The Effect of Adding Vildagliptin Versus Glimepiride to Metformin on Markers of Inflammation, Thrombosis, and Atherosclerosis in Diabetic Patients With Symptomatic Coronary Artery Diseases
Phase: PHASE4
Conditions: Coronary Artery Disease, Diabetes Mellitus, Type 2
Sponsor: Damanhour University

 
 
UNIVERSITY
 
AMANHOUR
D
 
FACULTY OF PHARMACY
 
 
 
 
 
 
 
 
 
The effect of adding Vildagliptin versus Glimepiride to Metformin on 
markers of inflammation, thrombosis, and atherosclerosis in diabetic 
patients with symptomatic Coronary Artery Diseases. 
Department of Post Graduate Studies and Research 
1/9/
2012
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mahmoud Kotb1, Rehab Werida2, Tarek Mostafa3, Gamal Omran4, Ahmed Skokry5 1. 
Department of Clinical Pharmacy, Alex. Armed Forces Hospital, Alexandria, Egypt. 2. 
Department of Clinical Pharmacy, Faculty of Pharmacy, Damanhour University, 
Damanhour, Egypt 3. Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta 
University, Tanta, Egypt. 4. Department of Biochemistry, Faculty of Pharmacy, 
Damanhour University, Damanhour, Egypt. 5. Department of Cardiology, Alex. Armed 
Forces Hospital, Alexandria, Egypt. 
 

 
 
 
 
 
1
 
 
Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
 
Scientific Protocol for (M.Sc.) Thesis in 
Pharmaceutical Science 
(Clinical  Pharmacy)
 
In partial Fulfilment of the
 
Requirements for the Degree of
 
(Master) 
By 
Pharmacist / Mahmoud Kotb Mahmoud Kabel
 
 Bachelor of Pharmaceutical Sciences Alexandria University (June 2008). 
 Doctor of Clinical pharmacy (Pharm D) (June 2015). 
Title of the thesis  
The effect of adding Vildagliptin versus Glimepiride to Metformin 
on markers of inflammation, thrombosis, and atherosclerosis in 
diabetic patients with symptomatic Coronary Artery Diseases. 
 
Under supervision of 
1- Prof. Gamal Abdelhai Omran . 
Professor of Biochemistry and Dean of Faculty of Pharmacy – Damanhour 
University.      
2- Dr. Ahmed Hamdy Ahmed fouad skokry. 
Head of Cardiology Dep. Alex. Armed Forces Hospital. 
3-  Ass. Prof. Tarek Mohamed Mostafa 
Associate Professor of Clinical Pharmacy -Faculty of Pharmacy- Tanta University. 
4- Dr. Rehab Werida  
Lecturer of Clinical Pharmacy -Faculty of Pharmacy – Damanhour University.      

 
 
 
 
 
2
 
 
Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
 
 
Abstract 
 
Diabetes mellitus is a chronic disease associated with a two- to fourfold increased risk 
of coronary artery diseases (CAD).(1, 2) Diabetes induces complex vascular changes, 
promoting accelerated atherosclerosis and hypercoagulability, as can be assessed 
indirectly by a number of markers. Principal perturbations include endothelial 
dysfunction, increased inflammatory plaque infiltration, adhesion molecule over-
expression, adverse effects of circulating fatty acids and advanced glycosylation end 
products. 
Vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), 
improves glycemic control by increasing the availability of endogenous incretin 
hormones, glucagon- like peptide-1 (GLP-1) and glucose-dependent insulinotropic 
polypeptide (GIP) (3). Complementing the pharmacological effect of metformin, 
vildagliptin enhances glucose-dependent insulin secretion and suppresses glucagon 
release, thereby improving glycemic control, and contributing to weight- neutrality and 
reduced hypoglycaemia(4) . Vildagliptin has demonstrated similar efficacy as an add-on 
to metformin when compared to SU with markedly reduced hypoglycaemia risk and no 
weight gain (5). 
 Animal studies have suggested numerous beneficial anti-atherosclerotic changes of 
dipeptidyl peptidase-4 inhibitors (DPP4i), well beyond the effects on blood glucose 
alone (6, 7). Additionally, anti-remodeling effects are proposed (8). However, this 
feature has not been established in a clinical setting. Reduction of inflammatory marker 
levels is of great clinical importance and has been shown to correlate with reduction in 
significant clinical events (1, 9). 
 
 

 
 
 
 
 
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Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
 
 
IL-1 is the pro-inflammatory mediator in both acute and chronic inflammation(10). It 
plays a major role in the activation of innate immunity(11), induces the synthesis and 
expression of multiple secondary inflammatory mediators including IL-6, IL-18 and IL-
33(12, 13), and is strongly associated with the development of atherosclerosis and 
impairment of cardiac function in diabetic patients(14). 
High sensitivity C-reactive protein (hs-CRP) is a marker of inflammation with a strong 
correlation with cardiovascular events even in normo-lipemic population (15). 
Reduction of hs-CRP has been demonstrated with vildagliptin-pioglitazone 
combination, but data from patients with symptomatic CAD and vildagliptin-metformin 
combination are lacking (16). 
Adiponectin is a hormone with regulatory metabolic function secreted from the adipose 
tissue. Reduced levels of adiponectin were shown to be associated with obesity, 
metabolic syndrome, and diabetes, and to promote the atherosclerotic process (17, 18). 
Higher levels have been found to be protective (19). Reduction in adiponectin levels 
induced by fatty diet has recently been shown to be corrected by DPP4i in mice (6), yet 
the effect in diabetic humans is unknown.  
Atherogenic index (AI) (LDL-C/ HDL-C) and coronary risk index (CRI) (TC/HDL-C) 
can be strong markers for predicting the risk of atherosclerosis and coronary heart 
disease and disclose the presence of LDL or TAG in the serum of related patients(20). 
Therefore, in the present study we plan to focus on possible anti-inflammatory and 
atherothrombotic protective effects of vildagliptin in a clinical setting. 
 
 
 
 
 
 

 
 
 
 
 
4
 
 
Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
 
Research Objectives 
 
The aim of this study is to evaluate the effect of adding Vildagliptin versus Glimepiride 
to Metformin on markers of inflammation, thrombosis, and atherosclerosis in diabetic 
patients with symptomatic CAD. 
 
Method & Proposal Steps 
 
 
1- Approval will be obtained from Research Ethics Committee of Faculty of 
Pharmacy, Damanhour University. 
2- All participants agreed to take part in this clinical study and provide informed 
consent. 
3- Patients with CAD and uncontrolled DM type 2 who's taking metformin only will 
be enrolled (n=80) from endocrinology clinic at Alexandria Armed Forces hospital. 
4-  Complete physical, laboratory, radiological assessment will be done for all patients 
to exclude any signs of inflammation or thrombosis. 
5- Serum samples will be collected for measuring the biomarkers. 
6- All enrolled patients will be mentioned as two groups; Group I (n=40) are patients 
who the endocrinologist prescribed them vildagliptin plus their metformin to 
control their blood sugar level. Group II (n=40) are patients who the 
endocrinologist prescribed them glimepiride plus their metformin. 
7- All patients will be followed up during 3 months’ period. 
8- At the end of 3 months on the new regimen, steps 4 and 5 will be repeated. 
9- Statistical tests appropriate to the study design will be conducted to evaluate the 
significance of the results. 
10- Measuring outcome: The primary outcome is the change of serum levels of the 
measured inflammatory markers after 3 months. 
11- Results, conclusion, discussion and recommendations will be given. 

 
 
 
 
 
5
 
 
Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
 
Inclusion criteria 
 Adult patients with Type II-diabetes mellitus on metformin who are planned to be 
managed with vildagliptin or glimepiride plus metformin at the time of inclusion. 
 Symptomatic Coronary Artery Diseases. (>30 days). 
 
Exclusion criteria 
 Hepatic impairment. 
 Active malignancy. 
 Planned surgical intervention. 
  Any signs of hypersensitivity or contraindication to study drugs developed. 
 Any patient with any signs of active infection or thrombosis at the time of 
assessment. 
 Addition of any antidiabetic medications or insulin during follows up. 
 Chronic inflammatory disease (i.e. inflammatory bowel disease, lupus, 
inflammatory arthritis, rheumatoid arthritis) or chronic infection (i.e. chronic 
diabetic foot infection). 
  Pregnancy, lactation or child-bearing potential. 
 
Methodology 
 Interleukin1 beta (IL-1ß) and Adiponectin will be determined by ELISA. 
 Lipid profile. 
 Atherogenic index (AI = LDL-C/HDL-C) and CRI (CRI = TC/HDL-C) will be 
calculated for all subjects. 
 High sensitivity C-reactive protein (hs-CRP) will be measured. 
 Hb A1C will be measured. 
 

 
 
 
 
 
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Damanhour UNIVERSITY
 
FACULTY OF PHARMACY
 
Department of Post Graduate 
Studies and Research
 
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Department of Post Graduate 
Studies and Research
 
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