age, sex, weight, body mass index and blood pressure were compared using the Student’s t-test. Categorical variables were compared using χ 2 test and Fisher’s exact test when appropriate. Differences in secondary efficacy measures between baseline and 24 weeks were compared using a paired t-test. A value of p < 0.05 was set as the threshold for significance. The effects of sitagliptin and voglibose on LV diastolic function (e’ and E/e’ ratio) were assessed by analysis of covariance (ANCOVA) after adjustment for covariates that included baseline e’ and E/e’ ratio, age, sitagliptin/voglibose use and concomitant thiazolidinedione use. Multivariate analysis of factors related to changes from baseline to 24 weeks in e’ and E/e’ ratio levels was performed. All analyses were performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA).

Results

Baseline characteristics

One hundred patients (59 men and 41 women, aged 67.1 ± 9.6 years) with type 2 diabetes were enrolled in this study. Fifty patients received sitagliptin (50 mg/day) treatment and 50 patients received voglibose (0.6 mg/day) treatment. Twenty patients were excluded including 7 who were lost to follow-up and 13 for protocol violation (not meeting inclusion criteria, 6 patients;LV ejection fraction <50 %, 1; under medical treatment with high-dose sulfonylurea.). The follow-up study was completed in 80 (80 %) of the patients; 40 received sitagliptin and 40 voglibose (Fig. 1). Baseline clinical characteristics, including age, sex, body mass index and the type of antidiabetic and antihypertensive medication are shown in Table 1. No patients died, developed cardiovascular events or were admitted to the hospital during the study.
Table 1

Baseline clinical characteristics

Variable

Sitagliptin n = 40

Voglibose n = 40

P value

Age, y

67.8 ± 10.5

66.7 ± 9.8

0.654

Women, n (%)

20(50)

14(35)

0.258

Diabetes duration, months (95 % CI)

48(6-240)

38.5(3-218)

0.145

Body mass index, kg/m2

27.7 ± 4.1

25.7 ± 4.3

0.038

Abdominal girth, cm

88.7 ± 14.3

85.9 ± 15.6

0.469

Current smoking

6(15)

4(10)

0.762

Regular alcohol drinkers

13(33)

17(43)

0.489

NYHA functional class

   

Class I, n (%)

17(43)

17(43)

1.000

Class II, n (%)

23(58)

22(55)

 

Class III, n (%)

0(0)

1(3)

 

Grades of Diastolic Dysfunction

   

0

1 (2.6)

3 (7.5)

0.0987

1

31 (79.5)

34 (85.0)

 

2

7 (17.9)

3 (7.5)

 

Diabetes complication+

7(18)

3(8)

0.311

Diabetic retinopathy

4(10)

2(5)

0.675

Diabetic nephropathy

3(8)

0(0)

0.241

Diabetic neuropathy

2(5)

0(0)

0.494

Hypertension

37(93)

32(80)

0.193

Hyperuricemia

31(78)

31(78)

1.000

Hyperlipidemia

5(13)

4(10)

1.000

Renal disturbance

7(18)

1(3)

0.057

Mean eGFR

74.8 ± 21.7

70.5 ± 15.3

0.304

Cerebrovascular disease

3(8)

1(3)

0.615

Myocardial infarction

5(13)

2(5)

0.432

Peripheral artery disease

3(8)

1(3)

0.615

Anti-diabetic drugs

   

Pioglitazone

14(35)

18(45)

0.494

Sulfonylurea

6(15)

3(8)

0.481

Metformin

7(18)

1(3)

0.057

α-GI

1(3)

0(0)

1.000

Antihypertensive drugs

   

ARB

28(70)

27(68)

1.000

Calcium channel blocker

26(65)

22(55)

0.494

Diuretics

15(38)

10(25)

0.335

Others

11(28)

10(25)

1.000

ACE-I

2(5)

3(8)

 

α-blocker

4(10)

1(3)

 

β-blocker

6(15)

4(10)

 

αβ-blocker

1(3)

1(3)

 

Aldosterone antagonist

2(5)

1(3)

 

Antihyperlipidemic drugs

   

Statins

24(60)

22(55)

0.821

Fibrate

2(5)

2(5)

1.000

Ezetimibe

5(13)

6(15)

1.000

Eicosapentaenoic acid

5(13)

2(5)

0.432

Antiplatelet agent

10(25)

12(30)

0.803

Nitrates

1(3)

1(3)

1.000

Allopurinol

1(3)

4(10)

0.359

Uricosuric agents

0(0)

1(3)

1.000

Values are means ± SD, number of patients (%), or median (95 % confidencel Interval). The continuous variables were compared using Student’s t-test, the categorical variables were compared using Fisher’s exact test, grades of diastolic dysfunction was compared using Cochran-Armitage trend test, and the duration of diabetes was compared using the Wilcoxon rank sum test

The primary endpoint

The e’ velocity and E/e’ ratio were comparable between the sitagliptin and voglibose groups at baseline. The e’ velocity and E/e’ ratio in both groups showed no changes between baseline and after a mean of 24 weeks (e’: sitagliptin +0.2 ± 1.1 cm/s and voglibose +0.3 ± 0.9 cm/s; E/e’: sitagliptin −0.3 ± 2.5 and voglibose −0.5 ± 2.3). There was also no difference in magnitude of the changes in e’ velocity and E/e’ ratio between the two groups (Table 2 and Fig. 2).
Table 2

Changes in e’ velocity and E/e’ ratio in the sitagliptin and voglibose group

Variable

Sitagliptin n = 40

Voglibose n = 40

Between-group difference

e’

   

Baseline at 0W

5.6 ± 1.3

5.5 ± 1.1

p = 0.664

at 24W

5.8 ± 1.3

5.8 ± 1.1

p = 0.997

Δe’: 24W-0W

0.2 ± 1.1

0.3 ± 0.9

p = 0.702

E/e’

   

Baseline at 0W

12.8 ± 4.3

11.6 ± 2.1

p = 0.109

at 24W

12.4 ± 3.4

11.1 ± 2.7

p = 0.060

ΔE/e’: 24W-0W

-0.3 ± 2.5

-0.5 ± 2.3

p = 0.804

Values are means ± SD

W weeks

Fig. 2

Changes in e’ and E/e’ between baseline and 24 weeks later. The e’ velocity and E/e’ ratio were comparable between sitagliptin and voglibose groups at baseline. The e’ velocity and E/e’ ratio showed no changes between baseline and a mean of 24 weeks later in both groups. There was also no significant difference in the magnitude of the changes in e’ velocity and E/e’ ratio between the two groups. e’, mitral annular early diastolic velocity; E/e’, ratio of mitral inflow velocity to e’ velocity; W, weeks

The effects of sitagliptin and voglibose on LV diastolic function (e’ and E/e’ ratio) were assessed by ANCOVA after adjustment for covariates that included baseline e’ and E/e’ ratio, age, sitagliptin/voglibose use and concomitant thiazolidinedione use. ANCOVA demonstrated that pioglitazone use is an independent factor associated with changes in e’ and E/e’ ratio (Table 3). Among patients not using pioglitazone, e' increased and E/e’ ratio decreased in both sitagliptin and voglibose groups (e’: sitagliptin +0.5 ± 1.1 cm/s and voglibose +0.5 ± 0.9 cm/s; E/e’: sitagliptin −1.0 ± 2.7 and voglibose −0.8 ± 2.4).
Table 3

Factors affecting e’ and E/e’ at week 24a

Dependent variable

Independent variable

Estimate

95 % CI

P value

e’ (24W)

e’ (0W)

0.525

0.309

0.742

<0.0001

Sitagliptin/Voglibose

-0.047

-0.455

0.362

0.821

Age — yr

-0.028

-0.054

-0.003

0.032

without/with TZD

0.547

0.130

0.965

0.011

E/e’ (24W)

E/e’ (0W)

0.615

0.471

0.758

<0.0001

Sitagliptin/Voglibose

0.688

-0.239

1.615

0.144

Age — yr

0.024

-0.025

0.072

0.334

without/with TZD

-1.411

-2.339

-0.483

0.003

95 % CIs and P values were calculated with the use of analysis of covariance (ANCOVA)

aCI denotes confidence interval

Multivariate analysis of factors related to changes from baseline to 24 weeks in e’ and E/e’ ratio levels showed for e’, without/with thiazolidinedione was not statistically significant only if adiponectin was added in the model, and for E/e’, without/with thiazolidinedione was statistically significant for all models, which implies that without/with thiazolidinedione could be an independent factor associated with changes in the E/e’ ratio (Table 4).
Table 4

Multivariate analysis of factors related to changes from baseline to week 24 in e’ and E/e’ ratio levelsa

Model

e’ [cm/s]

E/e’

 

Change from baseline

P valueb

R2

Change from baseline

P valueb

R2

 

Beta (95 % CI)

Beta (95 % CI)

 

Model1—Primary model

  

0.500

  

0.609

Baseline

0.525 (0.309 to 0.742)

<.0001

 

0.615 (0.471 to 0.758)

<.0001

 

Sitagliptin/Voglibose

-0.047 (-0.455 to 0.362)

0.8206

 

0.688 (-0.239 to 1.615)

0.1436

 

Age—yr

-0.028 (-0.054 to -0.003)

0.0317

 

0.024 (-0.025 to 0.072)

0.3335

 

Without/with TZD

0.547 (0.130 to 0.965)

0.0109

 

-1.411 (-2.339 to -0.483)

0.0034

 

Model2—Add demographic valuesb

  

0.522

  

0.641

Baseline

0.520 (0.298 to 0.742)

<.0001

 

0.603 (0.456 to 0.750)

<.0001

 

Sitagliptin/Voglibose

-0.069 (-0.504 to 0.365)

0.7509

 

0.683 (-0.271 to 1.636)

0.1576

 

Age—yr

-0.025 (-0.052 to 0.002)

0.0739

 

0.013 (-0.037 to 0.064)

0.5964

 

Female/Male

0.243 (-0.195 to 0.681)

0.2718

 

-1.114 (-2.092 to -0.137)

0.0261

 

BMI (0W)

0.033 (-0.019 to 0.084)

0.2140

 

-0.037 (-0.155 to 0.081)

0.5306

 

SBP (0W)

-0.005 (-0.020 to 0.011)

0.5454

 

-0.002 (-0.036 to 0.031)

0.8917

 

Pulse (0W)

-0.003 (-0.025 to 0.019)

0.7882

 

0.022 (-0.028 to 0.071)

0.3911

 

Without/with TZD

0.662 (0.216 to 1.108)

0.0042

 

-1.732 (-2.711 to -0.753)

0.0007

 

Model3—Add complicationsb

  

0.518

  

0.626

Baseline

0.487 (0.253 to 0.721)

<.0001

 

0.584 (0.425 to 0.744)

<.0001

 

Sitagliptin/Voglibose

0.018 (-0.426 to 0.462)

0.9362

 

0.642 (-0.331 to 1.615)

0.1922

 

Age—yr

-0.031 (-0.057 to -0.004)

0.0228

 

0.030 (-0.020 to 0.081)

0.2389

 

Diabetes complication

-0.395 (-1.038 to 0.247)

0.2238

 

0.721 (-0.799 to 2.241)

0.3473

 

Hypertension

0.202 (-0.410 to 0.814)

0.5131

 

-0.527 (-1.908 to 0.854)

0.4491

 

Hyperlipidemia

0.219 (-0.317 to 0.755)

0.4177

 

-0.886 (-2.086 to 0.313)

0.1450

 

Renal disturbance

-0.219 (-1.000 to 0.562)

0.5780

 

0.277 (-1.453 to 2.007)

0.7502

 

Without/with TZD

0.511 (0.068 to 0.954)

0.0244

 

-1.302 (-2.271 to -0.334)

0.0092

 

Model4—Add laboratory valuesb

  

0.525

  

0.642

Baseline

0.542 (0.314 to 0.770)

<.0001

 

0.615 (0.469 to 0.761)

<.0001

 

Sitagliptin/Voglibose

-0.127 (-0.568 to 0.314)

0.5671

 

0.669 (-0.314 to 1.651)

0.1790

 

Age—yr

-0.023 (-0.053 to 0.006)

0.1220

 

0.029 (-0.027 to 0.084)

0.3045

 

WBC (0W)

-0.000 (-0.000 to 0.000)

0.7030

 

0.000 (-0.000 to 0.000)

0.2013

 

AST (0W)

0.012 (-0.008 to 0.032)

0.2398

 

0.003 (-0.040 to 0.046)

0.8871

 

BUN (0W)

0.009 (-0.045 to 0.063)

0.7380

 

-0.019 (-0.139 to 0.101)

0.7498

 

Glucagon (0W)

-0.001 (-0.012 to 0.010)

0.8296

 

-0.010 (-0.034 to 0.014)

0.3929

 

Adiponectin (0W)

-0.017 (-0.049 to 0.016)

0.3067

 

-0.030 (-0.102 to 0.041)

0.4020

 

IVSTh (0W)

-0.192 (-1.847 to 1.463)

0.8175

 

-1.323 (-5.000 to 2.353)

0.4749

 

Without/with TZD

0.380 (-0.181 to 0.941)

0.1808

 

-1.675 (-2.916 to -0.434)

0.0089

 

Model5—Add adiponectinc

  

0.511

  

0.620

Baseline

0.516 (0.299 to 0.732)

<.0001

 

0.623 (0.480 to 0.766)

<.0001

 

Sitagliptin/Voglibose

-0.080 (-0.490 to 0.330)

0.6991

 

0.587 (-0.344 to 1.519)

0.2129

 

Age—yr

-0.025 (-0.051 to 0.001)

0.0637

 

0.033 (-0.016 to 0.083)

0.1858

 

Adiponectin (0W)

-0.018 (-0.047 to 0.011)

0.2169

 

-0.046 (-0.112 to 0.019)

0.1610

 

Without/with TZD

0.388 (-0.099 to 0.876)

0.1169

 

-1.807 (-2.884 to -0.730)

0.0013

 

Model6—Remove TZD

  

0.493

  

0.560

Baseline

0.480 (0.266 to 0.695)

<.0001

 

0.624 (0.472 to 0.777)

<.0001

 

Sitagliptin/Voglibose

-0.067 (-0.481 to 0.347)

0.7471

 

0.566 (-0.429 to 1.561)

0.2605

 

Age—yr

-0.026 (-0.052 to 0.001)

0.0580

 

0.025 (-0.028 to 0.078)

0.3505

 

Adiponectin (0W)

-0.030 (-0.055 to -0.005)

0.0187

 

0.010 (-0.050 to 0.070)

0.7331

 

aThe analysis was performed in the full analysis set, with the use of analysis of covariance, WBC denotes white blood cell, AST aspartate transaminase, BUN blood urea nitrogen, IVSTh interventricular septum thickness, and TZD thiazolidinedione

bStatistically significant variables (alpha = 0.05) were selected from measured demographics, complications and laboratory variables with the use of two sample t-tests, according to without/with TZD groups in the full analysis set

cFor e’, without/with TZD was not statistically significant (alpha = 0.05) only if adiponectin was added in the model

Secondary efficacy measures

The GLP-1 level increased from baseline to 24 weeks later in the sitagliptin group but not in the voglibose group (4.8 ± 4.7 pmol/L vs. 7.3 ± 5.5 pmol/L, p < 0.05, respectively). The decreases in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group (−0.7 ± 0.6 % vs. −0.3 ± 0.4 %, p < 0.005 and −1.3 ± 3.2 kg vs. 0.4 ± 2.8 kg, p < 0.05, respectively). There were no significant differences in the changes in C-peptide, lipid profile, oxidative stress marker and inflammatory marker between the two groups (Table 5 and Fig. 3). In only the sitagliptin group, and not the voglibose group, did the systolic blood pressure and LV septal wall thickness decrease 24 weeks later (135 ± 16 mmHg vs. 128 ± 10 mmHg and 0.97 ± 0.15 mm vs. 0.93 ± 0.14 mm, respectively) (Table 6).
Table 5

Changes in secondary efficacy measures in the sitagliptin and voglibose group

Variable

Sitagliptin

Voglibose

Between-group difference

 

Mean ± SD

P value

Mean ± SD

P value

P value

Glucose

     

Baseline at 0W

145 ± 58

 

133 ± 42

 

0.304

At 24W

127 ± 26

 

133 ± 27

 

0.354

24W-0W

-23 ± 60

0.047

1 ± 43

0.916

0.083

HbA1c

     

Baseline at 0W

7.1 ± 0.7

 

6.9 ± 0.5

 

0.273

At 24W

6.4 ± 0.4

 

6.7 ± 0.5

 

0.026

24W-0W

-0.7 ± 0.6

<0.0001

-0.3 ± 0.4

0.0004

0.002

GIP

     

Baseline at 0W

191 ± 214

 

159 ± 211

 

0.517

At 24W

149 ± 161

 

162 ± 148

 

0.759

24W-0W

-21 ± 226

0.314

0.6 ± 1.6

0.041

0.749

CD34

     

Baseline at 0W

1.1 ± 0.7

 

0.9 ± 0.6

 

0.239

At 24W

1.1 ± 0.5

 

0.9 ± 0.7

 

0.160

24W-0W

0.1 ± 0.5

0.435

0.0 ± 0.5

0.772

0.430

Total cholesterol

     

Baseline at 0W

184 ± 27

 

185 ± 33

 

0.944

At 24W

178 ± 29

 

183 ± 37

 

0.522

24W-0W

-3 ± 30

0.603

0 ± 29

0.991

0.709

Triglyceride

     

Baseline at 0W

155 ± 107

 

141 ± 74

 

0.486

At 24W

132 ± 62

 

127 ± 72

 

0.803

24W-0W

-15 ± 94

0.391

-13 ± 52

0.190

0.905

HDL-C

     

Baseline at 0W

51 ± 12

 

56 ± 16

 

0.106

At 24W

52 ± 14

 

53 ± 15

 

0.930

24W-0W

0.8 ± 7.9

0.551

-3.6 ± 8.2

0.010

0.021

Adiponectin

     

Baseline at 0W

11.0 ± 8.3

 

13.3 ± 8.7

 

0.222

At 24W

11.7 ± 8.8

 

12.9 ± 7.3

 

0.528

24W-0W

0.5 ± 1.8

0.092

-0.3 ± 2.9

0.539

0.150

MDA-LDL

     

Baseline at 0W

106 ± 34

 

110 ± 37

 

0.658

At 24W

113 ± 34

 

109 ± 36

 

0.591

24W-0W

9 ± 32

0.118

1 ± 38

0.860

0.364

8-OHdG

     

Baseline at 0W

11.7 ± 7.9

 

13.5 ± 10.0

 

0.392

At 24W

11.4 ± 7.4

 

14.8 ± 14.6

 

0.221

24W-0W

-0.2 ± 10.0

0.903

1.5 ± 16.9

0.596

0.605

hs-CRP

     

Baseline at 0W

3869 ± 9072

 

1358 ± 2511

 

0.099

At 24W

1933 ± 5101

 

661 ± 691

 

0.147

24W-0W

-1929 ± 6798

0.098

-380 ± 1186

0.059

0.186

PTX-3

     

Baseline at 0W

1.8 ± 1.0

 

2.4 ± 2.7

 

0.206

At 24W

1.5 ± 0.8

 

1.6 ± 0.8

 

0.557

24W-0W

-0.3 ± 0.7

0.006

-0.3 ± 1.2

0.104

0.974

e-GFR

     

Baseline at 0W

75 ± 22

 

71 ± 15

 

0.304

At 24W

69 ± 19

 

72 ± 16

 

0.411

24W-0W

-5 ± 12

0.014

0 ± 9

0.903

0.036

BNP, pg/ml

     

Baseline at 0W

39 ± 48

 

34 ± 35

 

0.600

At 24W

40 ± 41

 

28 ± 24

 

0.160

24W-0W

1 ± 40

0.923

-5 ± 22

0.164

0.443

GIP gastric inhibitory peptide, GLP-1 glucagon-like peptide-1, CD34 C-peptide, MDA-LDL malondialdehyde-modified low density lipoprotein, 8-OHdG 8-hydroxy-2′-deoxyguanosine, hs-CRP high-sensitive C-reactive protein, PTX-3pentraxin-3, eGFR estimated glomerular filtration rate, BNP B-type natriuretic peptide

Fig. 3

Changes in HbA1c, FBS, GLP-1 and body weight between baseline and 24 weeks later. The decreases in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group. GLP-1 level increased from baseline to 24 weeks later in the sitagliptin group but not in the voglibose group. FBS, fasting blood sugar; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; NGSP, National Glycohemoglobin Standardization Program; W, weeks

Table 6

Changes in hemodynamic and echocardiographic parameters in the sitagliptin and voglibose group

Variable

Sitagliptin

Voglibose

Between-group difference

 

Mean ± SD

P value

Mean ± SD

P value

P value

SBP, mmHg

     

Baseline at 0W

135 ± 16

 

131 ± 13

 

0.180

At 24W

128 ± 10

 

129 ± 15

 

0.855

24W-0W

-7 ± 17

0.022

-2 ± 15

0.496

0.184

DBP, mmHg

     

Baseline at 0W

74 ± 13

 

75 ± 10

 

0.818

At 24W

71 ± 10

 

75 ± 11

 

0.108

24W-0W

-2 ± 14

0.344

1 ± 10

0.779

0.349

Pulse, b.p.m.

     

Baseline at 0W

71 ± 11

 

71 ± 10

 

0.903

At 24W

69 ± 12

 

71 ± 11

 

0.483

24W-0W

-1 ± 12

0.653

0 ± 12

0.816

0.625

Body weight

     

Baseline at 0W

69 ± 10

 

67 ± 12

 

0.294

At 24W

68 ± 11

 

67 ± 13

 

0.736

24W-0W

-1.3 ± 3.2

0.018

0.4 ± 2.8

0.433

0.020

a’, cm/s

     

Baseline at 0W

8.4 ± 1.6

 

9.0 ± 1.6

 

0.110

At 24W

8.1 ± 1.8

 

9.0 ± 1.6

 

0.031

24W-0W

-0.3 ± 1.7

0.316

0.2 ± 1.4

0.468

0.214

s’, cm/s

     

Baseline at 0W

6.6 ± 1.1

 

7.2 ± 1.2

 

0.019

At 24W

6.8 ± 1.4

 

7.0 ± 1.1

 

0.609

24W-0W

0.2 ± 1.4

0.398

-0.2 ± 1.4

0.412

0.237

Dct

     

Baseline at 0W

234 ± 41

 

237 ± 39

 

0.769

At 24W

236 ± 42

 

233 ± 43

 

0.765

24W-0W

1 ± 41

0.885

-4 ± 35

0.525

0.604

E velocity, m/s

     

Baseline at 0W

68 ± 16

 

62 ± 11

 

0.048

At 24W

69 ± 14

 

63 ± 14

 

0.047

24W-0W

1 ± 10

0.569

0 ± 12

0.879

0.803

A velocity, m/s

     

Baseline at 0W

82 ± 19

 

79 ± 18

 

0.421

At 24W

80 ± 19

 

74 ± 14

 

0.150

24W-0W

-1 ± 13

0.537

-4 ± 10

0.020

0.299

E/A ratio

     

Baseline at 0W

0.9 ± 0.3

 

0.8 ± 0.2

 

0.424

At 24W

0.9 ± 0.2

 

0.9 ± 0.3

 

0.668

24W-0W

0.0 ± 0.2

0.402

0.0 ± 0.2

0.157

0.651

Septal thickness, mm

     

Baseline at 0W

1.0 ± 0.2

 

0.9 ± 0.1

 

0.069

At 24W

0.9 ± 0.1

 

0.9 ± 0.1

 

0.502

24W-0W

0.0 ± 0.1

0.015

0.0 ± 0.1

0.876

0.083

LVEF, %

     

Baseline at 0W

68 ± 7

 

71 ± 7

 

0.209

At 24W

68 ± 6

 

66 ± 9

 

0.179

24W-0W

0 ± 8

0.967

-5 ± 8

0.001

0.013

LVMI, g/m2

     

Baseline at 0W

93 ± 20

 

85 ± 18

 

0.085

At 24W

90 ± 17

 

86 ± 18

 

0.239

24W-0W

-3 ± 13

0.195

1 ± 14

0.551

0.183

LA volume index, ml/m2

     

Baseline at 0W

27.7 ± 5.9

 

26.1 ± 7.6

 

0.346

At 24W

27.7 ± 7.5

 

26.6 ± 6.3

 

0.508

24W-0W

0.3 ± 5.0

0.734

0.8 ± 5.6

0.448

0.733

Urine albumin, mg/g/Cr

     

Baseline at 0W

37 ± 66

 

31 ± 41

 

0.603

At 24W

39 ± 94

 

28 ± 50

 

0.533

24W-0W

-1 ± 50

0.889

-5 ± 30

0.339

0.723

BUN

     

Baseline at 0W

17 ± 5

 

16 ± 5

 

0.760

At 24W

16 ± 3

 

16 ± 4

 

0.824

24W-0W

0 ± 3

0.759

0 ± 4

0.740

0.959

Adverse events

Adverse events were observed in 2 patients in the sitagliptin group (hypoglycemia and liver dysfunction) and 4 patients in the voglibose group (diarrhea, edema and gastrointestinal symptoms) (Table 7). Mild hypoglycemia of a patient in the sitagliptin group improved rapidly with dose reduction of sulfonylurea. Hospitalizations because of HF or cardiovascular events were not observed during the study period.
Table 7

Adverse events

Events

Sitagliptin

Voglibose

 

n = 40

n = 40

 

2 cases (5.0)

4 cases (10.0)

Hypoglycemia

1 (2.5)

0 (0.0)

Diarrhea

0 (0.0)

4 (10.0)

Edema

0 (0.0)

3 (7.5)

Gastrointestinal symptom

0 (0.0)

2 (5.0)

Liver dysfunction

1 (2.5)

0 (0.0)

Total events

2

9

Number of cases (%) is shown

Discussion

This study is the first randomized trial to compare the impact of glycemic control with sitagliptin and voglibose on LV diastolic function. Our study demonstrated that both sitagliptin and voglibose reduce HbA1c, but the magnitude of reduction of HbA1c was greater in the sitagliptin group and had a greater increase in the GLP-1 level. However, despite the improved glycemic control, the e’ velocity and E/e’ ratio did not show significant improvement after 24-week treatment with sitagliptin or voglibose. There was also no significant difference in the change in the e’ velocity and E/e’ ratio between the two groups.

The plasma BNP level, New York Heart Association (NYHA) functional class and the grades of diastolic function (ASE/EAE) did not show significant improvement in either group. Therefore, we conclude that sitagliptin and voglibose had no impact on e’ velocity or E/e’ ratio in patients with type 2 diabetes and impaired diastolic function.

Elevated HbA1c has been a marker of increased risk of developing HF in patients with diabetes [10, 11]. Poor glycemic control and associated hyperglycemia may be causally related to the development of HF by two mechanisms: (i) through promotion of atherosclerosis and the ensuing coronary artery disease [21] and (ii) by development of a specific diabetic cardiomyopathy by direct damage to the heart muscle [4, 5]. However, studies examining treatment strategies of intensive glucose control, such as the UKPDS and the more recently completed ACCORD and ADVANCE studies have not shown statistically significant reductions in HF events in patients assigned to more intensive glucose control strategies when compared with those assigned to standard therapy [2224]. In our study, the blood glucose level was lowered with sitagliptin and voglibose though the reduction of HbA1c was greater in the sitagliptin group, which also had an associated greater increase in the GLP-1 level. Reduction of body weight and systolic blood pressure was also found in the sitagliptin group. These apparently beneficial changes were not, however, associated with an increase in e’ velocity or with a reduction in E/e’ ratio in either groups.

Recently, the SAVOR-TIMI 53 trial showed that DPP-4i may increase the risk of HF [25], which is of concern. In this trial, more patients in the saxagliptin group than in the placebo group were hospitalized for HF (3.5 % vs. 2.8 %, according to the 2-year Kaplan–Meier estimates; hazard ratio 1.27, 95 % CI = 1.07–1.51; p = 0.007). However, our results indicate that the BNP value, e’ velocity and E/e’ ratio do not change during sitagliptin use and, thus, sitagliptin may not be associated with an increased risk of HF or other serious adverse events. Therefore, we can conclude that both sitagliptin and voglibose can be safely used for patients with type 2 diabetes without an increased risk of worsening LV diastolic function.

Although thiazolidinediones activate the peroxisome proliferator-activated receptor γ (PPARγ) system and improve insulin sensitivity to reduce cardiovascular events [26], they are reported to be associated with an increased risk of HF by augmentation of fluid retention [27]. Interestingly, our data demonstrated that pioglitazone is an independent factor that affects the temporal changes in the e’ velocity and E/e’ ratio. The e’ velocity significantly increased in both sitagliptin and voglibose groups if the patients who received pioglitazone were excluded. By contrast, the patients who used pioglitazone showed decreased e’ velocity and increased E/e’ ratio at the follow-up assessment. These data indicate that sitagliptin and voglibose might improve LV diastolic function by themselves, and that pioglitazone may attenuate the beneficial impact of these drugs on LV diastolic function. However, it is uncertain whether pioglitazone may worsen HF, because no patient who used pioglitazone was hospitalized with HF.

An excessive activity of circulating DPP4 was also found to be independently associated with subclinical LV dysfunction in T2DM patients [28]. Decreased adiponectin levels were associated with LV diastolic dysfunction in patients with known or suspected coronary artery disease [29]. Hibuse et al. reported that serum adiponectin level was elevated after a three-month treatment with sitagliptin [30], and that abenefical effect of sitagliptin on LV diastolic dysfunction is expected. However, there was no significant increase in serum adiponectin level (0.5 ± 1.8, p = 0.092) after 24 weeks of treatment with sitagliptin in this study.

Sitagliptin was associated with an increase in GLP-1, but voglibose was not. Increased GLP-1 may augment diuresis and natriuresis by inhibiting sodium reabsorption from the proximal renal tubule [31]. GLP-1 induces an endothelium-dependent vasorelaxation that is dependent on nitric oxide generation, and this may contribute to reduced peripheral vascular resistance [32]. Clinical and experimental studies have shown that DPP-4i has a moderate blood pressure lowering effect [33]. In this study, sitagliptin significantly lowered SBP, but voglibose did not (135 ± 16 mmHg vs. 128 ± 10 mmHg, respectively). There are many studies that demonstrate that reduced systolic blood pressure is associated with regression of LV mass, an increase in e’ velocity and a reduction of HF events [34]. Sitagliptin significantly decreased septal wall thickness in our study, but did not decrease LVMI after the 24-week treatment. In the LV hypertrophy rat model induced by isoproterenol infusion, we previously demonstrated that vildagliptin treatment was associated with a reduction in LV mass compared with the control group [35]. However, the duration of exposure to the study drugs may not have been long enough to reverse the effects of years of diastolic dysfunction processes in patients. The present study does not exclude the possibility of either benefit or increased risk with a longer duration of sitagliptin therapy.

Owing to the limited sample size, this study is statistically underpowered

However, there was almost no difference (much less than 0.8 cm/s; assumption) of the change in e’ in the estimated value between the two groups in this study. So, even if the target number of cases had been achieved, based on current datasets, it would be unlikely that a statistically significant difference would have been obtained.

There are few data about the effect of anti-diabetic drugs on LV diastolic dysfunction. von Bibra et al. reported that 16 weeks of treatment with rosiglitazone improved LV diastolic dysfunction evaluated by Doppler echocardiography (e’; 7.9 cm/s → 8.9 cm/s, Δe’ = 1.0 cm/s) [20]. However, it remains unknown whether and how anti-diabetic drugs including DPP-4i improve LV diastolic function in patients with type 2 diabetes for now. Further investigation is needed in this area.

We evaluated diastolic function by measuring the e’ velocity and the E/e’ ratio at the septal side of the mitral annulus. Nagueh et al. reported that it is preferable to use the average e’ velocity obtained from the septal and lateral sides of the mitral annulus. We evaluated the changes of e’ and the E/e’ (24 W-0 W) in this study, and our study population excluded patients with LV ejection fraction < 50 % and myocardial infarction within the previous 24 weeks, thus single-site (septal e’) measurements could be applicable.

Limitations

We acknowledge several limitations in the present study. First, although this study was multicenter and randomized, the drug participation was open-label. Therefore, we used a biomarker, e’ velocity, as the primary endpoint. Secondly, we did not measure plasma DPP-4 activity. The study of dos Santos et al. [16] reported that positive correlations were observed between plasma DPP-4 activity and LV end-diastolic pressure and lung congestion in rats.

We did not know whether 50 mg sitagliptin could successfully inhibit plasma DPP-4 activity. We used 50 mg of sitagliptin, which is a standard starting dosage for this medication in Japan, however, outside of Japan, double this dose, i.e. 100 mg of sitagliptin, is generally used. A meta-analysis revealed that, despite the smaller sitagliptin dose of only 50 mg, a greater HbA1c reduction (−0.99 % versus placebo) was observed in Japanese than in non-Japanese patients [36].

Thirdly, because of the small number of patients, we could not assess whether sitagliptin or pioglitazone can attenuate HF events in patients, as this study is statistically underpowered.

Fourth, 6-month treatment might be too short to improve the e’ velocity or E/e’ ratio. Fifth, echocardiographic studies were performed at each institution by experienced physicians or sonographers and the results were sent to the study center for analysis. These processes are close to those pertaining to real, clinical situations, and diastolic function echocardiographic parameters were supposed to be highly reproducible if performed by experts [37], but inter-institution variability in the examinations may exist and may have influenced the results of this study.

To estimate the inter-institution variability is difficult because the number of cases per institution were too low to evaluate it.

Finally, selection criteria of this study population are strict. It is because we wanted to assess the net effect of DPP inhibitor on LV diastolic function in this study. It is necessary to note whether your patient corresponds to such a patient population or not.

Conclusion

Our trial showed that sitagliptin reduces HbA1c levels more greatly than voglibose does, but that neither was associated with improvement in the echocardiographic parameters of LV diastolic function in patients with diabetes.

Abbreviations

BMI: 

Body mass index

BNP: 

Brain natriuretic peptide

DPP-4: 

Dipeptidyl peptidase IV

eGFR: 

Estimated glomerular filtration rate

FBS: 

Fasting blood sugar

GIP: 

Gastric inhibitory peptide

GLP-1: 

Glucagon-like peptide-1

GI: 

Glucosidase inhibitor

HF: 

Heart failure

hs-CRP: 

High-sensitivity C-reactive protein

8-OHdG: 

8-hydroxy-2′-deoxyguanosine

IGT: 

Impaired glucose tolerance

MDA-LDL: 

Malondialdehyde-modified low density lipoprotein

NGSP: 

National glycohemoglobin standardization Program

NYHA: 

New York heart association

PTX-3: 

Pentraxin-3

TTE: 

Trans-thoracic echocardiography

TZD: 

Thiazolidinedione

Declarations

Acknowledgements

This study was supported by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases.

The authors would like to thank Tetsutaro Hamano for assistance with statistical analysis. We also thank the 3D study investigators: Kazufumi Nakamura, 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), Tsutomu Takagi, MD (Takagi Cardiology Clinic), Kumiko Hirata, MD (Wakayama Medical University) and Junichi Yoshikawa, MD (Nishinomiya Watanabe Cardiovascular Center).

Financial support

This study was supported by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases.

Authors’ Affiliations

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

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© Oe et al. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), 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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