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Keywords:

  • dipeptidyl peptidase-4;
  • HbA1c;
  • incretin hormones;
  • pioglitazone

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Aim:  The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone to component monotherapy.

Methods:  This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA1c in patients receiving initial combination therapy compared with pioglitazone monotherapy.

Results:  After 24-week treatment, adjusted mean changes in HbA1c from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were −1.4 ± 0.1%, −1.7 ± 0.1%, −1.9 ± 0.1% and −1.1 ± 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were −1.9 ± 0.2, −2.4 ± 0.2, −2.8 ± 0.2 and −1.3 ± 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy.

Conclusions:  First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

The clinical benefits of good glycaemic control are well established [1]. However, the traditional stepwise approach beginning with diet and exercise and sequentially adding and titrating does not address the multifactorial nature of T2DM and the critical value of early intervention to avoid progressive beta-cell failure [2]. The most recent modification of the American Diabetes Association (ADA) recommendations goes beyond the evidence-based target HbA1c of less than 7% for diabetes populations at large and calls for individualized goals for patients to attempt to achieve a HbA1c target as close to normal as possible without significant hypoglycaemia and/or unwanted adverse events (AEs) [3]. This recommendation implies that patients with T2DM will require multiple pharmacological combinations much earlier to accomplish these goals, with careful therapy selection to avoid AEs and hypoglycaemia. Indeed, most recent guidelines for the pharmacological management of T2DM have become more aggressive, with specific recommendations on the progressive use of combination strategies if HbA1c remains more than 7% in an attempt to attain and sustain the increasingly stringent glycaemic targets [4].

However, clinical inertia with failure to advance therapy despite persistently elevated HbA1c levels above target has been a major problem [5,6], but perhaps the increasing use of combination therapy as a first-line intervention in T2DM may facilitate resolution of this compliance issue.

Initial combination therapy using two Oral Antidiabetic Drug (OAD) with complementary mechanisms of action is an alternative approach that may provide better or more sustained glycaemic control, or allow the use of lower doses of the component OADs to minimize any dose-related AEs.

Vildagliptin is a selective dipeptidyl peptidase (DPP)-4 inhibitor that improves glycaemic control in patients with T2DM by increasing both α- and β-cell responsiveness to glucose [7,8]. Vildagliptin has been shown to decrease HbA1c when given as monotherapy [9,10] or in combination with metformin [11], but its effects in combination with a thiazolidinedione (TZD) remain to be determined.

The present study compared the efficacy and tolerability of initial combination therapy with vildagliptin, which improves islet function, and the TZD pioglitazone, which enhances insulin sensitivity, to the monotherapy components. For the monotherapy arms, doses of 100 mg q.d. for vildagliptin and 30 mg q.d. for pioglitazone were chosen and compared with the combination of vildagliptin/pioglitazone (100/30 mg q.d.) and to a low-dose combination of 50/15 mg q.d.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Study design

This was a 24-week, double-blind, randomized, active-controlled, parallel-group study conducted at 145 centres in eight countries, including the United States, four countries in Europe and three in Asia. Eligible patients were randomized to receive vildagliptin 100 mg q.d. (n = 154), pioglitazone 30 mg q.d. (n = 161), or a vildagliptin/pioglitazone combination of 100/30 mg q.d. (‘high dose’, n = 148) or 50/15 mg q.d. (‘low dose’, n = 144). The doses of pioglitazone used were selected based on those recommended (for either monotherapy or combination with a sulfonylurea or metformin) in the prescribing information. Treatment blinding was maintained with a double-dummy technique.

Study population

The study enrolled patients diagnosed with T2DM and who had HbA1c between 7.5 and 11.0% at screening while receiving no pharmacological treatment for at least 12 weeks prior to screening and no OAD for more than three consecutive months at any time in the past. Male and female patients aged 18–80 years, body mass index (BMI) range of 22–45 kg/m2 and with FPG <15 mmol/l were eligible to participate.

Patients were excluded if they had a history of type 1 or secondary forms of diabetes, acute metabolic diabetic complications, myocardial infarction, unstable angina or coronary artery bypass surgery within the previous 6 months, congestive heart failure, liver disease such as cirrhosis or chronic active hepatitis, or any contraindications and warnings according to the country-specific label for pioglitazone. Patients with any of the following laboratory abnormalities were also excluded: alanine aminotransferase or aspartate aminotransferase >2.5 times the upper limit of normal (ULN); direct bilirubin >1.3 times the ULN; serum creatinine levels >220 μmol/l, clinically significant abnormal TSH or fasting triglycerides (TGs) >7.9 mmol/l.

Study assessments

HbA1c, fasting plasma glucose (FPG), body weight and vital signs were measured at each study visit. Standard haematology and biochemistry laboratory assessments were made at each visit except week 16. Fasting lipid profiles and free fatty acids (FFA) were measured, and ECGs were performed at screening (week −2) and at weeks 0, 12 and 24. Standard breakfast meal tests (500 kcal; 60% CHO, 30% fat and 10% protein) were performed at week 0 and week 24 or study endpoint for assessment of prandial glucose control and β-cell function in patients agreeing to participate (approximately 19% of randomized patients). Insulin secretory rate (ISR) was calculated by deconvolution of plasma C-peptide levels [12]. The 2-h area under the curve (AUC) for ISR and glucose were calculated with the trapezoidal method, and the ratio of ISR AUC to glucose AUC was used as a measure of β-cell function.

All AEs were recorded. Patients were provided with glucose monitoring devices and supplies and instructed on their use. Hypoglycaemia was defined as symptoms suggestive of low blood glucose confirmed by self-monitored blood glucose (SMBG) measurement <3.1 mmol/l plasma glucose equivalent. Severe hypoglycaemia was defined as any episode requiring the assistance of another party.

All laboratory assessments were made by a central laboratory (Covance-US, Indianapolis, IN, USA) with standardized and validated procedures according to Good Laboratory Practice. HbA1c was measured using ion exchange high-performance liquid chromatography.

Data analysis

The primary efficacy variable was the change from baseline in HbA1c at study endpoint in the intention-to-treat (ITT) population using last observation carried forward for patients who discontinued early. The ITT population comprises all patients who received at least one dose of study medication and for whom a baseline and at least one postbaseline efficacy assessment was available. Secondary efficacy parameters included changes in FPG, fasting plasma lipids and body weight. Changes from baseline in primary and secondary endpoints were analysed using an analysis of variance (ancova) model, with treatment and pooled centre as the classification variables and baseline value as the covariate. The primary comparisons were made to test for superiority of the vildagliptin/pioglitazone combination (100/30 mg q.d.) to pioglitazone monotherapy. Secondary comparisons were made to test for superiority of the vildagliptin/pioglitazone combination (100/30 mg q.d.) to vildagliptin monotherapy and for superiority of the low-dose combination (50/15 mg q.d.) to pioglitazone (30 mg q.d.) monotherapy. Chi-square tests were performed to compare the percentage of patients achieving ADA target HbA1c level at endpoint. Repeated measures ancovas were performed to determine the significance of the between-group differences in HbA1c. Comparability of baseline characteristics across treatment groups was assessed by F test for continuous variables and by Cochran–Mantel–Haenszel chi-square test for categorical variables.

Ethics and good clinical practice

All the participants provided written informed consent. The protocol was approved by the independent ethics committee/institutional review board at each study site, and the study was conducted in accordance with the Declaration of Helsinki, using Good Clinical Practice.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Patients studied

A total of 607 patients were randomized, and 592 comprised the ITT population. Table 1 reports the demographic and baseline metabolic characteristics of the randomized population and figure 1 summarizes disposition of patients from screening through study endpoint. The groups were well balanced, with HbA1c averaging 8.7% and FPG averaging 10.7 mmol/l, with a mean age of 51.5 years and disease duration of 2.1 years in the combined cohort. More than two-third of the patients (70.2%) presented with an HbA1c above 8% and 35%, with an HbA1c above 9%. Reflecting the location of study centres, participants were predominantly Asian (45%) or Caucasian (approximately 40%). Patients were on average overweight, with a mean BMI of 29.2 kg/m2, and a mean waist circumference of approximately 97 cm. The study was completed by ≥80% of patients in each treatment group (figure 1).

Table 1.  Baseline characteristics of the randomized population
Mean ± s.d. or n (%)Pioglitazone 30 mg q.d.Vildagliptin + pioglitazone 50/15 mg q.d.Vildagliptin + pioglitazone 100/30 mg q.d.Vildagliptin 100 mg q.d.p value*
  • BMI (body mass index); FPG (fasting plasma glucose), FFA (free fatty acids).

  • *

    Comparability of baseline characteristics assessed by F test for continuous variables and by Cochran–Mantel–Haenszel chi-square test for categorical variables.

n161144148154 
Age (years)52.4 ± 10.351.0 ± 11.051.0 ± 11.351.4 ± 10.80.6421
Sex 0.5735
 Male103 (64.0)84 (58.3)86 (58.1)98 (63.6) 
 Female58 (36.0)60 (41.7)62 (41.9)56 (36.4) 
Race 0.6256
 Asian69 (42.9)68 (47.2)66 (44.7)70 (45.5) 
 Caucasian71 (44.1)52 (36.1)56 (37.8)60 (39.0) 
 Hispanic or Latino14 (8.7)15 (10.4)23 (15.5)17 (11.0) 
 All other7 (4.3)9 (6.3)3 (2.0)7 (4.5) 
BMI (kg/m2)28.9 ± 5.529.0 ± 5.429.6 ± 5.829.4 ± 5.80.6544
HbA1c (%)8.7 ± 1.08.8 ± 0.98.8 ± 1.18.6 ± 1.00.5208
HbA1c group
 ≤9.0%106 (65.8)93 (64.6)92 (62.2)106 (68.8) 
 >9.0%55 (34.2)51 (35.4)56 (37.8)48 (31.2) 
FPG (mmol/l)10.5 ± 3.110.7 ± 2.710.9 ± 2.710.6 ± 2.70.6370
Disease duration (years)2.2 ± 3.32.0 ± 3.22.0 ± 3.11.9 ± 3.10.8418
Fasting lipid parameters (mmol/l)
Triglycerides2.3 ± 0.12.5 ± 0.22.4 ± 0.12.5 ± 0.10.4485
Total cholesterol5.3 ± 0.15.2 ± 0.15.2 ± 0.15.4 ± 0.10.3473
LDL-cholesterol3.2 ± 0.13.1 ± 0.13.1 ± 0.13.2 ± 0.10.6136
HDL-cholesterol1.13 ± 0.031.10 ± 0.031.09 ± 0.021.09 ± 0.030.6011
Non-HDL-cholesterol4.1 ± 0.14.1 ± 0.14.1 ± 0.14.3 ± 0.10.2490
FFA0.51 ± 0.030.57 ± 0.030.62 ± 0.030.58 ± 0.030.0229
image

Figure 1. Disposition of patients from screening through completion. ITT, intention-to-treat ; AE, adverse event; ALV, abnormal laboratory value; UTE, unsatisfactory therapeutic event; PV, protocol violation; PWC, patient withdrew consent; LFU, lost to follow up; Adm, administrative problems.

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Efficacy

Figure 2 depicts the time course of the mean HbA1c during 24-week treatment (panel A), and the percentage of patients achieving ADA-recommended target level of HbA1c (<7.0%) at study endpoint (panel B). Mean HbA1c decreased progressively during the first 16 weeks of treatment then tended to remain stable from week 16 to week 24 in each treatment group. The adjusted mean reduction in HbA1c from baseline to endpoint was significantly greater in patients receiving either the 100/30 mg combination (−1.9 ± 0.1%, p < 0.001) or the 50/15 mg combination (−1.7 ± 0.1%, p = 0.039) than in patients receiving pioglitazone monotherapy (−1.4 ± 0.1%). The adjusted mean change in HbA1c in patients receiving vildagliptin monotherapy was −1.1 ± 0.1% (p < 0.001 vs. 100/30 mg). As illustrated in figure 2b, a significantly higher percentage of patients (65.0%) receiving the high-dose combination had endpoint HbA1c < 7.0% than patients receiving monotherapy with either pioglitazone (42.9%, p < 0.001) or vildagliptin (42.5%, p < 0.001).

image

Figure 2. (a) Mean (±s.e.) HbA1c during 24-week treatment with vildagliptin (100 mg q.d., open circles, n = 150 at baseline, 136 at week 24), pioglitazone (30 mg q.d., open squares, n = 157 at baseline, 135 at week 24) or vildagliptin combined with pioglitazone at doses of 100/30 mg q.d. (closed triangles, n = 146 at baseline, 128 at week 24) or 50/15 mg q.d. (closed diamonds, n = 139 at baseline, 114 at week 24) in drug-naive patients with T2DM. ***p < 0.001 for vildagliptin/pioglitazone (vilda/pio) 100/30 mg q.d. vs. pioglitazone monotherapy. p values for vildagliptin/pioglitazone 50/15 mg q.d. vs. pioglitazone monotherapy at weeks 4, 12, 16 and 24 were 0.039, 0.003, 0.006 and 0.020 respectively. (b) Percentage of patients achieving endpoint HbA1c < 7.0%. Pioglitazone monotherapy (30 mg q.d., open bars, n = 157); high-dose vildagliptin/pioglitazone combination (100/30 mg q.d., checkered bars, n = 146); low-dose vildagliptin/pioglitazone combination (50/15 mg q.d., hatched bars, n = 139); vildagliptin monotherapy (100 mg q.d., closed bars, n = 150). ***p < 0.001 combo vs. either monotherapy.

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A preplanned subanalysis of the primary endpoint was also performed based on initial HbA1c level. In patients with baseline HbA1c > 9.0% receiving the high-dose combination, the mean change from a baseline HbA1c of 10.0% was −2.8 ± 0.2%. In those receiving the low-dose combination, vildagliptin monotherapy or pioglitazone monotherapy the mean changes from baseline HbA1cs of 9.8, 9.9 and 9.8% respectively, were −2.3 ± 0.2%, −1.5 ± 0.2% and −1.8 ± 0.2% respectively (figure 3).

image

Figure 3. Mean change from baseline to endpoint in HbA1c in patients with baseline HbA1c > 9.0%. Pioglitazone monotherapy (30 mg q.d., open bars, n = 54); high-dose vildagliptin/pioglitazone (vilda/pio) combination (100/30 mg q.d., checkered bars, n = 54); low-dose vildagliptin/pioglitazone combination (50/15 mg q.d., hatched bars, n = 49); vildagliptin monotherapy (100 mg q.d., closed bars, n = 46). ***p < 0.001 combo vs. pioglitazone monotherapy.

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Fasting glucose, meal tests, fasting lipids and body weight

Figure 4a depicts the time course of the mean FPG during 24-week treatment with the vildagliptin/pioglitazone combination or component monotherapy. Fasting glucose decreased sharply from baseline to week 4 in each group of patients. In those receiving vildagliptin monotherapy, FPG was stable from week 4 to week 24. In patients receiving either combination dose strength or pioglitazone monotherapy, FPG decreased from week 4 to week 12 and remained stable from week 12 to week 24. The adjusted mean change in FPG was −1.9 ± 0.2, −2.4 ± 0.2, −2.8 ± 0.2 and −1.3 ± 0.2 mmol/l in patients receiving pioglitazone monotherapy, low-dose combination, high-dose combination and vildagliptin monotherapy respectively. The decrease with both the high-dose (p < 0.001) and low-dose combination (p = 0.022) was significantly greater than with pioglitazone monotherapy.

image

Figure 4. (a) Mean (±s.e.) FPG during 24-week treatment with vildagliptin (100 mg q.d., open circles, n = 150 at baseline, 135 at week 24), pioglitazone (30 mg q.d., open squares, n = 157 at baseline, 134 at week 24), or vildagliptin combined with pioglitazone at doses of 100/30 mg q.d. (closed triangles, n = 146 at baseline, 128 at week 24) or 50/15 mg q.d. (closed diamonds, n = 139 at baseline, 116 at week 24) in drug-naive patients with T2DM. ***p < 0.001 for vildagliptin/pioglitazone (vilda/pio) 100/30 mg q.d. vs. pioglitazone monotherapy. p values for vildagliptin/pioglitazone 50/15 mg q.d. vs. pioglitazone monotherapy at weeks 4, 12, 16 and 24 were 0.030, 0.017, 0.040 and 0.036 respectively. (b) Adjusted mean (±s.e.) change in peak prandial glucose excursion during meal tests after 24-week treatment with pioglitazone monotherapy (30 mg q.d., open bars, n = 26), low-dose vildagliptin/pioglitazone combination (50/15 mg q.d., hatched bars, n = 27), high-dose vildagliptin/pioglitazone combination (100/30 mg q.d., checkered bars, n = 27) or vildagliptin monotherapy (100 mg q.d., closed bars, n = 32). *p < 0.05, ***p < 0.001 combo vs. pioglitazone monotherapy. (c) Adjusted mean (±s.e.) change in β-cell function index (insulin secretory rate AUC0–120÷ glucose AUC0–120) excursion during meal tests after 24-week treatment with pioglitazone monotherapy (30 mg q.d., open bars, n = 9), low-dose vildagliptin/pioglitazone combination (50/15 mg q.d., hatched bars, n = 11), high-dose vildagliptin/pioglitazone combination (100/30 mg q.d., checkered bars, n = 11) or vildagliptin monotherapy (100 mg q.d., closed bars, n = 10). *p < 0.05 vs. pioglitazone monotherapy.

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A standard breakfast meal challenge was performed at baseline and endpoint in a subset of patients with baseline characteristics representative of the ITT population. The incremental glucose AUC0–4h at baseline averaged 13.8 ± 1.1, 13.9 ± 1.2, 13.4 ± 1.5 and 14.2 ± 1.2 mmol/l h in patients randomized to pioglitazone monotherapy, low-dose combination, high-dose combination and vildagliptin monotherapy respectively. Relative to baseline, this decreased significantly in each treatment group, and relative to pioglitazone monotherapy, the decrease was significantly greater with both the low-dose combination (between-group difference in the adjusted mean change in incremental glucose AUC0–4h=−3.8 ± 1.6 mmol/l h, p = 0.024) and the high-dose combination (−5.2 ± 1.3 mmol/l h, p < 0.001).

Figure 4 also depicts the adjusted mean changes in peak prandial glucose excursions (panel B) and the β-cell function index (insulin secretory rate AUC0–2h÷ glucose AUC0–2h, panel C) during the standard meal tests. The peak prandial glucose excursion was significantly decreased relative to baseline in each treatment group, and relative to pioglitazone monotherapy, the peak prandial glucose excursion was significantly decreased in patients receiving low-dose (−1.1 ± 0.5 mmol/l, p = 0.017) or high-dose (−2.0 ± 0.4 mmol/l, p < 0.001) combination treatment. Beta-cell function improved relative to baseline in patients receiving vildagliptin monotherapy and both combination treatment groups. Relative to pioglitazone monotherapy, β-cell function was significantly increased in patients receiving the low-dose combination (+8.0 ± 3.7 pmol/min/m2/mmol/l, p = 0.046), but the between-treatment difference (combination – pioglitazone) in the adjusted mean change in the β-cell function index was not statistically significant for the 100/30 mg combination treatment group (5.5 ± 4.1 pmol/min/m2/mmol/l, p = 0.196).

Table 2 reports the changes in fasting lipid parameters observed during 24-week treatment with vildagliptin, pioglitazone, low-dose and high-dose combination. Monotherapy with pioglitazone decreased fasting TG (−13.4%), but increased HDL-cholesterol (+17.5%) and LDL-cholesterol (+9.1%). Monotherapy with vildagliptin decreased fasting TG (−5.8%) and increased HDL-cholesterol (+7.7%). Low-dose combination therapy decreased TG (−4.8%) and increased HDL-cholesterol (+10.6%). All other changes in lipids in these three treatment arms were minimal (less than 3% change from baseline). The high-dose combination improved all fasting lipid parameters relative to baseline, and relative to pioglitazone monotherapy, the 100/30 mg combination elicited significantly greater decreases in total cholesterol (between-group difference =−5.6 ± 1.8%, p < 0.001), LDL (between-group difference =−10.5 ± 4.9%, p = 0.033) and non-HDL-cholesterol (between-group difference =−6.8 ± 2.5% p = 0.008). In addition, small decreases in FFA levels were observed in each treatment group, with the largest improvements being observed in the high-dose combination group (−10%) and the pioglitazone monotherapy group (−5%).

Table 2.  Fasting lipid parameters
Mean ± s.e.nAdjusted mean per cent changeBetween-group difference (combination – pioglitazone)p value
  1. Vilda/pio, vildagliptin/pioglitazone; FFA, free fatty acids.

Triglycerides
 Vildagliptin/pioglitazone 100/30 mg q.d.144−18.1 ± 2.9−4.7 ± 4.10.252
 Vilda/Pio 50/15 mg q.d.136−4.8 ± 3.68.9 ± 5.00.073
 Vildagliptin 100 mg q.d.146−5.8 ± 3.1 
 Pioglitazone 30 mg q.d.155−13.4 ± 2.8 
Total cholesterol
 Vilda/Pio 100/30 mg q.d.144−3.1 ± 1.3−5.6 ± 1.80.001
 Vilda/Pio 50/15 mg q.d.1361.0 ± 1.3−1.4 ± 1.80.448
 Vildagliptin 100 mg q.d.146−1.7 ± 1.3 
 Pioglitazone 30 mg q.d.1552.5 ± 1.2 
LDL-cholesterol
 Vilda/Pio 100/30 mg q.d.129−1.4 ± 3.6−10.5 ± 4.90.033
 Vilda/Pio 50/15 mg q.d.1221.9 ± 3.8−7.1 ± 5.10.164
 Vildagliptin 100 mg q.d.138−0.4 ± 2.1 
 Pioglitazone 30 mg q.d.1469.1 ± 3.4 
HDL-cholesterol
 Vilda/Pio 100/30 mg q.d.14012.1 ± 2.1−5.4 ± 2.90.058
 Vilda/Pio 50/15 mg q.d.13310.6 ± 2.0−7.1 ± 2.70.009
 Vildagliptin 100 mg q.d.1477.7 ± 1.8 
 Pioglitazone 30 mg q.d.15117.5 ± 2.0 
Non-HDL-cholesterol
 Vilda/Pio 100/30 mg q.d.140−7.1 ± 1.8−6.8 ± 2.50.008
 Vilda/Pio 50/15 mg q.d.133−1.2 ± 2.0−0.8 ± 2.70.759
 Vildagliptin 100 mg q.d.146−3.6 ± 1.5 
 Pioglitazone 30 mg q.d.151−0.3 ± 1.8 
FFA
 Vilda/pio 100/30 mg q.d.60−9.9 ± 8.7−4.9 ± 12.30.689
 Vilda/pio 50/15 mg q.d.55−2.5 ± 9.4−1.4 ± 12.60.911
 Vildagliptin 100 mg q.d.53−3.0 ± 12.1 
 Pioglitazone 30 mg q.d.61−5.0 ± 8.8 

Body weight did not change from a mean baseline of 82 kg to endpoint in patients receiving vildagliptin monotherapy (+0.2 ± 0.3 kg), but increased similarly in patients receiving pioglitazone monotherapy (+1.5 ± 0.3 kg) and low-dose combination therapy (+1.4 ± 0.3 kg) from baselines of 81 and 80 kg, respectively. The increase from baseline (82 kg) in body weight in patients receiving the 100/30 mg combination (+2.1 ± 0.3 kg) was also not significantly different from the pioglitazone monotherapy group (between-group difference = 0.7 ± 0.5 kg).

Tolerability

During the 24-week study, all the treatments appeared to be well tolerated. Table 3 reports the number and percentage of patients experiencing the most common specific AEs. The most frequently reported AEs in the study were weight gain, headache and peripheral oedema. The AEs of weight gain and oedema were less common in patients receiving the low-dose combination than in those receiving pioglitazone monotherapy. In addition, these AEs were less common on vildagliptin monotherapy compared with pioglitazone monotherapy. Further, in a predefined analysis, increases in weight of more than 10% from baseline were observed in 2.1% of patients in the low-dose combination group and in 3.7% of patients in the pioglitazone monotherapy group. The majority of AEs reported were classified as mild or moderate and unrelated to study medication. AEs led to discontinuation in 2.6% of patients receiving vildagliptin monotherapy, 6.8% of patients receiving pioglitazone monotherapy, and 6.3% and 4.7% of patients receiving the low-dose and high-dose combination regimens respectively.

Table 3.  Common adverse events (AEs occurring in >3% of any treatment group)
n (%)Pioglitazone 30 mg q.d., n = 161Vildagliptin + pioglitazone 50/15 mg q.d., n = 144Vildagliptin + pioglitazone 100/30 mg q.d., n = 148Vildagliptin 100 mg q.d., n = 153
Any AE83 (51.5)66 (45.8)75 (50.7)78 (51.0)
Weight increased8 (5.0)3 (2.1)11 (7.4)1 (0.7)
Headache5 (3.1)5 (3.5)9 (6.1)5 (3.3)
Peripheral oedema15 (9.3)5 (3.5)9 (6.1)8 (5.2)
Dizziness8 (5.0)3 (2.1)7 (4.7)9 (5.9)
Upper respiratory tract infection7 (4.3)5 (3.5)6 (4.1)6 (3.9)
Asthenia2 (1.2)4 (2.8)5 (3.4)3 (2.0)
Nasopharyngitis6 (3.7)4 (2.8)4 (2.7)4 (2.6)

Hypoglycaemia was limited to one mild event (SMBG >2.8 mmol/l) in one patient each (0.7%) receiving high-dose combination and vildagliptin monotherapy, both precipitated by a missed meal. In addition, one patient in the pioglitazone monotherapy presented an asymptomatic low blood glucose level after strenuous exercise.

Severe AEs were infrequent in all treatment groups, with no apparent relation to treatment or dose of combination therapy.

No major changes or consistent trends over time were observed for any haematological, biochemical, urinalysis parameter or vital signs, and the frequency of treatment-emergent ECG abnormalities was low and comparable in all treatment groups.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

The present study is the first to examine the effects of initial combination therapy with a DPP-4 inhibitor and a TZD as first-line therapy in treatment-naive patients with T2DM. From a theoretical standpoint, combining vildagliptin, which improves both α- [7] and β-cell function [8], and pioglitazone, which enhances peripheral insulin action [13], is an attractive and logical therapeutic approach. Indeed, preclinical studies in Zucker fatty rats showed that this combination fully normalized glucose tolerance when given at doses that were essentially ineffective as monotherapy [14]. Thus, the present findings that first-line treatment with vildagliptin and pioglitazone (both in high- and low-dose combination) provided better glycaemic control than the individual component monotherapy, essentially confirmed the prediction of an enhanced glucose-lowering effect by combining the two approaches. Most notably, despite a relatively high baseline HbA1c (>8% in 70% of the patients), the high-dose combination allowed 65% of patients to achieve the ADA-recommended target level of HbA1c of <7.0% with minimal hypoglycaemia (<1%) and with no increase in body weight relative to pioglitazone monotherapy after 24-week treatment. There were also significant improvements in total, LDL and non-HDL-cholesterol levels with the high-dose combination relative to pioglitazone monotherapy. In line with the potential for DPP-4 inhibition to offer a novel approach to reducing cardiovascular risk in patients with T2DM, it has also been shown that 4-week treatment with vildagliptin significantly decreased postprandial lipaemia [15]. Conclusions regarding the influence of the vildagliptin/pioglitazone combination on the overall cardiovascular-risk profile will require further investigation.

This study also explored whether the dose-related AEs of pioglitazone (e.g. oedema and weight gain) could be avoided by using a lower dose of the TZD combined with vildagliptin. As expected, it was found that, indeed, the low-dose combination (vildagliptin 50 mg/pioglitazone 15 mg) elicited a significantly greater reduction in HbA1c (−1.7%) than did pioglitazone monotherapy with 30 mg (−1.4%) with fewer AEs of peripheral oedema (3.5 vs. 9.3%) and ‘weight increased’ (2.1 vs. 5%).

Given the contribution of both insulin resistance and islet dysfunction to the development and progression of T2DM [16], combining an insulin sensitizer-like pioglitazone and an agent such as vildagliptin, which improves α- and β-cell function, is a rational approach. One mechanistic advantage this offers is that as shown in the present study, there is no increase in hypoglycaemia, as seen when insulin secretagogues are combined with insulin sensitizers [17,18] because the insulinotropic effects of vildagliptin are glucose dependent [19]. Also, unlike sulfonylureas, vildagliptin reduces inappropriate postmeal glucagon secretion in patients with T2DM [7], which contributes significantly to vildagliptin-mediated reductions of postprandial hyperglycaemia [15]. This reduces the ‘demand’ for insulin, mitigating insulin resistance and thus increasing measures of insulin sensitivity as reported recently, both in drug-naive [20,21] and in metformin-treated patients [22].

The mechanism by which TZD activation of PPAR gamma receptors reduces insulin resistance is now relatively well understood [23]. Correcting lipotoxicity by reducing FFA production and TG deposition in target tissues, TZDs improve both hepatic and peripheral insulin sensitivity [24]. Animal studies have shown that TZDs also decrease islet TG content [25], and this is the proposed mechanism by which TZDs may improve islet function [26]. Thus, multiple mechanisms are brought into play with the combination of a DPP-4 inhibitor and a TZD and allow better glycaemic control without hypoglycaemia.

Although a stepwise approach to treatment starting with diet and exercise, addition and titration of a single oral agent, then addition of a second agent is most commonly used, success with this approach is often less than desired. Clinical inertia leads to a progressive cycle of treatment failure, with patients frequently failing to achieve or maintain therapeutic goals [5,6,27]. Further, findings from the Epidemiology of Diabetes Interventions and Complications (EDIC) study of participants in the Diabetes Control and Complications Trial (DCCT) emphasizes the critical value of early and aggressive glycaemic control that results in sustained benefits on diabetes complications [28]. Of course, these findings need to be replicated in patients with T2DM, but it is clear that there are good reasons to make every attempt to get patients to glycaemic targets as early and as safely as possible. Initial combination therapy with a DPP-4 inhibitor and a TZD appears to hold considerable promise in this regard.

In summary, first-line treatment with vildagliptin/pioglitazone (both high- and low-dose regimens) provided better glycaemic control than each component monotherapy with minimal hypoglycaemia. The high-dose combination (100/30 mg q.d.) allowed 65% of patients to achieve target HbA1c < 7%, with a tolerability profile comparable with pioglitazone (30 mg q.d.) monotherapy. The low-dose combination (50/15 mg q.d.) provided both efficacy and tolerability benefit over pioglitazone 30 mg q.d. Thus, we conclude that the initial combination of vildagliptin, a highly selective DPP-4 inhibitor suitable for once daily dosing, and the TZD pioglitazone, simultaneously addresses the multiple defects in T2DM through addressing complementary mechanisms and appears to be an effective means to achieving good glycaemic control while attenuating drug-related AEs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

The authors acknowledge the investigators and staff at the 145 participating sites, the operational support from Yasmina Amiour, and the editorial assistance of, and helpful discussion with Beth Dunning Lower, PhD. This study was funded by Novartis Pharmaceuticals Corporation. A list of investigators is provided in the Appendix. This trial (NCT00101803) is registered with ClinicalTrials.gov.

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  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix
List of investigators

Czech Republic: Dr Stepan Svacina, Dr Zdenek Pistek, Dr Zdena Pavlovka, Dr Eva Talasova, Dr Marie Hornackova. India: Dr Mohan Y. Badgandi, Dr Rakesh Sahay, Dr Nikhil Tandon, Dr C. S. Yagnik. Italy: Prof. Francesco Dotta, Dr Mario Sprovieri, Dr Cecilia Invitti, Prof. Antonio Tiengo, Dr Walter Donadon, Dr Ezio Degli Esposti, Dr Luigi Sciangula, Prof. Diego Geroldi. Korea: Prof. Moon-Kyu Lee, Prof. Kun-Ho Yoon, Prof. Bong-Soo Cha, Prof. Jeong-Taek Woo, Prof. Sun-Woo Kim, Prof. In-Ju Kim, Prof. Jeong-Hyun Park, Prof. Dong-Seop Choi, Prof. Sung-Woo Park, Prof. Kyung-Soo Ko, Prof. Sei-Hyun Baik, Prof. Hyoung-Woo Lee, Dr Hye-Soon Kim, Prof. Tae-Sun Park, Prof. Hak-Chul Jang. Slovakia: Dr Jaroslav Fabry, Dr Marian Hranai, Dr Emil Martinka, Dr Marek Macko, Dr Jarmila Okapcova, Dr Milan Behuncik. Taiwan: Dr Yi-Jen Hung, Dr Chao-Hung Wang, Dr Chwen-Tzuei Chang, Dr Rue-Tsuan Liu, Dr Chuen-Den Tseng, Dr Chien-Wen Chou, Dr Ming-Chia Hsieh. United Kingdom: Dr Paul Goozee, Dr Mary A. Whitehead, Dr Dennis M. Allin, Dr Najib Seedat, Dr Barry Glekin, Dr Arun Baksi, Dr John Calvert, Dr Hugh Jones. Dr John Langan, Dr Geoffrey Butcher. USA: Dr Martin Lester, Dr Spencer B. Jones, Dr Andrew Ahmann, Dr Arthur B. Pitterman, Dr John J. Champlin, Dr Puneet Narayan, Dr Marc S. Rendell, Dr Sriranga V. Prasad, Dr Kashif Latif, Dr Richard H. Egelhof, Dr Naynesh R. Patel, Dr Anne M. Reddy, Dr Berto Zamora, Dr Scott W. Yates, Dr Julio Rosenstock, Dr Jayaram B. Naidu, Dr Hartmut Koelsch, Dr Lawrence Alder, Dr Jane E. Mossberg, Dr Robert S. Lipetz, Dr Richard M. Glover, Dr Gary A. Tarshis, Dr Jewel A. Stevens, Dr Steven K. Elliott, Dr John A. Mallory, Dr Alan D. Forker, Dr Daniel J. Suiter, Dr Thad Clements, Dr Luis E. Morales, Dr James R. Shoemaker, Dr Gary A. Erdy, Dr James E. Gutmann, Dr David C. Subich, Dr Jeff Aalberg, Dr Alan V. Safdi, Dr Stephanie Young, Dr Timothy L. Jackson, Dr Richard Kelly, Dr Marwan N. Sabbagh, Dr Harry S. Studdard, Dr Gregory Smith, Dr Richard B. Christensen, Dr Paul W. Davis, Dr John G. Spangler, Dr Timothy E. Folse, Dr Jane E. Rohlf, Dr Patrick Ogilvie, Dr Michael W. Lin, Dr Ronald Sockolov, Dr John Gaffney, Dr Mariusz Jerzy Klin, Dr Jill M. Constantine, Dr Antoinette A. Pragalos, Dr Sherwyn L. Schwartz, Dr Larry L. Doehring, Dr Paula Springer, Dr Lyndon E. Mansfield, Dr V. Jerome Mirkil, Dr Jerry R. Mitchell, Dr Kimy Charani, Dr John W. McGettigan, Dr Andre Burton, Dr Ellis R. Levin, Dr Michael Delphia, Dr Samuel T. Verzosa, Dr Michael A. Azorr, Dr Eli Ipp, Dr Mario A. Henriquez, Dr Angelique Barreto, Dr Floyd Willis, Dr John Earl, Dr Sajjad A. Savul, Dr John Reinhardt, Dr Alexander White, Dr David M. Witkin, Dr Ronald J. Sell, Dr Christopher J. Superczynski, Dr Tracy T. Phillips, Dr Charles W. Knight, Dr Burton W. Lazar, Dr Beth Koestler, Dr John Mageli, Dr Daniel B. Sheerer, Dr John J. Eck, Dr Gregory A. Ledger, Dr Corey G. Anderson, Dr Martin VanCleef, Dr Rafael Canadas, Dr Joel N. Diamond, Dr Fatima Phillips.