Received Date : 14-Oct-2013
Accepted Article
Revised Date : 01-Mar-2014 Accepted Date : 09-May-2014 Article type
: Research Article
Comparison of vildagliptin and glimepiride: effects on glycaemic
control, fat tolerance and inflammatory markers in people with Type 2 diabetes
G. Derosa1,2, A. Bonaventura1, L. Bianchi1, D. Romano1, E. Fogari1, A. D’Angelo1 and P. Maffioli1
1
Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S.
Matteo, and 2Centre for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University
of Pavia, Pavia, Italy Correspondence: Giuseppe Derosa. E-mail: [email protected]
What's new? •
Vildagliptin was found to cause greater reductions in fasting plasma insulin levels and post-oral fat load insulin peak compared with glimepiride.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dme.12499 This article is protected by copyright. All rights reserved.
•
The homeostasis model assessment of insulin resistance index was shown to increase with
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glimepiride and decrease with vildagliptin. •
Vildagliptin increased the insulin sensitivity index compared with glimepiride.
•
Vildagliptin reduced total cholesterol and LDL cholesterol levels, both during fasting and after an oral fat load test.
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Vildagliptin increased adiponectin and reduced high-sensitivity C-reactive protein levels, both during fasting and after an oral fat load test.
Abstract Aims To compare the effects of vildagliptin with those of glimepiride on glycaemic control, fat tolerance and inflammatory markers in people with Type 2 diabetes mellitus receiving metformin treatment. Methods A total of 167 participants were randomized to vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day, for 6 months. We evaluated the following variables: BMI; glycaemic control; fasting plasma insulin; homeostasis model assessment of insulin resistance index; fasting plasma proinsulin; glucagon; lipid profile; adiponectin; high-sensitivity C-reactive protein; interleukin-6; and tumour necrosis factor-α. A euglycaemic-hyperinsulinaemic clamp procedure and an oral fat load test were also performed. Results Despite a similar decrease in HbA1c levels (P = 0.009, and P = 0.008, respectively), body weight
increased with glimepiride (P = 0.048 vs baseline) and decreased with vildagliptin (P = 0.041 vs baseline and vs glimepiride). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were significantly lower with vildagliptin compared with glimepiride (P = 0.035 and 0.047). M value, an index of insulin sensitivity, increased with vildagliptin, both compared with baseline and with glimepiride (P = 0.028 and 0.039, respectively). Vildagliptin improved all post-oral fat load peaks of lipid profile compared with glimepiride. Adiponectin levels were higher (P = 0.035) and high-sensitivity C-reactive protein levels were
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lower (P = 0.038) with vildagliptin vs glimepiride. During the oral fat load test, interleukin-6, high-sensitivity
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C-reactive protein and tumour necrosis factor-α peaks were lower and adiponectin peak was higher in the vildagliptin group than in the glimepiride group. There was a higher dropout rate as a result of hypoglycaemia in the glimepiride group than in the vildagliptin group. Conclusions Vildagliptin was more effective than glimepiride in reducing post-oral fat load peaks of lipidtrafficking adipocytokines and inflammatory markers.
Introduction Targeting hyperglycaemia is of key importance in the management of Type 2 diabetes mellitus, because lowering glycaemia reduces both acute symptoms and the risk of retinopathy and cardiovascular disease [1]. The key defect underlying hyperglycaemia in Type 2 diabetes is islet dysfunction, which has three components: impaired insulin secretion [2]; defective suppression of glucagon secretion [3]; and reduced islet cell mass [4]. For a long time, sulfonylureas have been recommended as a second-line treatment for Type 2 diabetes when metformin alone was not enough to achieve adequate glycaemic control [5]; however, despite being effective in improving glycaemic control, sulfonylurea use is limited by the high rate of hypoglycaemia [6]. Recent breakthroughs in the understanding of incretin-based therapies have provided additional options for the treatment of Type 2 diabetes, including glucagon-like peptide-1
receptor agonists [7] and dipeptidyl peptidase-4 inhibitors [8]. Among dipeptidyl peptidase-4 inhibitors, vildagliptin has been licensed at the recommended dose of 50 mg twice daily, in combination with either metformin or pioglitazone, and at the recommended dose of 50 mg once daily in combination with sulfonylureas where glycaemic control is suboptimal [9]. Vildagliptin administered 50 mg twice a day in addition to metformin, proved to have a positive action on β-cell function [10], on reducing some
adipocytokine levels related to inflammation [11] and on insulin resistance [12] compared with placebo. Recent studies have shown associations between postprandial lipid trafficking and cardiovascular disease in people with Type 2 diabetes [13]. Postprandial clearance of dietary fat from the circulation can take at least
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12 h [14]. Postprandial serum lipid metabolism may be improved as insulin sensitivity is enhanced by
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augmentation of glucagon-like peptide-1 levels with dipeptidyl peptidase-4
inhibition [15,16].
Adipocytokines and inflammatory peptides may also be influenced by these inter-related metabolic processes. To date, there have been no studies directly assessing the effect of vildagliptin on postprandial lipid trafficking. The aim of the present study, therefore, was to compare the effects of vildagliptin with those of glimepiride on both fasting and post-meal glycaemia, lipid profiles and inflammatory markers in people with Type 2 diabetes mellitus. All these factors had been suboptimally controlled with metformin monotherapy.
Materials and methods Study design This randomized, double-blind, controlled study was conducted at the Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. The study protocol was approved by our institutional review board and was conducted in accordance with the Declaration of Helsinki and its amendments.
Participants We enrolled 178 white people aged ≥ 18 years, of both sexes, with Type 2 diabetes mellitus, according to the criteria included in the European Society of Cardiology and European Association for the Study of Diabetes guidelines [17], and with uncontrolled Type 2 diabetes mellitus [HbA1c53–75 mmol/mol (7.0–
9.0%)] who were receiving metformin therapy at the maximum tolerated dose. Suitable participants, identified from review of case notes and/or computerized clinic registers, were contacted by the investigators in person or by telephone. Anti-hypertensive drugs, which modify glucose and lipid metabolism, were maintained unchanged during the study.
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Subjects with uncontrolled hypertension (systolic blood pressure ≥160 mmHg and diastolic blood pressure
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≥90 mmHg) were not included in the study. Subjects were also excluded if they had a history of ketoacidosis or had unstable or rapidly progressive diabetic retinopathy, nephropathy or neuropathy, impaired hepatic function (defined as plasma aminotransferase and/or gamma-glutamyltransferase levels higher than the upper limit of normal for age and sex), impaired renal function (defined as serum creatinine level higher than the upper limit of normal for age and sex), or severe anaemia. Those taking statins or drugs affecting lipid profile were also excluded to avoid interference with the oral fat load test, as well as those with serious cardiovascular disease (e.g. New York Heart Association class I–IV congestive heart failure or a history of myocardial infarction or stroke) or cerebrovascular conditions within 6 months before study enrolment. People with a history of pancreatitis were excluded. Women who were pregnant or breastfeeding or of childbearing age and not taking adequate contraceptive precautions were also excluded. All participants provided written informed consent to participate.
Treatment After 1 month of active run-in, during which the metformin dose was kept stable, participants were assigned to receive, in addition to metformin, vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day for 6 months. Both vildagliptin and glimepiride were supplied as identical, opaque, white capsules in coded bottles to ensure the blind status of the study. All medications were provided free of charge, thanks to funding made available by the University of Pavia. Randomization was performed by drawing envelopes containing randomization codes prepared by a statistician. The code was only available to the person responsible for the statistical analysis. The code was only broken after database lock, but could have been broken for individual participants in case of emergency. Medication compliance was assessed by counting the number of pills returned at the time of specified clinic visits. At baseline, we weighed participants and gave them a bottle containing a supply of study medication for at least 100 days. Throughout the study, we instructed the participants to take their
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first dose of new medication on the day after they received it. At the same time, all unused medication was
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retrieved for inventory.
Diet and Exercise Participants began a controlled-energy diet (~600 kcal daily deficit), based on American Heart Association recommendations [18], that included 50% of calories from carbohydrates, 30% from fat (6% saturated) and 20% from proteins, with a maximum cholesterol content of 300 mg/day and 35 g/day of fibre. Participants did not receive vitamins or mineral preparations during the study. Standard dietary advice was given by a dietician and/or specialist doctor. A dietician and/or specialist doctor provided monthly instruction on dietary intake recording procedures as part of a behaviour modification programme and later used the participant’s food diaries for counselling. The participants were also encouraged to increase their physical activity by walking briskly for 20–30 min, 3–5 times per week, or by cycling. The recommended changes in physical activity throughout the study were assessed at each visit using the participant’s activity diary.
Assessments Before starting the study, all participants underwent an initial screening assessment that included a medical history, physical examination, vital signs and a 12-lead electrocardiogram. BMI, HbA1c, fasting plasma
glucose, postprandial plasma glucose and fasting plasma insulin levels, homeostasis model assessment of insulin resistance index, fasting plasma proinsulin levels, fasting plasma proinsulin/fasting plasma insulin ratio, glucagon, total cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides, adiponectin, high-
sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α were evaluated at baseline, at randomization and after 3 and 6 months. Furthermore, at the time of randomization and at the end of the
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study all participants underwent a euglycaemic-hyperinsulinaemic clamp procedure to evaluate M value, an
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index of insulin sensitivity, and an oral fat load test.
For the tolerability assessments, all adverse events were recorded. All plasma variables were determined after a 12-h overnight fast, with the exception of postprandial plasma glucose, determined 2 h after a standardized meal. Venous blood samples were taken for all participants between 08:00 and 09:00 h. We used plasma obtained by addition of Na2-EDTA 1 mg/ml, and centrifuged at 3000 × g for 15 min at 4°C.
Immediately after centrifugation, the plasma samples were frozen and stored at -80°C for no more than 3 months. All measurements were performed in a central laboratory. Measurement of single variables and the glucose clamp technique used have been described previously [12,19,20].
Oral fat load test The oral fat load test was performed between 08:00 and 09:00 h after a 12-h fast and a 3-day abstention from alcohol intake. Participants were also asked to refrain from heavy exercise during the preceding days. The test drink consisted of 350 ml whipping cream (35 % fat), ~30 ml chocolate-flavoured syrup, ~15 g granulated sugar and ~15 g instant non-fat dried milk. This drink contained 1147 kcal, of which 12% were from protein, 20% from carbohydrate and 68% from fat. It had 472 mg cholesterol and a polyunsaturated/saturated ratio of 0.06. A weight-adjusted meal (1 g fat per kg body weight) was served with ~400 ml of the mixture. The fat load mixture was consumed within 10 min. After the ingestion of the oral fat load, participants were only allowed to drink water during the following 12 h. Blood samples were drawn before and 3, 6, 9 and 12 h after the oral fat load. Participants were required to sit in the hospital hall; only walking at standard pace within the hospital perimeter was permitted.
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Statistical Analysis
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A per-protocol analysis was conducted in participants who completed the study. With a difference of at least 10% compared with the baseline taken to indicate clinical significance and an α error of 0.05, the actual sample size was adequate to obtain a power > 0.80 for all measured variables. Continuous variables were tested using two-way repeated-measures ANOVA to assess overall differences in postprandial
responses. The incremental area under the curve was calculated as the increased response above baseline minus any drop below baseline, based on the trapezoid rule. Non-parametric tests were also used in the statistical analysis, when the data were not normally distributed (Kolmogorov–Smirnov test). Outcome variables with a skewed distribution were transformed to a log scale before statistical testing. Intervention effects were adjusted for additional potential confounders (sex, smoking status) using ANCOVA. ANOVA was
also used to assess the significance within and between groups. The statistical significance of the independent effects of treatments on the other variables was determined using ANCOVA taking the baseline level of each variable as a covariate. Paired tests were also used: a one-sample t-test to compare values obtained before and after treatment administration and two-sample t-tests to compare the change score (final minus baseline) for a given variable between the two groups. Statistical analysis of data was performed using SPSS software version 14.0 (SPSS Inc., Chicago, IL, USA). Data are presented as means ± SD. For all statistical analyses, a P value < 0.05 was taken to indicate statistical significance.
Results A total of 178 participants were enrolled in the study. Of these, 167 were randomized and 153 completed the study (Fig. 1). A higher dropout rate as a result of hypoglycaemia was recorded in the glimepiride group. Concurrent medications taken by participants are listed in Table 1.
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After 6 months, there was an increase in body weight with glimepiride compared with baseline (P = 0.048),
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and a decrease in body weight with vildagliptin, compared with baseline and with glimepiride (P = 0.041 for both; Table 2). A similar decrease in HbA1c, fasting plasma glucose and postprandial plasma glucose was recorded with
both glimepiride and vildagliptin after 3 and 6 months, with no differences between groups (Table 2).
No variations in lipid profile were recorded in the glimepiride group, while in the vildagliptin group there were reductions in total cholesterol (P = 0.032), LDL cholesterol (P = 0.046) and triglycerides (P = 0.047) after 6 months compared with baseline and with glimepiride (P = 0.048, 0.044 and 0.041, respectively). No changes in HDL cholesterol were observed, but the total cholesterol/HDL cholesterol ratio was lower with vildagliptin, both compared with baseline (P = 0.023) and with glimepiride (P = 0.032; Table 2).
Fasting plasma insulin increased after 6 months of glimepiride (P = 0.046), but did not change with vildagliptin. The fasting plasma insulin levels in the vildagliptin group were lower than those in the glimepiride group at the end of the study. Homeostasis model assessment of insulin resistance index was higher in the glimepiride group after 6 months, while it was lower in the vildagliptin group, both compared with baseline and with glimepiride (P = 0.041 and 0.047, respectively). Fasting plasma proinsulin decreased with both treatments vs baseline (P = 0.044 in the glimepiride group and P = 0.040 in the vildagliptin group). The fasting plasma proinsulin/fasting plasma insulin ratio decreased with both glimepiride and vildagliptin (P = 0.042, and 0.043, respectively; Table 2). Glucagon levels decreased after 6 months of vildagliptin, although no differences were recorded in the between-group comparison. There was an increase in M value at the end of the study in the vildagliptin group, and this difference was significant, both compared with baseline and with the glimepiride group (P = 0.028 and 0.039, respectively; Table 2).
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Adiponectin levels increased after 6 months with both glimepiride (P = 0.034 vs baseline) and vildagliptin (P
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= 0.002 vs baseline), but the adiponectin levels in the vildagliptin group were significantly higher than those in the glimepiride group (P = 0.035). Both glimepiride and vildagliptin decreased high-sensitivity C-reactive protein (P = 0.041 and 0.021, respectively), but the decrease was greater with vildagliptin than with glimepiride (P = 0.038). There were trends towards reductions in interleukin-6 and tumour necrosis factor-α in the vildagliptin group and not in the glimepiride group, but this difference did not achieve statistical significance (Table 2). There were significant differences in post-oral fat load peaks between the glimepiride and the vildagliptin groups. In particular, vildagliptin reduced fasting plasma insulin, total cholesterol, LDL cholesterol and triglyceride post-oral fat load peaks, and increased HDL cholesterol peak compared with glimepiride. Interleukin-6, high-sensitivity C-reactive protein and tumour necrosis factor-α peaks were also reduced, and the adiponectin peak was increased by vildagliptin compared with glimepiride. Figures 2 and 3 show all the variations among the different variables during oral fat load. The area under the curve values, calculated during the baseline oral fat load and the end of study oral fat load in each group, are shown in Table 3.
Discussion In the present study we observed similar effects of vildagliptin to those of glimepiride in improving glycaemic control, with vildagliptin treatment also resulting in body weight reductions. This confirmed the results already reported by Ferrannini et al. [21] and Matthews et al. [22]. These authors reported that
vildagliptin and glimepiride treatment resulted in the same reduction in HbA1c levels, with glimepiride
causing more hypoglycaemic events and body weight gain. With regard to insulin resistance and insulin secretion, vildagliptin decreased the homeostasis model assessment of insulin resistance index, and increased the M value compared with glimepiride. In addition, it led to a reduction in fasting plasma proinsulin/fasting plasma insulin ratio, suggesting a protective action of
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vildagliptin on β-cells. An increased ratio of proinsulin to insulin, in fact, is considered to be an early marker
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of islet dysfunction resulting from a disproportionate release of proinsulin from β-cells [23]. This is consistent with our previous study comparing vildagliptin, glimepiride and pioglitazone [24]. With regard to oral fat load, previously reported data showed that an oral fat load induces a complex and massive systemic inflammatory response that includes an increase of interleukin-6, tumour necrosis factor-α, high-sensitivity C-reactive protein and cell adhesion molecules, even before triglycerides significantly rise [25]. Studies have also shown that nitrites/nitrates and adiponectin levels significantly decreased and metalloproteinases-2 and -9 significantly increased after a standardized oral fat load in healthy participants [26]. These data have also been confirmed in people with hypertension [27] and in people with dyslipidaemia [28,29]. The antidiabetic drug acarbose 100 mg three times a day was more effective than placebo in improving glycaemic control and lipid profile, in reducing the post-oral fat load peaks of various markers, including insulin resistance biomarkers, and in reducing various inflammatory markers, after 7 months of therapy [30,31]. A comparison of pioglitazone and glibenclamide showed that pioglitazone was more effective in mitigating the variations of lipid components and inflammation markers in people with Type 2 diabetes after an oral fat load [32]. In the present study, vildagliptin proved to be more effective than glimepiride in reducing post-oral fat load peaks of lipid-trafficking adipocytokines and inflammatory markers. This is consistent with a study by Barbieri et al. [33] that assessed the effect of dipeptidyl peptidase-4 inhibitors on intima-media thickness, a surrogate marker for early atherosclerosis. They observed that both sitagliptin and vildagliptin reduced intima-media thickness, probably through the reduction of daily inflammation and oxidative stress. Vildagliptin was shown to be more effective than sitagliptin in reducing intima-media thickness, probably because of its greater ability to reduce daily glucose excursions [34]. Reduction of daily glucose excursions led to a reduction in hypoglycaemic events, with a consequent lower activation of the sympathetic system. Activation of the sympathetic system has numerous implications, including surges of heart rate and blood pressure and also increases in pro-inflammatory and pro-coagulant effects. This hypothesis will be further evaluated in a currently ongoing trial [35].
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The present study has some limitations, such as its short duration and the fact that we did not evaluate if
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the beneficial effects of vildagliptin were sustained after the cessation of therapy. Another limitation is that we evaluated a limited number of adipocytokines, concentrating our attention on a few of these. Longer studies are needed to investigate whether the positive effects of vildagliptin on inflammation levels could lead to a reduction in the number of cardiovascular events linked to Type 2 diabetes. In conclusion, despite having a similar effect on glycaemic control, vildagliptin proved to be more effective than glimepiride in protecting β-cell function and in reducing post-oral fat load peaks of lipid-trafficking adipocytokines and inflammatory markers.
Funding sources None.
Competing interests None declared.
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FIGURE 1 Reasons for patients premature withdrawal from the study from baseline to the end of the study. FIGURE 2 Variations in metabolic variables during the oral fat load test in the glimepiride group (n =70) and the vildagliptin group (n =83) at the end of the study. ^P< 0.05 vs glimepiride.
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FIGURE 3 Inflammatory marker variations during oral fat load in the glimepiride group (n =70) and the +
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vildagliptin (n =83) group at the end of the study. ^P< 0.05 vs glimepiride; P< 0.01 vs glimepiride.
Table 1 Concomitant medications taken by participants during the study Glimepiride, n (%)
Vildagliptin, n (%)
81
86
Anti-hypertensive drugs
52 (64.2)
55 (63.9)
Angiotensin-converting enzyme inhibitors
24 (46.1)
Angiotensin receptor blockers
23 (44.2)
Calcium antagonists
17 (32.7)
20 (36.4)
5 (9.6)
4 (7.3)
10 (19.2)
12 (21.8)
Anti-aggregant therapy
49 (60.5)
47 (54.6)
Acetylsalicylic acid
42 (85.7)
40 (85.1)
Ticlopidine
5 (10.2)
4 (8.5)
Clopidogrel
2 (4.1)
3 (6.4)
No. participants
β-blockers
Diuretics
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24 (43.6)
28 (50.9)
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Table 2 Data variations for patients completing the study in both glimepiride (70 participants) and vildagliptin (83 participants) group
Participants, n Sex, M/F
Glimepiride
Vildagliptin
P vs baseline
Baseline
6 months
Baseline
6 months
70
70
83
83
36/34
36/34
42/44
42/41
P vs glimepiride
Glimepiride Vildagliptin
Mean ± SD age, years
56.8 ± 8.9
59.8 ± 9.9
Smoking status, M/F
11/10
Mean ± SD diabetes duration, months
6.7 ± 3.5
6.9 ± 4.7
Mean ± SD height, m
1.67 ± 0.06
1.66 ± 0.05
Mean ± SD weight, kg
77.2 ± 6.3
78.2 ± 6.9
77.8 ± 6.9
76.3 ± 6.0
0.048
0.041
0.041
Mean ± SD BMI, kg/m2
27.7 ± 1.3
28.0 ± 1.7
27.9 ± 1.6
27.4 ± 1.2
0.047
0.044
0.049
Mean ± SD HbA1c, mmol/mol
62 ± 12
50 ± 20
63 ± 14
52 ± 19
0.009
0.008
0.081
Mean ± SD HbA1c, %
7.8 ± 0.8
6.7 ± 0.3
7.9 ± 0.9
6.9 ± 0.4
0.006
0.007
0.089
Mean ± SD fasting plasma glucose, mmol/l
7.7 ± 0.9
6.9 ± 0.4
7.8 ± 1.0
7.1 ± 0.6
0.009
0.009
0.081
Mean ± SD postprandial plasma glucose, mmol/l
9.8 ± 1.1
8.8 ± 0.7
10.1 ± 1.3
9.1 ± 0.8
0.008
0.009
0.073
Mean ± SD fasting plasma insulin, μU/ml
18.3 ± 3.8
20.1 ± 5.2
19.1 ± 4.4
18.4 ± 3.9
0.046
0.055
0.035
Mean ± SD HOMA-IR
6.26 ± 2.23
6.16 ± 2.59
6.62 ± 2.42
5.81 ± 1.84
0.091
0.041
0.047
Mean ± SD fasting plasma proinsulin, μU/ml
5.57 ± 3.94
4.10 ± 2.89
5.87 ± 4.35
4.45 ± 3.11
0.044
0.040
0.053
9/11
14/11
13/11
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0.304 ± 1.33
0.204 ± 1.07
0.307 ± 1.44
0.242 ± 1.19
0.042
0.043
0.086
Mean ± SD glucagon, pmol/l
57.2 ± 8.2
50.2 ± 6.3
59.6 ± 9.7
47.1 ± 5.2
0.063
0.035
0.059
Mean ± SD M value, μmol/min/kg)
5.1 ± 2.4
5.7 ± 3.3
5.3 ± 2.8
6.3 ± 3.9
0.071
0.028
0.039
Mean ± SD total cholesterol, mmol/l
4.9 ± 0.5
4.9 ± 0.5
5.01 ± 0.6
4.6 ± 0.4
0.098
0.032
0.048
Mean ± SD LDL cholesterol, mmol/l
3.6 ± 0.4
3.5 ± 0.4
3.6 ± 0.4
3.2 ± 0.3
0.092
0.046
0.044
Mean ± SD HDL cholesterol, mmol/l
1.0 ± 0.1
1.1 ± 0.2
1.1 ± 0.2
1.2 ± 0.2
0.088
0.089
0.091
Mean ± SD triglycerides, mmol/l
1.6 ± 0.6
1.5 ± 0.3
1.5 ± 0.5
1.2± 0.2
0.089
0.047
0.041
Mean ± SD total cholesterol/HDL ratio
4.9 ± 0.3
4.9 ± 0.3
4.5 ± 0.4
3.8 ± 0.1
0.097
0.023
0.032
Mean ± SD adiponectin, μg/ml
4.5 ± 1.3
5.2 ± 1.9
4.8 ± 1.6
5.8 ± 2.4
0.034
0.002
0.035
Mean ± SD highsensitivity C-reactive protein, mg/l
2.2 ± 1.3
1.7 ± 1.0
2.2 ± 1.3
1.4 ± 0.7
0.041
0.021
0.038
Mean ± SD interleukin-6, pg/ml
3.78 ± 2.37
3.01 ± 2.03
3.85 ± 2.52
2.91 ± 1.82
0.064
0.029
0.064
2.4 ± 1.4
2.2 ± 1.2
2.6 ± 1.7
1.8 ± 0.8
0.087
0.032
0.056
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Mean ± SD fasting plasma proinsulin/fasting plasma insulin ratio
Mean ± SD tumour necrosis factor-α, ng/ml
HOMA-IR, homeostasis model assessment of insulin resistance index.
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Table 3 Area under curve (× 12 h) values during the baseline oral fat load test and oral fat load at the end of the study in the glimepiride and the vildagliptin groups Glimepiride group Baseline oral fat load, mean ± SD
Blood glucose, mg/dl
63394.13±4694.69
Plasma insulin, μU/ml
8458.31±1118.26
Vildagliptin group
P vs baseline
P vs glimepiride
End of study oral fat load, mean ± SD
Baseline oral fat load, mean ± SD
End of study oral fat load, mean ± SD
Glimepiride
Vildagliptin
52718.54±3946.78
60821.84±4293.15
53617.82±4096.38
0.044
0.038
0.088
10751.27±1294.87
9354.54±1417.60
8591.63±1213.17
0.041
0.067
0.047
120371.62±25638.17
101379.56±15182.43
0.082
0.039
0.045
86283.41±4113.53
71044.13±3443.58
0.088
0.035
0.044
28157.25±4918.36
33291.74±5721.32
0.064
0.056
0.079
59667.08±7816.74
49118.07±6058.39
0.061
0.046
0.048
2693.46±501.56
4138.64±663.09
0.042
0.008
0.041
1194.35±719.08
813.06±420.47
0.045
0.041
0.043
3192.75±921.67
2236.41±638.87
0.075
0.045
0.064
Total cholesterol, mg/dl
116892.63±21849.11
115728.16±21044.31
LDL cholesterol, mg/dl
83624.28±3918.76
83916.34±3981.64
HDL cholesterol, mg/dl
25817.05±4121.97
29284.18±4628.55
Triglycerides, mg/dl
78236.26±9742.64
51839.82±6531.96
Adiponectin, μg/ml
2328.15±477.32
3684.71±598.27
High-sensitivity Creactive protein, mg/l
1187.92±708.61
904.63±512.04
Interleukin-6,
2939.57±817.29
2689.87±764.31
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Accepted Arti pg/ml
Tumour necrosis factor-α, ng/ml
1684.72±619.33
1489.11±543.83
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1917.14±694.83
1138.49±429.18
0.069
0.031
0.061
ccepted Articl
Figure 1.
Patients assessed for eligibility n=178
11 patients were not randomized because of: • • • •
diarrhoea (2 women) nausea (1 man and 1 woman) vomiting (1 woman) gastrointestinal discomfort (3 women and 2 men)
Patients randomized n=167
Allocated to metformin + glimepiride n=81
Allocated to metformin + vildagliptin n=86
Discontinuated 11
Discontinuated 3
•
• •
•
hypoglycaemia (fasting plasma glucose < 3.33 mmol/l) (3 men and 5 women) consent withdrawn (1 woman)
Completed the study n=70
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consent withdrawn (1 woman) lost to follow-up (2 women)
Completed the study n=83
23
Plasma Insulin (microU/ml)
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Figure 2.
21 Glimepiride
19 Vildagliptin
17
^
^
^
0
3
6
^
15
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Hours (h)
9
12
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Figure 3.
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Accepted Article
Revised Date : 01-Mar-2014 Accepted Date : 09-May-2014 Article type
: Research Article
Comparison of vildagliptin and glimepiride: effects on glycaemic
control, fat tolerance and inflammatory markers in people with Type 2 diabetes
G. Derosa1,2, A. Bonaventura1, L. Bianchi1, D. Romano1, E. Fogari1, A. D’Angelo1 and P. Maffioli1
1
Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S.
Matteo, and 2Centre for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University
of Pavia, Pavia, Italy Correspondence: Giuseppe Derosa. E-mail: [email protected]
What's new? •
Vildagliptin was found to cause greater reductions in fasting plasma insulin levels and post-oral fat load insulin peak compared with glimepiride.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dme.12499 This article is protected by copyright. All rights reserved.
•
The homeostasis model assessment of insulin resistance index was shown to increase with
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glimepiride and decrease with vildagliptin. •
Vildagliptin increased the insulin sensitivity index compared with glimepiride.
•
Vildagliptin reduced total cholesterol and LDL cholesterol levels, both during fasting and after an oral fat load test.
•
Vildagliptin increased adiponectin and reduced high-sensitivity C-reactive protein levels, both during fasting and after an oral fat load test.
Abstract Aims To compare the effects of vildagliptin with those of glimepiride on glycaemic control, fat tolerance and inflammatory markers in people with Type 2 diabetes mellitus receiving metformin treatment. Methods A total of 167 participants were randomized to vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day, for 6 months. We evaluated the following variables: BMI; glycaemic control; fasting plasma insulin; homeostasis model assessment of insulin resistance index; fasting plasma proinsulin; glucagon; lipid profile; adiponectin; high-sensitivity C-reactive protein; interleukin-6; and tumour necrosis factor-α. A euglycaemic-hyperinsulinaemic clamp procedure and an oral fat load test were also performed. Results Despite a similar decrease in HbA1c levels (P = 0.009, and P = 0.008, respectively), body weight
increased with glimepiride (P = 0.048 vs baseline) and decreased with vildagliptin (P = 0.041 vs baseline and vs glimepiride). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were significantly lower with vildagliptin compared with glimepiride (P = 0.035 and 0.047). M value, an index of insulin sensitivity, increased with vildagliptin, both compared with baseline and with glimepiride (P = 0.028 and 0.039, respectively). Vildagliptin improved all post-oral fat load peaks of lipid profile compared with glimepiride. Adiponectin levels were higher (P = 0.035) and high-sensitivity C-reactive protein levels were
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lower (P = 0.038) with vildagliptin vs glimepiride. During the oral fat load test, interleukin-6, high-sensitivity
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C-reactive protein and tumour necrosis factor-α peaks were lower and adiponectin peak was higher in the vildagliptin group than in the glimepiride group. There was a higher dropout rate as a result of hypoglycaemia in the glimepiride group than in the vildagliptin group. Conclusions Vildagliptin was more effective than glimepiride in reducing post-oral fat load peaks of lipidtrafficking adipocytokines and inflammatory markers.
Introduction Targeting hyperglycaemia is of key importance in the management of Type 2 diabetes mellitus, because lowering glycaemia reduces both acute symptoms and the risk of retinopathy and cardiovascular disease [1]. The key defect underlying hyperglycaemia in Type 2 diabetes is islet dysfunction, which has three components: impaired insulin secretion [2]; defective suppression of glucagon secretion [3]; and reduced islet cell mass [4]. For a long time, sulfonylureas have been recommended as a second-line treatment for Type 2 diabetes when metformin alone was not enough to achieve adequate glycaemic control [5]; however, despite being effective in improving glycaemic control, sulfonylurea use is limited by the high rate of hypoglycaemia [6]. Recent breakthroughs in the understanding of incretin-based therapies have provided additional options for the treatment of Type 2 diabetes, including glucagon-like peptide-1
receptor agonists [7] and dipeptidyl peptidase-4 inhibitors [8]. Among dipeptidyl peptidase-4 inhibitors, vildagliptin has been licensed at the recommended dose of 50 mg twice daily, in combination with either metformin or pioglitazone, and at the recommended dose of 50 mg once daily in combination with sulfonylureas where glycaemic control is suboptimal [9]. Vildagliptin administered 50 mg twice a day in addition to metformin, proved to have a positive action on β-cell function [10], on reducing some
adipocytokine levels related to inflammation [11] and on insulin resistance [12] compared with placebo. Recent studies have shown associations between postprandial lipid trafficking and cardiovascular disease in people with Type 2 diabetes [13]. Postprandial clearance of dietary fat from the circulation can take at least
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12 h [14]. Postprandial serum lipid metabolism may be improved as insulin sensitivity is enhanced by
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augmentation of glucagon-like peptide-1 levels with dipeptidyl peptidase-4
inhibition [15,16].
Adipocytokines and inflammatory peptides may also be influenced by these inter-related metabolic processes. To date, there have been no studies directly assessing the effect of vildagliptin on postprandial lipid trafficking. The aim of the present study, therefore, was to compare the effects of vildagliptin with those of glimepiride on both fasting and post-meal glycaemia, lipid profiles and inflammatory markers in people with Type 2 diabetes mellitus. All these factors had been suboptimally controlled with metformin monotherapy.
Materials and methods Study design This randomized, double-blind, controlled study was conducted at the Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. The study protocol was approved by our institutional review board and was conducted in accordance with the Declaration of Helsinki and its amendments.
Participants We enrolled 178 white people aged ≥ 18 years, of both sexes, with Type 2 diabetes mellitus, according to the criteria included in the European Society of Cardiology and European Association for the Study of Diabetes guidelines [17], and with uncontrolled Type 2 diabetes mellitus [HbA1c53–75 mmol/mol (7.0–
9.0%)] who were receiving metformin therapy at the maximum tolerated dose. Suitable participants, identified from review of case notes and/or computerized clinic registers, were contacted by the investigators in person or by telephone. Anti-hypertensive drugs, which modify glucose and lipid metabolism, were maintained unchanged during the study.
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Subjects with uncontrolled hypertension (systolic blood pressure ≥160 mmHg and diastolic blood pressure
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≥90 mmHg) were not included in the study. Subjects were also excluded if they had a history of ketoacidosis or had unstable or rapidly progressive diabetic retinopathy, nephropathy or neuropathy, impaired hepatic function (defined as plasma aminotransferase and/or gamma-glutamyltransferase levels higher than the upper limit of normal for age and sex), impaired renal function (defined as serum creatinine level higher than the upper limit of normal for age and sex), or severe anaemia. Those taking statins or drugs affecting lipid profile were also excluded to avoid interference with the oral fat load test, as well as those with serious cardiovascular disease (e.g. New York Heart Association class I–IV congestive heart failure or a history of myocardial infarction or stroke) or cerebrovascular conditions within 6 months before study enrolment. People with a history of pancreatitis were excluded. Women who were pregnant or breastfeeding or of childbearing age and not taking adequate contraceptive precautions were also excluded. All participants provided written informed consent to participate.
Treatment After 1 month of active run-in, during which the metformin dose was kept stable, participants were assigned to receive, in addition to metformin, vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day for 6 months. Both vildagliptin and glimepiride were supplied as identical, opaque, white capsules in coded bottles to ensure the blind status of the study. All medications were provided free of charge, thanks to funding made available by the University of Pavia. Randomization was performed by drawing envelopes containing randomization codes prepared by a statistician. The code was only available to the person responsible for the statistical analysis. The code was only broken after database lock, but could have been broken for individual participants in case of emergency. Medication compliance was assessed by counting the number of pills returned at the time of specified clinic visits. At baseline, we weighed participants and gave them a bottle containing a supply of study medication for at least 100 days. Throughout the study, we instructed the participants to take their
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first dose of new medication on the day after they received it. At the same time, all unused medication was
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retrieved for inventory.
Diet and Exercise Participants began a controlled-energy diet (~600 kcal daily deficit), based on American Heart Association recommendations [18], that included 50% of calories from carbohydrates, 30% from fat (6% saturated) and 20% from proteins, with a maximum cholesterol content of 300 mg/day and 35 g/day of fibre. Participants did not receive vitamins or mineral preparations during the study. Standard dietary advice was given by a dietician and/or specialist doctor. A dietician and/or specialist doctor provided monthly instruction on dietary intake recording procedures as part of a behaviour modification programme and later used the participant’s food diaries for counselling. The participants were also encouraged to increase their physical activity by walking briskly for 20–30 min, 3–5 times per week, or by cycling. The recommended changes in physical activity throughout the study were assessed at each visit using the participant’s activity diary.
Assessments Before starting the study, all participants underwent an initial screening assessment that included a medical history, physical examination, vital signs and a 12-lead electrocardiogram. BMI, HbA1c, fasting plasma
glucose, postprandial plasma glucose and fasting plasma insulin levels, homeostasis model assessment of insulin resistance index, fasting plasma proinsulin levels, fasting plasma proinsulin/fasting plasma insulin ratio, glucagon, total cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides, adiponectin, high-
sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α were evaluated at baseline, at randomization and after 3 and 6 months. Furthermore, at the time of randomization and at the end of the
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study all participants underwent a euglycaemic-hyperinsulinaemic clamp procedure to evaluate M value, an
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index of insulin sensitivity, and an oral fat load test.
For the tolerability assessments, all adverse events were recorded. All plasma variables were determined after a 12-h overnight fast, with the exception of postprandial plasma glucose, determined 2 h after a standardized meal. Venous blood samples were taken for all participants between 08:00 and 09:00 h. We used plasma obtained by addition of Na2-EDTA 1 mg/ml, and centrifuged at 3000 × g for 15 min at 4°C.
Immediately after centrifugation, the plasma samples were frozen and stored at -80°C for no more than 3 months. All measurements were performed in a central laboratory. Measurement of single variables and the glucose clamp technique used have been described previously [12,19,20].
Oral fat load test The oral fat load test was performed between 08:00 and 09:00 h after a 12-h fast and a 3-day abstention from alcohol intake. Participants were also asked to refrain from heavy exercise during the preceding days. The test drink consisted of 350 ml whipping cream (35 % fat), ~30 ml chocolate-flavoured syrup, ~15 g granulated sugar and ~15 g instant non-fat dried milk. This drink contained 1147 kcal, of which 12% were from protein, 20% from carbohydrate and 68% from fat. It had 472 mg cholesterol and a polyunsaturated/saturated ratio of 0.06. A weight-adjusted meal (1 g fat per kg body weight) was served with ~400 ml of the mixture. The fat load mixture was consumed within 10 min. After the ingestion of the oral fat load, participants were only allowed to drink water during the following 12 h. Blood samples were drawn before and 3, 6, 9 and 12 h after the oral fat load. Participants were required to sit in the hospital hall; only walking at standard pace within the hospital perimeter was permitted.
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Statistical Analysis
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A per-protocol analysis was conducted in participants who completed the study. With a difference of at least 10% compared with the baseline taken to indicate clinical significance and an α error of 0.05, the actual sample size was adequate to obtain a power > 0.80 for all measured variables. Continuous variables were tested using two-way repeated-measures ANOVA to assess overall differences in postprandial
responses. The incremental area under the curve was calculated as the increased response above baseline minus any drop below baseline, based on the trapezoid rule. Non-parametric tests were also used in the statistical analysis, when the data were not normally distributed (Kolmogorov–Smirnov test). Outcome variables with a skewed distribution were transformed to a log scale before statistical testing. Intervention effects were adjusted for additional potential confounders (sex, smoking status) using ANCOVA. ANOVA was
also used to assess the significance within and between groups. The statistical significance of the independent effects of treatments on the other variables was determined using ANCOVA taking the baseline level of each variable as a covariate. Paired tests were also used: a one-sample t-test to compare values obtained before and after treatment administration and two-sample t-tests to compare the change score (final minus baseline) for a given variable between the two groups. Statistical analysis of data was performed using SPSS software version 14.0 (SPSS Inc., Chicago, IL, USA). Data are presented as means ± SD. For all statistical analyses, a P value < 0.05 was taken to indicate statistical significance.
Results A total of 178 participants were enrolled in the study. Of these, 167 were randomized and 153 completed the study (Fig. 1). A higher dropout rate as a result of hypoglycaemia was recorded in the glimepiride group. Concurrent medications taken by participants are listed in Table 1.
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After 6 months, there was an increase in body weight with glimepiride compared with baseline (P = 0.048),
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and a decrease in body weight with vildagliptin, compared with baseline and with glimepiride (P = 0.041 for both; Table 2). A similar decrease in HbA1c, fasting plasma glucose and postprandial plasma glucose was recorded with
both glimepiride and vildagliptin after 3 and 6 months, with no differences between groups (Table 2).
No variations in lipid profile were recorded in the glimepiride group, while in the vildagliptin group there were reductions in total cholesterol (P = 0.032), LDL cholesterol (P = 0.046) and triglycerides (P = 0.047) after 6 months compared with baseline and with glimepiride (P = 0.048, 0.044 and 0.041, respectively). No changes in HDL cholesterol were observed, but the total cholesterol/HDL cholesterol ratio was lower with vildagliptin, both compared with baseline (P = 0.023) and with glimepiride (P = 0.032; Table 2).
Fasting plasma insulin increased after 6 months of glimepiride (P = 0.046), but did not change with vildagliptin. The fasting plasma insulin levels in the vildagliptin group were lower than those in the glimepiride group at the end of the study. Homeostasis model assessment of insulin resistance index was higher in the glimepiride group after 6 months, while it was lower in the vildagliptin group, both compared with baseline and with glimepiride (P = 0.041 and 0.047, respectively). Fasting plasma proinsulin decreased with both treatments vs baseline (P = 0.044 in the glimepiride group and P = 0.040 in the vildagliptin group). The fasting plasma proinsulin/fasting plasma insulin ratio decreased with both glimepiride and vildagliptin (P = 0.042, and 0.043, respectively; Table 2). Glucagon levels decreased after 6 months of vildagliptin, although no differences were recorded in the between-group comparison. There was an increase in M value at the end of the study in the vildagliptin group, and this difference was significant, both compared with baseline and with the glimepiride group (P = 0.028 and 0.039, respectively; Table 2).
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Adiponectin levels increased after 6 months with both glimepiride (P = 0.034 vs baseline) and vildagliptin (P
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= 0.002 vs baseline), but the adiponectin levels in the vildagliptin group were significantly higher than those in the glimepiride group (P = 0.035). Both glimepiride and vildagliptin decreased high-sensitivity C-reactive protein (P = 0.041 and 0.021, respectively), but the decrease was greater with vildagliptin than with glimepiride (P = 0.038). There were trends towards reductions in interleukin-6 and tumour necrosis factor-α in the vildagliptin group and not in the glimepiride group, but this difference did not achieve statistical significance (Table 2). There were significant differences in post-oral fat load peaks between the glimepiride and the vildagliptin groups. In particular, vildagliptin reduced fasting plasma insulin, total cholesterol, LDL cholesterol and triglyceride post-oral fat load peaks, and increased HDL cholesterol peak compared with glimepiride. Interleukin-6, high-sensitivity C-reactive protein and tumour necrosis factor-α peaks were also reduced, and the adiponectin peak was increased by vildagliptin compared with glimepiride. Figures 2 and 3 show all the variations among the different variables during oral fat load. The area under the curve values, calculated during the baseline oral fat load and the end of study oral fat load in each group, are shown in Table 3.
Discussion In the present study we observed similar effects of vildagliptin to those of glimepiride in improving glycaemic control, with vildagliptin treatment also resulting in body weight reductions. This confirmed the results already reported by Ferrannini et al. [21] and Matthews et al. [22]. These authors reported that
vildagliptin and glimepiride treatment resulted in the same reduction in HbA1c levels, with glimepiride
causing more hypoglycaemic events and body weight gain. With regard to insulin resistance and insulin secretion, vildagliptin decreased the homeostasis model assessment of insulin resistance index, and increased the M value compared with glimepiride. In addition, it led to a reduction in fasting plasma proinsulin/fasting plasma insulin ratio, suggesting a protective action of
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vildagliptin on β-cells. An increased ratio of proinsulin to insulin, in fact, is considered to be an early marker
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of islet dysfunction resulting from a disproportionate release of proinsulin from β-cells [23]. This is consistent with our previous study comparing vildagliptin, glimepiride and pioglitazone [24]. With regard to oral fat load, previously reported data showed that an oral fat load induces a complex and massive systemic inflammatory response that includes an increase of interleukin-6, tumour necrosis factor-α, high-sensitivity C-reactive protein and cell adhesion molecules, even before triglycerides significantly rise [25]. Studies have also shown that nitrites/nitrates and adiponectin levels significantly decreased and metalloproteinases-2 and -9 significantly increased after a standardized oral fat load in healthy participants [26]. These data have also been confirmed in people with hypertension [27] and in people with dyslipidaemia [28,29]. The antidiabetic drug acarbose 100 mg three times a day was more effective than placebo in improving glycaemic control and lipid profile, in reducing the post-oral fat load peaks of various markers, including insulin resistance biomarkers, and in reducing various inflammatory markers, after 7 months of therapy [30,31]. A comparison of pioglitazone and glibenclamide showed that pioglitazone was more effective in mitigating the variations of lipid components and inflammation markers in people with Type 2 diabetes after an oral fat load [32]. In the present study, vildagliptin proved to be more effective than glimepiride in reducing post-oral fat load peaks of lipid-trafficking adipocytokines and inflammatory markers. This is consistent with a study by Barbieri et al. [33] that assessed the effect of dipeptidyl peptidase-4 inhibitors on intima-media thickness, a surrogate marker for early atherosclerosis. They observed that both sitagliptin and vildagliptin reduced intima-media thickness, probably through the reduction of daily inflammation and oxidative stress. Vildagliptin was shown to be more effective than sitagliptin in reducing intima-media thickness, probably because of its greater ability to reduce daily glucose excursions [34]. Reduction of daily glucose excursions led to a reduction in hypoglycaemic events, with a consequent lower activation of the sympathetic system. Activation of the sympathetic system has numerous implications, including surges of heart rate and blood pressure and also increases in pro-inflammatory and pro-coagulant effects. This hypothesis will be further evaluated in a currently ongoing trial [35].
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The present study has some limitations, such as its short duration and the fact that we did not evaluate if
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the beneficial effects of vildagliptin were sustained after the cessation of therapy. Another limitation is that we evaluated a limited number of adipocytokines, concentrating our attention on a few of these. Longer studies are needed to investigate whether the positive effects of vildagliptin on inflammation levels could lead to a reduction in the number of cardiovascular events linked to Type 2 diabetes. In conclusion, despite having a similar effect on glycaemic control, vildagliptin proved to be more effective than glimepiride in protecting β-cell function and in reducing post-oral fat load peaks of lipid-trafficking adipocytokines and inflammatory markers.
Funding sources None.
Competing interests None declared.
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2. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 2003; 46: 3–19.
3. Dunning BE, Foley JE, Ahrén B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005; 48: 1700–1713.
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4. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell
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FIGURE 1 Reasons for patients premature withdrawal from the study from baseline to the end of the study. FIGURE 2 Variations in metabolic variables during the oral fat load test in the glimepiride group (n =70) and the vildagliptin group (n =83) at the end of the study. ^P< 0.05 vs glimepiride.
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FIGURE 3 Inflammatory marker variations during oral fat load in the glimepiride group (n =70) and the +
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vildagliptin (n =83) group at the end of the study. ^P< 0.05 vs glimepiride; P< 0.01 vs glimepiride.
Table 1 Concomitant medications taken by participants during the study Glimepiride, n (%)
Vildagliptin, n (%)
81
86
Anti-hypertensive drugs
52 (64.2)
55 (63.9)
Angiotensin-converting enzyme inhibitors
24 (46.1)
Angiotensin receptor blockers
23 (44.2)
Calcium antagonists
17 (32.7)
20 (36.4)
5 (9.6)
4 (7.3)
10 (19.2)
12 (21.8)
Anti-aggregant therapy
49 (60.5)
47 (54.6)
Acetylsalicylic acid
42 (85.7)
40 (85.1)
Ticlopidine
5 (10.2)
4 (8.5)
Clopidogrel
2 (4.1)
3 (6.4)
No. participants
β-blockers
Diuretics
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24 (43.6)
28 (50.9)
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Table 2 Data variations for patients completing the study in both glimepiride (70 participants) and vildagliptin (83 participants) group
Participants, n Sex, M/F
Glimepiride
Vildagliptin
P vs baseline
Baseline
6 months
Baseline
6 months
70
70
83
83
36/34
36/34
42/44
42/41
P vs glimepiride
Glimepiride Vildagliptin
Mean ± SD age, years
56.8 ± 8.9
59.8 ± 9.9
Smoking status, M/F
11/10
Mean ± SD diabetes duration, months
6.7 ± 3.5
6.9 ± 4.7
Mean ± SD height, m
1.67 ± 0.06
1.66 ± 0.05
Mean ± SD weight, kg
77.2 ± 6.3
78.2 ± 6.9
77.8 ± 6.9
76.3 ± 6.0
0.048
0.041
0.041
Mean ± SD BMI, kg/m2
27.7 ± 1.3
28.0 ± 1.7
27.9 ± 1.6
27.4 ± 1.2
0.047
0.044
0.049
Mean ± SD HbA1c, mmol/mol
62 ± 12
50 ± 20
63 ± 14
52 ± 19
0.009
0.008
0.081
Mean ± SD HbA1c, %
7.8 ± 0.8
6.7 ± 0.3
7.9 ± 0.9
6.9 ± 0.4
0.006
0.007
0.089
Mean ± SD fasting plasma glucose, mmol/l
7.7 ± 0.9
6.9 ± 0.4
7.8 ± 1.0
7.1 ± 0.6
0.009
0.009
0.081
Mean ± SD postprandial plasma glucose, mmol/l
9.8 ± 1.1
8.8 ± 0.7
10.1 ± 1.3
9.1 ± 0.8
0.008
0.009
0.073
Mean ± SD fasting plasma insulin, μU/ml
18.3 ± 3.8
20.1 ± 5.2
19.1 ± 4.4
18.4 ± 3.9
0.046
0.055
0.035
Mean ± SD HOMA-IR
6.26 ± 2.23
6.16 ± 2.59
6.62 ± 2.42
5.81 ± 1.84
0.091
0.041
0.047
Mean ± SD fasting plasma proinsulin, μU/ml
5.57 ± 3.94
4.10 ± 2.89
5.87 ± 4.35
4.45 ± 3.11
0.044
0.040
0.053
9/11
14/11
13/11
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0.304 ± 1.33
0.204 ± 1.07
0.307 ± 1.44
0.242 ± 1.19
0.042
0.043
0.086
Mean ± SD glucagon, pmol/l
57.2 ± 8.2
50.2 ± 6.3
59.6 ± 9.7
47.1 ± 5.2
0.063
0.035
0.059
Mean ± SD M value, μmol/min/kg)
5.1 ± 2.4
5.7 ± 3.3
5.3 ± 2.8
6.3 ± 3.9
0.071
0.028
0.039
Mean ± SD total cholesterol, mmol/l
4.9 ± 0.5
4.9 ± 0.5
5.01 ± 0.6
4.6 ± 0.4
0.098
0.032
0.048
Mean ± SD LDL cholesterol, mmol/l
3.6 ± 0.4
3.5 ± 0.4
3.6 ± 0.4
3.2 ± 0.3
0.092
0.046
0.044
Mean ± SD HDL cholesterol, mmol/l
1.0 ± 0.1
1.1 ± 0.2
1.1 ± 0.2
1.2 ± 0.2
0.088
0.089
0.091
Mean ± SD triglycerides, mmol/l
1.6 ± 0.6
1.5 ± 0.3
1.5 ± 0.5
1.2± 0.2
0.089
0.047
0.041
Mean ± SD total cholesterol/HDL ratio
4.9 ± 0.3
4.9 ± 0.3
4.5 ± 0.4
3.8 ± 0.1
0.097
0.023
0.032
Mean ± SD adiponectin, μg/ml
4.5 ± 1.3
5.2 ± 1.9
4.8 ± 1.6
5.8 ± 2.4
0.034
0.002
0.035
Mean ± SD highsensitivity C-reactive protein, mg/l
2.2 ± 1.3
1.7 ± 1.0
2.2 ± 1.3
1.4 ± 0.7
0.041
0.021
0.038
Mean ± SD interleukin-6, pg/ml
3.78 ± 2.37
3.01 ± 2.03
3.85 ± 2.52
2.91 ± 1.82
0.064
0.029
0.064
2.4 ± 1.4
2.2 ± 1.2
2.6 ± 1.7
1.8 ± 0.8
0.087
0.032
0.056
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Mean ± SD fasting plasma proinsulin/fasting plasma insulin ratio
Mean ± SD tumour necrosis factor-α, ng/ml
HOMA-IR, homeostasis model assessment of insulin resistance index.
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Table 3 Area under curve (× 12 h) values during the baseline oral fat load test and oral fat load at the end of the study in the glimepiride and the vildagliptin groups Glimepiride group Baseline oral fat load, mean ± SD
Blood glucose, mg/dl
63394.13±4694.69
Plasma insulin, μU/ml
8458.31±1118.26
Vildagliptin group
P vs baseline
P vs glimepiride
End of study oral fat load, mean ± SD
Baseline oral fat load, mean ± SD
End of study oral fat load, mean ± SD
Glimepiride
Vildagliptin
52718.54±3946.78
60821.84±4293.15
53617.82±4096.38
0.044
0.038
0.088
10751.27±1294.87
9354.54±1417.60
8591.63±1213.17
0.041
0.067
0.047
120371.62±25638.17
101379.56±15182.43
0.082
0.039
0.045
86283.41±4113.53
71044.13±3443.58
0.088
0.035
0.044
28157.25±4918.36
33291.74±5721.32
0.064
0.056
0.079
59667.08±7816.74
49118.07±6058.39
0.061
0.046
0.048
2693.46±501.56
4138.64±663.09
0.042
0.008
0.041
1194.35±719.08
813.06±420.47
0.045
0.041
0.043
3192.75±921.67
2236.41±638.87
0.075
0.045
0.064
Total cholesterol, mg/dl
116892.63±21849.11
115728.16±21044.31
LDL cholesterol, mg/dl
83624.28±3918.76
83916.34±3981.64
HDL cholesterol, mg/dl
25817.05±4121.97
29284.18±4628.55
Triglycerides, mg/dl
78236.26±9742.64
51839.82±6531.96
Adiponectin, μg/ml
2328.15±477.32
3684.71±598.27
High-sensitivity Creactive protein, mg/l
1187.92±708.61
904.63±512.04
Interleukin-6,
2939.57±817.29
2689.87±764.31
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Tumour necrosis factor-α, ng/ml
1684.72±619.33
1489.11±543.83
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1917.14±694.83
1138.49±429.18
0.069
0.031
0.061
ccepted Articl
Figure 1.
Patients assessed for eligibility n=178
11 patients were not randomized because of: • • • •
diarrhoea (2 women) nausea (1 man and 1 woman) vomiting (1 woman) gastrointestinal discomfort (3 women and 2 men)
Patients randomized n=167
Allocated to metformin + glimepiride n=81
Allocated to metformin + vildagliptin n=86
Discontinuated 11
Discontinuated 3
•
• •
•
hypoglycaemia (fasting plasma glucose < 3.33 mmol/l) (3 men and 5 women) consent withdrawn (1 woman)
Completed the study n=70
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consent withdrawn (1 woman) lost to follow-up (2 women)
Completed the study n=83
23
Plasma Insulin (microU/ml)
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Figure 2.
21 Glimepiride
19 Vildagliptin
17
^
^
^
0
3
6
^
15
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Hours (h)
9
12
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Figure 3.
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