Clinical trial NCT04198948
Conditions: Diabetes Mellitus, Type 2
Sponsor: University of Sarajevo
Start date: 2019-03-04; Completion date: 2019-08-05
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Proton pump inhibitors (PPIs) are treatment of choice for different gastrointestinal disorders common in type 2 diabetes. Sulfonylureas (SUs) are anti-diabetes agents particularly widely used in developing countries. Gliclazide, a recommended SU drug, is metabolised in part by CYP2C19, the main enzyme responsible for the PPI metabolism.

A randomised, placebo-controlled, two-sequence, two-period crossover study will be performed to explore whether gliclazide pharmacokinetics (PK) and pharmacodynamics (PD) are altered upon co-administration with omeprazole. Sixteen healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers (EM/UM), will receive placebo or omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. Plasma concentration of gliclazide will be measured for 24 hours, and plasma glucose and insulin levels up to 12 hours after gliclazide administration.

Detailed description:

Arms: arm 1: Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive placebo under same conditions in a cross-over manner. arm 2: Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive omeprazole under same conditions in a cross-over manner.
Interventions: intervention 1: Omeprazole intervention 2: Placebo oral tablet intervention 3: Gliclazide
Intervention descriptions: intervention 1: Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods. intervention 2: Placebo will be administered orally once daily for 5 days in one of the two treatment periods. intervention 3: Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
STUDY PROTOCOL 
 
Study Title: “Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid 
Metabolisers” 
Study Acronym:  
INTERGLIKOM 
Version Number and Date: Version 1.0, 14/09/2018 
Principal Investigators 
Assist. Prof. Dr. Tanja Dujić, Faculty of Pharmacy, University of Sarajevo, Mobitel: 061 304 155 
Assist. Prof. Dr. Aida Kulo Ćesić, Faculty of Medicine, University of Sarajevo, Mobitel: 061 566 169 
 
Principal Investigator at the research site 
Prim. Dr. Dragan Stevanović, General Hospital ”Prim. Dr. Abdulah Nakaš”, Mobitel: 061 159 420 
 
 
Partners 
Faculty of Pharmacy University of Sarajevo 
Assist. Prof. Dr. Tanja Dujić 
Assist. Prof. Dr. Tamer Bego 
Assist. Prof. Dr. Maja Malenica 
Assist. Prof. Dr. Ervina Bečić 
Assist. Prof. Dr. Belma Imamović 
Mirza Dedić, MSc 
Prof. Dr. Adlija Čaušević 
Prof. Dr. Miroslav Šober 
 
Faculty of Medicine University of Sarajevo 
Assist. Prof. Dr. Aida Kulo Ćesić 
Prof. Dr. Jasna Kusturica 
Prof. Dr. Svjetlana Loga-Zec 
 
General Hospital ”Prim. Dr. Abdulah Nakaš” 
 
Prim. Dr. Dragan Stevanović 
 
Dr. Anela Šubo 
 
International partner 
School of Medicine, University of Dundee, United Kingdom 
 
Prof. Dr. Ewan Pearson 
 
Dr. Jeffrey Huang 
 
NCT04198948 


2 
 
 
 
PROTOCOL APPROVAL 
“Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid Metabolisers” 
 
Signature 
By signing this document, I am confirming that I have read, understood and approved the protocol 
for the above study. I accept to perform the study in accordance with this protocol. 
 
Prim. Dr. Dragan Stevanović 
 
 
 
Principal Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid 
Metabolisers 
 
 
Introduction 
 
Type 2 diabetes (T2D) is a global health problem affecting more than 370 million people worldwide. 
According to the estimations of the International Diabetes Federation, Bosnia and Herzegovina has 
one of the highest prevalence of diabetes in Europe, 12.3%.1 Despite development of novel 
pharmacological agents, sulfonylureas (SUs) remain the most commonly prescribed drugs after 
metformin in the treatment of T2D, because of their high efficacy, extensive experience and least cost.2 
Due to their low cost compared to some of the newer agents, SUs are particularly widely used in low 
and middle income countries, where they have been recommended as treatment of choice for T2D.3  
The most common and potentially most serious adverse effect of sulfonylurea therapy is 
hypoglycaemia.4 Severe hypoglycaemia may result in significant morbidity, including higher risk of 
dementia, stroke and mortality.5-7 Among different SUs, gliclazide has been recommended as a first 
choice in many countries, as it seems to be associated with lower risk of hypoglycaemia and lower 
morbidity and mortality compared with other SUs.8,9 Furthermore, gliclazide has been included on the 
WHO Model List of Essential Medicines, based on safety data in elderly patients. Nevertheless, in a 
recent population-based cohort study, gliclazide showed a similar risk of hypoglycaemia compared 
with other SUs.10 
Gliclazide is extensively metabolised in the liver to inactive metabolites. Although CYP2C9 is involved 
in the metabolism of gliclazide,11 the pharmacokinetics (PK) and pharmacodynamics (PD) of gliclazide 
seem to be affected mainly by CYP2C19 genetic polymorphisms.12,13   
Gastrointestinal problems, such as gastroesophageal reflux disease (GERD) are common in T2D.14 A 
recent meta-analysis involving 9,067 cases and 81,968 controls showed a significant association 
between diabetes and the risk of GERD.15 The prevalence of GERD symptoms in patients with T2D could 
be as high as 40%.14 Therefore, millions of individuals are managing blood glucose and GERD 
concomitantly.16 Proton pump inhibitors (PPIs) are the medications of choice for GERD, and are 
primarily metabolised by CYP2C19.17 The potential for drug-drug interactions is highest for omeprazole 
and its stereo-isomer esomeprazole, which are metabolised almost entirely by CYP2C19.17,18 
Furthermore, it has been shown that impact of PPIs on the PK, PD, and therapeutic response to drugs 
metabolised by CYP2C19 could depend on CYP2C19 genotype, with highest effect seen in CYP2C19 
normal metabolisers (extensive metabolisers, EM)19,20 and ultrarapid metabolisers (UM).21 
 
 
Project aims 
 
Considering the high prevalence of use of PPIs,22 the greater incidence of GERD in T2D and likely high 
concomitant use of PPIs with gliclazide, and the possibility of their interaction via CYP2C19, the primary 
aim of this pilot clinical study is to explore potential drug-drug interaction between gliclazide and 
omeprazole in CYP2C19 EM/UM metabolisers. The specific aims are: 
 
1. To explore whether gliclazide PK is altered upon co-administration with omeprazole in healthy 
volunteers, CYP2C19 EM/UM metabolisers 
2. To explore whether gliclazide PD is altered upon co-administration with omeprazole in healthy 
volunteers, CYP2C19 EM/UM metabolisers 
 
 


4 
 
Preliminary data 
To our knowledge, there have been no studies exploring potential interaction between any PPI and 
gliclazide, in animals or humans. To explore this possible drug-drug interaction, we performed 
preliminary observational analyses in the large population-based GoDARTS study (UK). Briefly, our 
preliminary data suggest that co-treatment with PPIs, especially omeprazole, increases the risk of 
hypoglycaemia in patients with CYP2C19 EM/UM phenotype treated with gliclazide. This has been 
confirmed by better glycaemic response (lower HbA1c) associated with PPI use in EM/UM patients 
treated with gliclazide. These results support a biologically plausible hypothesis of possible interaction 
between PPIs and gliclazide, in relation to CYP2C19 genotype. 
 
 
Study population 
The study protocol will be approved by the Ethics Committee of the General Hospital “Prim. Dr. 
Abdulah Nakaš” and the Ethics Committee of the Faculty of Medicine, University of Sarajevo, Sarajevo, 
Bosnia and Herzegovina (B&H). All procedures will be conducted at the Department of Internal 
Medicine of the General Hospital in line with the Good Clinical Practice and the Declaration of Helsinki. 
Prior to inclusion in the study, the nature and purpose of the study will be explained, in both written 
and verbal form, to each volunteer who will then give the informed written consent to participate in 
the study. 
Volunteers will be initially recruited through advertising by using leaflets, posters and social networks 
(e.g. Facebook). At least 40 volunteers will be recruited and pre-screened for CYP2C19 genotype. Based 
on the frequency of CYP2C19*2 variant in B&H population of ~17%,23 we expect that about two-thirds 
of screened individuals will be non-carriers of the *2 allele. The recruitment will end when the minimal 
number of 16 individuals, non-carriers of *2 allele, is reached. Only these individuals (CYP2C19 EM/UM 
metabolisers) will be included in the drug interaction study after confirmation of their health status.  
 
Inclusion criteria for screening (genotyping) 
• 
Men 
• 
Age 18-30 years 
• 
Non-smokers 
 
Exclusion criteria for screening (genotyping) 
• 
medical history of hepatic, renal, gastrointestinal and hematologic disease or any acute or 
chronic disease  
• 
any chronic drug therapy 
• 
drug allergy to sulfonylureas and/ or PPIs  
• 
history of drug abuse 
 
Genotyping 
Genomic DNA will be extracted from blood samples by using commercial DNA extraction kits. 
Polymorphisms in the CYP2C19 gene: CYP2C19*2 (rs4244285) and CYP2C19*17 (rs12248560), CYP2C9 
gene: CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910) and a variant in the POR gene encoding a CYP450 
redox partner, enzyme P450 oxidoreductase (POR), POR*28 (rs1057868), will be genotyped by specific 
Drug Metabolism SNP genotyping assays. Genetic test results for CYP2C19 variants will be obtained at 
the screening, before the randomisation. Only individuals, non-carriers of the CYP2C19*2 allele will be 
included further in the clinical study. Results obtained for other three variants in the CYP2C9 and POR 
genes will be used as covariates in the statistical analysis.24 


5 
 
Inclusion criteria for drug interaction study 
• 
CYP2C19 normal/ ultrarapid metabolisers (non-carriers of the CYP2C19*2 allele) 
 
Exclusion criteria for drug interaction study 
• 
abnormalities in physical examination, ECG and routine clinical laboratory tests (including 
fasting blood glucose concentration) 
• 
medication use during the 14 days prior and during the study periods 
• 
grapefruit, grapefruit juice, alcohol, beverages or food containing methylxanthines use 
during 72 h prior and during the study periods 
Participants will be randomised to specific treatment sequences using SAS Proc Plan procedure.  
 
 
 
Wash-out (> 7 days) 
Wash-out (> 7 days) 
Gliclazide + Omeprazole 
Gliclazide + Placebo 
Recruitment 
Informed consent 
Screening and genotyping 
Confirmation of health status  
Randomisation of 16 volunteers 
Gliclazide + Omeprazole 
Gliclazide + Placebo 
Non-carriers of CYP2C19*2 allele 
Informed consent 


6 
 
Drug interaction study design 
A randomised, placebo controlled, two-sequence, two-period crossover study, with at least a 7-day 
washout period between the study periods will be conducted to compare the effects of gliclazide (40 
mg, half of an 80 mg tablet of Diprian®, Hemofarm d.o.o. Banja Luka, B&H, orally) and placebo with 
those of gliclazide combined with omeprazole (20 mg, Ulcosan®, Bosnalijek d.d. Sarajevo, B&H, orally). 
Prior to administration of gliclazide, omeprazole or placebo will be administered once daily at 8 AM 
for 4 days (on day 1 until day 4) to assure PD steady-state. At 8 AM of the day 5, after an overnight fast 
(last meal at 9 pm of the previous day), the participants will be given a single dose of 40 mg gliclazide 
with 240 mL of water together with omeprazole or with placebo according to their treatment 
assignment.  
The volunteers will be given both drugs (gliclazide + omeprazole or gliclazide + placebo) in a sitting 
position and they will not be permitted to lie down or sleep for the next 4 h after taking gliclazide. They 
will be under direct medical supervision throughout the 24 h following drug administration. 
In order to counteract the blood glucose-lowering action of gliclazide, subjects will receive 
standardized meals: a breakfast at 30 min after gliclazide intake, snacks after 2 and 3 h, a lunch (warm 
meal) after 4 h, a snack after 6 h, a dinner after 8 h, and additional snacks at 10 h and 12 h after drug 
administration. The larger meals should be eaten within 10 minutes, and snacks within 5 minutes. No 
other food and drink (with the exception of water) or strenuous activities will be allowed. 
 
 
Schematic design of the drug interaction study 
 
• 
Period 1 
- Eight (8) subjects will receive treatment A on days D 1–5 
- Eight (8) subjects will receive treatment B on days D 1–5 
• 
Wash-out period D6–14   
• 
Period 2 
- Eight (8) subjects will receive treatment B on days D 15–19 
- Eight (8) subjects will receive treatment A on days D 15–19 
 
Treatment 
Treatment A: days 1–4, administration of placebo with 240 mL of water 
          day 5, administration of placebo + 40 mg gliclazide with 240 mL of water 
Treatment B: days 1–4, administration of 20 mg omeprazole with 240 mL of water 
     
          day 5, administration of 20 mg omeprazole + 40 mg gliclazide with 240 mL of water 
 
 
 
 
 
 
 
                D1–5                                                  D6–D14*                                          D15–19 
*Wash-out period of at least 7 days 
 
1–5 day placebo + 
5th day gliclazide 40 mg  
1–5 day omeprazole 20 mg 
+ 5th day gliclazide 40 mg 
1–5 day placebo + 
5th day gliclazide 40 mg  
1–5 day omeprazole 20 mg 
+ 5th day gliclazide 40 mg 
Wash-out 


7 
 
Blood collection 
Venous blood samples will be collected on day 5 and day 19 for gliclazide, glucose and insulin 
quantification, through an indwelling intravenous cannula in the arm or by direct venepuncture (in the 
case of cannula blockage).  
A total of 17 blood samples, 5 ml each, will be taken, thus the total blood volume of 85 ml will be taken 
during 24 hours, which is over 5 times less than the standard 450 ml drawn during voluntary blood 
donation.  
Blood sampling for gliclazide quantification 
• 
gliclazide: pre-dose (0 h), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, and 24 h 
Blood sampling for glucose and insulin quantification 
• 
glucose: pre-dose (0 h), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10 and 12 h 
• 
insulin: pre-dose (0 h), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10 and 12 h 
Blood glucose levels will be measured immediately after sampling. Serum samples for insulin and 
gliclazide quantification will be obtained and stored in properly labelled tubes at -80°C until the 
analysis. 
 
Gliclazide concentration analysis 
Serum gliclazide concentration will be analysed at the Biomarker and Drug Analysis Core Facility, 
School of Medicine, University of Dundee, by using a stable isotope dilution LC-MS method. 
 
Glucose and insulin quantification 
Glucose concentrations will be measured at the laboratory of the General Hospital. 
Insulin concentrations will be quantified by enzyme-linked immunosorbent assay (ELISA) using 
commercially available kit. 
 
Pharmacokinetic analysis 
• 
Cmax: Gliclazide maximum concentration  
• 
tmax: Time to reach Cmax 
• 
AUC0–t: Area under the concentration–time curve (AUC) up to the last concentration 
measured 
• 
AUC0–: Area under the concentration–time curve (AUC) extrapolated to infinity  
• 
t1/2: Elimination half-life 
• 
CL/F: Apparent oral clearance 
• 
Vd/F: Apparent volume of distribution 
 
PK parameters will be calculated by a noncompartmental analysis using PKSolver a program for PK and 
PD data analysis in Microsoft Excel. Gliclazide maximum concentration (Cmax) and time to reach Cmax 
(tmax) will be determined by the inspection of the concentration–time data. The area under the plasma 
gliclazide concentration–time curve (AUC) up to the last concentration measured (AUC0–t) will be 
determined using the linear trapezoidal rule. The AUC will be extrapolated to infinity (AUCt–) using 
Ct/kel, where Ct is the last measured gliclazide concentration and kel is the elimination rate constant 
that will be estimated from the slope of the best-fit line determined by linear regression analysis of 
the log-transformed concentration-time curve. The elimination half-life (t1/2) will be calculated using 
the following equation: t1/2=ln(2)/kel. The apparent oral clearance (CL/F) will be calculated as 
dose/AUC0–. The apparent volume of distribution (Vd/F) will be calculated as dose/AUC x kel. 
 
 
 


8 
 
Pharmacodynamic parameters 
• 
Cmin: Glucose minimum concentration 
• 
Cavg 0-4: Average glucose concentration in the period 0–4 h  
• 
Cavg 0-12: Average glucose concentration in the period 0–12 h 
• 
AUC0-4: Area under the glucose concentration–time curve from 0 to 4 h  
• 
AUC0-12: Area under the glucose concentration–time curve from 0 to 12 h  
 
• 
Cmin: Insulin minimum concentration 
• 
Cavg 0-4: Average insulin concentration in the period 0–4 h 
• 
Cavg 0-12: Average insulin concentration in the period 0–12 h 
• 
AUC0-4: Area under the insulin concentration–time curve from 0 to 4 h 
• 
AUC0-12: Area under the insulin concentration–time curve from 0 to 12 h 
 
To compare the PD effects of gliclazide, the areas under the glucose and insulin concentration–time 
curve from 0 to 4, and 0 to 12 h after the administration of gliclazide will be calculated using the linear 
trapezoidal rule. The minimum glucose and insulin concentration will be determined by observation of 
the concentration–time data, and mean concentrations from 0 to 4 h and from 0 to 12 h will be 
calculated by dividing the area under the glucose/insulin concentration–time curve by the 
corresponding time interval. 
 
Safety assessment and precaution measures 
The volunteers will undergo a detailed physical, ECG, and laboratory examination upon inclusion in the 
drug interaction study. The subjects will be contacted within 14 days of study completion in order to 
confirm the adequate post-study status. 
 
If any clinical reasons arise that could endanger health status of the subjects by taking blood samples, 
the blood samples will not be drawn. Considering that bruising, bleeding, infection or pain may occur 
at the site of venepuncture and cannulation, these procedures will be performed by experienced 
medical staff to minimise the risk of excessive bleeding or bruising, and a topical anaesthetic may be 
used, if required, to reduce the pain.  
 
Since this combination of drugs can potentially induce risk of hypoglycaemia, administration of the two 
drugs will be carried out in the hospital where the subjects will be hospitalised for 24 h and will be 
continuously under direct medical supervision. In order to avoid the risk of hypoglycaemia, subjects 
will receive 8 meals (breakfast, lunch, dinner and 5 snacks). In case of any symptom suggestive of 
hypoglycaemia (nervousness, sweating, intense hunger, trembling, weakness, palpitations), the blood 
glucose level will be measured using a glucometer and one of the standard measures of raising blood 
sugar will be applied, such as administration of 20% oral glucose solution, glucose solution for 
intravenous use, or glucagon for intramuscular use. 
 
In addition, systolic and diastolic blood pressure and heart rate will be measured in the supine position 
after a 5-minute rest, before drug intake and during the PK profiles at 2, 4, 12 and 24 hours after 
gliclazide administration. 
 
Power analysis 
For identification of clinically relevant drug-drug interaction, we will use the bioequivalence approach. 
The main outcome to be evaluated is the exposure to gliclazide, expressed as AUC0–t. Sample size 
calculation was performed using SAS Proc Power procedure for equivalence test in 2x2 crossover 
design.25 For an equivalence range of 80–125%, the within-subject coefficient of variation for the AUC 
values for gliclazide of 7.8% based on previous PK studies,26,27 and expected test/reference geometric 


9 
 
mean ratios between 87–115%, 14 volunteers (7 individuals per sequence) are required to show the 
lack of interaction with 85% power. To account for potential drop-outs due to non-compliance or loss 
of follow up (assuming a drop-rate of 10%), a total of 16 subjects, CYP2C19 EM/UM metabolisers, will 
be randomised. To achieve this number, minimally 40 volunteers will be initially recruited. 
 
Statistical analysis 
The geometric mean will be calculated for each PK and PD parameter. Logarithmic transformation will 
be used for PK variables, except tmax, before the analysis. The ratios of the geometric means with 90% 
confidence intervals (CI) will be assessed by linear mixed models between the two treatment 
assignments: gliclazide and omeprazole coadministration to that of gliclazide and placebo. The 
statistical analyses will be performed using the SAS 9.3 software (SAS Institute Inc., Cary, NC). 
 
Original scientific contribution and clinical significance of the research 
This research will establish whether omeprazole can alter PK/PD of gliclazide, and thus increase the 
risk of serious hypoglycaemia with this recommended SU drug. 
 
This study can unravel new, previously unrecognized drug-drug and drug-drug-gene interactions. If 
clinically relevant alterations in gliclazide PK/PD parameters are established, our findings can lead to 
changes in clinical practice with the aim of preventing serious, potentially life-threatening 
hypoglycaemia induced by gliclazide treatment.  
 
Confidentiality and data protection 
All clinical, laboratory and genetic data will be processed in a manner designed to protect the identity 
of the participants, in accordance with the rules of personal data protection and the guidelines of the 
Good Clinical Practice. Participants’ privacy will be respected in all published and other public written 
data that will result from this study. 
 
Withdrawal from the study 
Participants are free to withdraw from the study at any time, without obligation to explain their 
decision. 
 
Insurance 
In accordance with the guidelines of Good Clinical Practice, the subjects will be insured under the terms 
of insurance for Clinical Trials. 
 
Compensation of costs 
The costs of participants arising from their participation in the screening visit will be reimbursed in the 
amount of 50.00 BAM upon completion, and the costs of participants arising from their participation 
in the drug interaction study will be reimbursed in the amount of 400.00 BAM upon completion of the 
study. The funds will be paid to the participants’ bank account. 
 
Adverse events 
 
Definitions 
An adverse event (AE) is any untoward medical event affecting a clinical trial participant. Each initial 
AE will be considered for severity, causality or expectedness and may be reclassified as a serious event 
or reaction based on prevailing circumstances. 
An adverse reaction (AR) is where it is suspected that an AE has been caused by a reaction to a trial 
drug. 


10 
 
A serious adverse event (SAE), serious adverse reaction (SAR) or suspected unexpected serious adverse 
reaction (SUSAR) is any AE, AR or UAR that at any dose: 
 
• 
results in death or is life threatening  
• 
requires hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect. 
 
Recording and reporting adverse events and serious adverse events 
The principal investigator should report any SAE that is both related to the research procedures and is 
unexpected, to the Ethics Committees which approved the study, and to the Faculty of Pharmacy 
University of Sarajevo, within 24 hours of the becoming aware of the event. 
 
An adverse event log will be maintained in the CRF. The principal investigator on this study is 
medically qualified and will assess all adverse events for expectedness, seriousness and causality and 
will follow up to resolution or to within 30 days of the end of the study. The seriousness of the 
adverse event will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 Publish Date: November 27, 2017 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_5x7.pdf). 
 
 
References 
1. 
Feng, Y., et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with 
antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 31, 1939-
1944 (2008). 
2. 
Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care 40, S4-S5 
(2017). 
3. 
Kalra, S., et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South 
Asia: A consensus statement. Indian journal of endocrinology and metabolism 19, 577-596 
(2015). 
4. 
Krentz, A.J. & Bailey, C.J. Oral antidiabetic agents: current role in type 2 diabetes mellitus. 
Drugs 65, 385-411 (2005). 
5. 
Zoungas, S., et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 
363, 1410-1418 (2010). 
6. 
Yaffe, K., et al. Association between hypoglycemia and dementia in a biracial cohort of older 
adults with diabetes mellitus. JAMA Intern Med 173, 1300-1306 (2013). 
7. 
Feinkohl, I., et al. Severe hypoglycemia and cognitive decline in older people with type 2 
diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 37, 507-515 (2014). 
8. 
Schramm, T.K., et al. Mortality and cardiovascular risk associated with different insulin 
secretagogues compared with metformin in type 2 diabetes, with or without a previous 
myocardial infarction: a nationwide study. European heart journal 32, 1900-1908 (2011). 
9. 
Schopman, J.E., et al. The incidence of mild and severe hypoglycaemia in patients with type 2 
diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. 
Diabetes Metab Res Rev 30, 11-22 (2014). 
10. 
van Dalem, J., et al. Risk of hypoglycaemia in users of sulphonylureas compared with 
metformin in relation to renal function and sulphonylurea metabolite group: population 
based cohort study. Bmj 354, i3625 (2016). 


11 
 
11. 
Elliot, D.J., et al. Identification of the human cytochromes P450 catalysing the rate-limiting 
pathways of gliclazide elimination. Br J Clin Pharmacol 64, 450-457 (2007). 
12. 
Zhang, Y., et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on 
pharmacokinetics of gliclazide MR in Chinese subjects. Br J Clin Pharmacol 64, 67-74 (2007). 
13. 
Shao, H., et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on 
pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J 
Clin Pharm Ther 35, 351-360 (2010). 
14. 
Wang, X., Pitchumoni, C.S., Chandrarana, K. & Shah, N. Increased prevalence of symptoms of 
gastroesophageal reflux diseases in type 2 diabetics with neuropathy. World journal of 
gastroenterology 14, 709-712 (2008). 
15. 
Sun, X.M., Tan, J.C., Zhu, Y. & Lin, L. Association between diabetes mellitus and 
gastroesophageal reflux disease: A meta-analysis. World journal of gastroenterology 21, 
3085-3092 (2015). 
16. 
Zdilla, M.J. Metformin With Either Histamine H2-Receptor Antagonists or Proton Pump 
Inhibitors: A Polypharmacy Recipe for Neuropathy via Vitamin B12 Depletion. Clinical 
diabetes : a publication of the American Diabetes Association 33, 90-95 (2015). 
17. 
Strand, D.S., Kim, D. & Peura, D.A. 25 Years of Proton Pump Inhibitors: A Comprehensive 
Review. Gut and liver (2016). 
18. 
Zvyaga, T., et al. Evaluation of six proton pump inhibitors as inhibitors of various human 
cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos 40, 1698-1711 
(2012). 
19. 
Uno, T., Sugimoto, K., Sugawara, K. & Tateishi, T. The role of cytochrome P2C19 in R-warfarin 
pharmacokinetics and its interaction with omeprazole. Therapeutic drug monitoring 30, 276-
281 (2008). 
20. 
Furuta, T., Iwaki, T. & Umemura, K. Influences of different proton pump inhibitors on the 
anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. British journal of 
clinical pharmacology 70, 383-392 (2010). 
21. 
Depta, J.P., et al. Clinical outcomes associated with proton pump inhibitor use among 
clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial 
infarction. Pharmacogenomics J 15, 20-25 (2015). 
22. 
Heidelbaugh, J.J., Kim, A.H., Chang, R. & Walker, P.C. Overutilization of proton-pump 
inhibitors: what the clinician needs to know. Therapeutic advances in gastroenterology 5, 
219-232 (2012). 
23. 
Semiz, S., et al. Analysis of CYP2C9*2, CYP2C19*2, and CYP2D6*4 polymorphisms in 
patientswith type 2 diabetes mellitus. Bosn J Basic Med Sci 10, 287-291 (2010). 
24. 
Dujic, T., et al. Interaction between variants in the CYP2C9 and POR genes and the risk of 
sulfonylurea-induced hypoglycaemia: A GoDARTS Study. Diabetes Obes Metab 20, 211-214 
(2018). 
25. 
Sun, P. Using SAS Proc Power to Perform Model-based Power Analysis for Clinical 
Pharmacology Studies. PharmaSUG2010 - Paper SP05 (2010). 
26. 
Najib, N., et al. Bioequivalence evaluation of two brands of gliclazide 80 mg tablets (Glyzide & 
Diamicron)--in healthy human volunteers. Biopharm Drug Dispos 23, 197-202 (2002). 
27. 
Park, J.Y., Kim, K.A., Kim, S.L. & Park, P.W. Quantification of gliclazide by semi-micro high-
performance liquid chromatography: application to a bioequivalence study of two 
formulations in healthy subjects. Journal of pharmaceutical and biomedical analysis 35, 943-
949 (2004).