Clinical trial NCT02536248
Conditions: Type 2 Diabetes Mellitus
Keywords: sitagliptin diabetes inflammation
Sponsor: Laval University
Start date: 2015-08-01; Completion date: 2017-10-31
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Inflammatory processes are increasingly being recognized as a critical step in the pathogenesis of both diabetes and heart disease and may constitute a biological link between the two diseases. Inflammatory cytokines increase vascular permeability, change vasoregulatory responses, increase leukocyte adhesion to endothelium, and facilitate thrombus formation by inducing procoagulant activity, inhibiting anticoagulant pathways, and impairing fibrinolysis. Leukocyte adhesion to arterial endothelial cells is thought to be an important step in the development of atherosclerosis, and adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and L-selectin, play key roles in this process. Therefore, identifying novel therapeutic approaches that would favorably affect inflammation, endothelial function, and glucose is of significant interest. Investigators have recently demonstrated that, relative to placebo, sitagliptin treatment resulted in a significant reduction in plasma levels of various inflammatory markers and cell adhesion molecules. The results also suggest that the beneficial effects of sitagliptin on both inflammation and endothelial function are most likely mediated by an elevation in plasma GLP-1 levels and global improvement of the glucose-insulin homeostasis. However, the mechanisms underlying the beneficial effects of sitagliptin on these markers remain to be fully elucidated. The proposed study will address this key issue.

Detailed description:

Arms: arm 1: Sitagliptin 100 mg/d for 6 weeks

Wash-out 14 days

Placebo for 6 weeks arm 2: Placebo for 6 weeks

Wash-out 14 days

Sitagliptin 100 mg/d for 6 weeks
Interventions: intervention 1: Sitagliptin intervention 2: Placebo
Intervention descriptions: intervention 1: Sitagliptin 100 mg/d for 6 weeks intervention 2: Placebo for 6 weeks

Protocol documents:
Prot_000.pdf: 
PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 1 
 
 
This protocol is CONFIDENTAL and no person is authorized to make it public or modify it without the written 
permission of Dr. Patrick Couture. This restriction on disclosure will apply to all future information provided 
about this study which is indicated as privileged or confidential. 
 
 
 
NCT NUMBER: 
NCT02536248 
 
DRUG NAME: 
 
SITAGLIPTIN 
 
 
STUDY TITLE: 
 
EFFECTS OF SITAGLIPTIN THERAPY ON THE KINETICS OF MARKERS 
OF LOW-GRADE INFLAMMATION AND CELL ADHESION MOLECULES IN 
PATIENTS WITH TYPE 2 DIABETES 
 
INVESTIGATORS: 
 
Patrick Couture MD, FRCPC, PhD 
 
 
 
 
André J. Tremblay, PhD  
 
 
 
Benoît Lamarche, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL DATE:  
February 12nd, 2015  


PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 2 
 
EFFECTS OF SITAGLIPTIN THERAPY ON THE KINETICS OF MARKERS OF LOW-GRADE INFLAMMATION AND CELL 
ADHESION MOLECULES IN PATIENTS WITH TYPE 2 DIABETES 
Inflammatory processes are increasingly being recognized as a critical step in the pathogenesis of both 
diabetes and heart disease and may constitute a biological link between the two diseases. Inflammatory 
cytokines increase vascular permeability, change vasoregulatory responses, increase leukocyte 
adhesion to endothelium, and facilitate thrombus formation by inducing procoagulant activity, inhibiting 
anticoagulant pathways, and impairing fibrinolysis. Leukocyte adhesion to arterial endothelial cells is 
thought to be an important step in the development of atherosclerosis, and adhesion molecules, such as 
intercellular adhesion molecule-1 (ICAM-1) and L-selectin, play key roles in this process. Therefore, 
identifying novel therapeutic approaches that would favorably affect inflammation, endothelial function, 
and glucose is of significant interest. We have recently demonstrated that, relative to placebo, sitagliptin 
treatment resulted in a significant reduction in plasma levels of various inflammatory markers and cell 
adhesion molecules1. Our results also suggest that the beneficial effects of sitagliptin on both 
inflammation and endothelial function are most likely mediated by an elevation in plasma GLP-1 levels 
and global improvement of the glucose-insulin homeostasis. However, the mechanisms underlying the 
beneficial effects of sitagliptin on these markers remain to be fully elucidated. The proposed study will 
address this key issue. 
The general objective of the proposed research is to investigate how sitagliptin therapy 
modulates the kinetics of various inflammatory markers and cell adhesion molecules in patients 
with type 2 diabetes. More specifically, we will: 
1. Examine the impact of sitagliptin therapy on the in vivo kinetics of key inflammatory markers 
associated with an increase risk of cardiovascular disease (C-reactive protein-CRP, plasminogen, 
von Willebrand factor-vWF). We hypothesize that sitagliptin therapy will decrease the production 
rate of these markers. Preliminary results from our group show that, compared with placebo, 
sitagliptin decreases CRP concentrations by 25.9% (placebo: 3.75±2.37 vs. sitagliptin: 2.78±2.04 
mg/L; P<0.0001) in patients with type 2 diabetes (see Figure 1A). 
2. Examine the impact of sitagliptin therapy on the in vivo kinetics of the cell adhesion molecules 
ICAM-1 and L-selectin associated with an increase risk of cardiovascular disease. We hypothesize 
that sitagliptin therapy will decrease the production rate of these molecules. Preliminary results 
from our group show that, compared with placebo, sitagliptin decreases ICAM-1 concentrations 
by 6.3% (placebo: 229±46 vs. sitagliptin: 213±46 ng/mL; P=0.004)  in patients with type 2 diabetes 
(see Figure 1B). 
Study Design and Methods  
All the analyses proposed will be performed on plasma samples collected during a previous 
research project supported by Merck (IISP#39262 – see attached manuscript for further details). The 
study design is illustrated in Figure 2. Plasminogen, L-selectin, and von Willebrand factor concentrations 
will be measured using commercial ELISA. Protein enrichment will be assessed using liquid 
chromatography-multiple reaction monitoring (LC-MRM) analysis. Samples will be analysed on a 
ABSciex 5500QTRAPTM hybrid triple quadrupole/linear ion trap mass spectrometer equipped with an 
Eksigent nanoLC AS2 cHiPLC nanoflex controlled by Analyst 1.6TM and with a nanospray ionization 
source (ABSciex, Framingham, MA, USA). This method has been used to assess apoB-48, B-100, apoC-
III, and apoE kinetics in the triglyceride-rich lipoprotein fraction in patients with type 2 diabetes (see 
attached manuscript). Similarly, kinetic parameters (production and fractional catabolic rates) of the 
various markers will be calculated using multi-compartmental modeling. 
Relevance and Importance 
Data generated over the course of the proposed research will lead to considerable advances in 
our understanding of the mechanisms underlying the beneficial effects of sitagliptin therapy on 
inflammation and endothelial function in patients with type 2 diabetes. 
 
1Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effects of sitagliptin therapy on markers of low-
grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism 2014;63(9):1141-1148. 


PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 3 
 
 
 
Figure 1 
 
Preliminary results from study IISP#39262 showing that sitagliptin therapy significantly decreases 
both CRP and ICAM-1 concentrations in patients with type 2 diabetes. 
 
 
 
 
 


PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 4 
 
 
 
Figure 2 
 
Design of the study IISP#39262 supported by Merck (see attached manuscript).  
All analyses of the current proposal will be performed on samples already collected during the 
study IISP#39262 
 
 

SAP_001.pdf: 
PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 1 
 
 
This protocol is CONFIDENTAL and no person is authorized to make it public or modify it without the written 
permission of Dr. Patrick Couture. This restriction on disclosure will apply to all future information provided 
about this study which is indicated as privileged or confidential. 
 
 
 
NCT NUMBER: 
NCT02536248 
 
DRUG NAME: 
 
SITAGLIPTIN 
 
 
STUDY TITLE: 
 
EFFECTS OF SITAGLIPTIN THERAPY ON THE KINETICS OF MARKERS 
OF LOW-GRADE INFLAMMATION AND CELL ADHESION MOLECULES IN 
PATIENTS WITH TYPE 2 DIABETES 
 
INVESTIGATORS: 
 
Patrick Couture MD, FRCPC, PhD 
 
 
 
 
André J. Tremblay, PhD  
 
 
 
Benoît Lamarche, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL DATE:  
February 12nd, 2015  


PI: Patrick Couture & Benoît Lamarche 
 
RESEARCH PROPOSAL 
 
 
 
Page 2 
 
 
SAMPLE SIZE, STATISTICAL ANALYSIS, DATA ANALYSIS AND EXPECTED RESULTS 
 
 
Data will be analyzed using a scheme for repeated measures. This power analysis is based 
on our previous results showing that treatment with sitagliptin 100 mg/d in similar diabetic subjects 
was associated with a 7.8% and 9.3% reduction in postprandial response of apoB-48 and VLDL-C, 
respectively (manuscript submitted to Diabetes, Obesity and Metabolism). A conservative power 
calculation was conducted while assuming that the standard deviation of the difference TRL kinetic 
parameters between each treatment phase will be 2-fold greater than the mean treatment effect. 
Power calculations indicated that a total of 20 patients entering this study with a desired power of 
80% will allow us to detect a treatment difference at a one sided 5%, if the true difference between 
the treatments is 9%. As mentioned above, this is based on the assumption that the standard 
deviation of the difference between placebo and sitagliptin treatment is 18%; i.e. 2-fold greater than 
the treatment effect per se. We are therefore confident that the present study design will allow us to 
obtain novel and scientifically rigorous data on the effects of sitagliptin on the kinetics of serum 
amyloid A in type 2 diabetic patients. 
 
Since the present study (NCT02536248) is a substudy of the main research project entitled: “A 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER STUDY TO EVALUATE THE EFFECTS 
OF SITAGLIPTIN ON THE KINETICS OF TRIGLYCERIDE-RICH LIPOPROTEINS APOLIPOPROTEIN B48 AND 
APOLIPOPROTEIN B100 IN PATIENTS WITH TYPE 2 DIABETES” (NCT01334229), the kinetics of Serum 
amyloid A have been analyzed with the same statistical approach. 
 
Furthermore, there was no Informed Consent Form because participants had already signed it in 
the previous study.