This dissertation evaluates the glycemic response of adding pioglitazone to glibenclamide and metformin in type 2 diabetic patients compared to monotherapy with glibenclamide and metformin. The study involved a total of 36 screened patients, with 15 meeting inclusion criteria, and assessed the efficacy, adverse reactions, and complications associated with the treatment regimens over six months. The results indicated that the combination therapy provided superior glycemic control and improved tolerability at lower doses, suggesting its potential to postpone insulin therapy.

1. EVALUATION OF GLYCEMIC RESPONSE OF ADDITION OF PIOGLITAZONE TO
GLIBENCLAMIDE AND METFORMIN HCL IN TYPE 2 DIABETIC PATIENTS ON COMPARISON WITH
GLIBENCLAMIDE AND METFORMIN MONOTHERAPY
A Dissertation Submitted
to
SRI VENKATESWARA UNIVERSITY,TIRUPATHI
In partial fulfillment for the award of degree in
MASTER OF PHARMACY
PHARMACOLOGY
By
D.SUKANYA
Reg; No.2800762009
Under the Guidance
Sri K V GOPINATH
PHARMACY DIVISION
SRI VENKATESWARA UNIVERSITY
TIRUPATI- 517502,(A.P),INDIA
APRIL - 2008

2. AIM
&
OBJECTIVE

3. Aim of the work
 To evaluate and compare the therapeutic response of
pioglitazone with glibenclamide and metformin vis-à-
vis the individual effects of each of these hypoglycemic
agents .

4. Objective of the work
 To evaluate the effects of the combination of pioglitazone with
glibenclamide and metformin vis-à-vis the individual effects of
each of these hypoglycemic agents.
 To compare the therapeutic efficacy or effect of the above
combination with metformin and its rational combinations
(retrospectively)
 To evaluate the possible best combination for managing diabetes
in standard care patients.
 To monitor adverse drug reactions.
 To evaluate the diabetic complications.
 To evaluate the etiology of diabetics.
 To calculate the Body Mass Index (BMI) as per the NIH software
and interpret with diabetes mellitus.
 To collect the demographic data based on One Touch Software.

5. Design of study
parallel case study design & retrospective study
Study Criteria
Inclusion criteria
The following categories of diabetic patients were included in the study.
 Patients belonging to Type 2 diabetes using pioglitazone, glibenclamide and
metformin Hydrochloride, and its rationale combinations.
 Body mass index > 23 and ≤ 45
 Systolic B.P ≤160 mm Hg and diastolic pressure ≤100 mm Hg.
 Hemoglobin > 12g/dl for males and > 10 g/dl for females.
 Serum creatinine < 1.5mg/dl for males and <1.4 mg/dl for female.
 Alanine aminotransferase ≤ 2.5x upper limit of normal.

6.  Thyroid-stimulating hormone levels ≤ the upper limit of the normal range and
the subject is clinically euthyroid
 No major illness or debility that in the investigators opinion prohibits the
subject from completing the study.
 Patients of age group 12 to 60 and above
 Patients who were willing to go for glucometer tests and related procedures.
 No use of oral or systemically injected glucocorticoids or use of weight loss
drug is allowed within the three months prior to randomization.
 Patients who are able to sign written informed consent.

7. Exclusion criteria
 Patients with chronic diseases like tuberculosis, severe heart diseases,
aspiration pneumonia, chronic obstructive pulmonary disease (COPD), and
cystic fibrosis.
 History of psychiatric disorder that will affect the subject’s ability to participate
in the study.
 History of alcohol or substance abuse within the 2 years prior to screening.
 Hypersensitivity to any of the drug or its combinations under study.
 Patient who are less than 90%compliant in drug usage.
 Voluntary withdrawal
 Pregnant women and children

8. The study has been divided into phases.
 Patients having clinical symptoms of diabetes.
 Review inclusion/exclusion criteria
 Diabetic diagnosis on basis of glucometer test (fasting and post prandial)
 Prescribing anti-diabetic drugs.
 Signing consent form by the patient.
 Designing of a standard data collection form to collect demographic data of
the patient (Annexure-I) or by using One Touch Software.
 Check patient’s Glucometer test.
 Assessment of outcome variables by standard statistical analysis.

9. Materials & Methodology
 Study Site
The study was conducted at TTD central hospital, Tirupati, Andhra Pradesh.
 Sample Size
Total 36 patients were screened and enrolled in the study, but only 15 diabetic
patients were satisfying the inclusion criteria
 Drugs
Glibenclamide, Metformin, pioglitazone

10. Drug profiles
Glibenclamide
 Systematic (IUPAC) name: 5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl) phenyl]ethyl]-2-
methoxy-benzamide
Chemical data
 Formula: C23H28ClN3O5S
 Mol. mass: 494.004 g/mol
Pharmacokinetic data
 Protein binding: Extensive
 Metabolism: Hepatic hydroxylation (CYP2C9-mediated)
 Half life: 10 hours
 Excretion: Renal and biliary
Therapeutic considerations
 Routes :Oral
 Dose: 1.25mg,2.5mg,and 5mg
 Trade names: Daonil, Euglucon.
 Mechanism of action:“ inhibiting ATP-sensitive potassium channels in pancreatic beta cells”.

11. Metformin
 Systematic (IUPAC) name: N,N-dimethylimidodicarbonimidic diamide
Chemical data
 Formula:C4H11N5
 Mol. mass:129.164 g/mol,165.63 g/mol (hydrochloride)
 Trade names: Glucophage, Riomet, Fortamet, Glumetza, Diabex, Diaformin,
Pharmacodynamic data
 Bioavailability:50 to 60% under fasting conditions
 Half life:6.2 hours
 Excretion: Active renal tubular excretion by OCT2
Therapeutic considerations
 Routes: Oral

12. pioglitazone
 Systematic (IUPAC) name: 5-((4-(2-(5-ethyl-2-pyridinyl)
ethoxy)phenyl)methyl)-,(+-)-2,4-thiazolidinedione
Chemical data
 Formula:C19H20N2O3S
 Mol. mass: 356.44 g/mol
 Brand name: Actos,Glustin
Pharmacokinetic data
 Protein binding:>99%
 Metabolism:liver (CYP2C8)
 Half life: 3–7 hours
 Excretion:in bile
 Routes: oral

13.  Instruments
 Glucometer (Life Scan, INC, Milpitas, CA 95035, USA, made in China),
 hemocytometer,
 six-channel ECG machine,
 sphygmomanometer, and
 UV spectrophotometer
 Duration of Study
6 months
 Main Sources of Data
 Patient interview
 Patient case notes
 Personnel medication record
 Glucometer tests results

14.  Methodology
 Patients giving informed consent and satisfying the inclusion criteria will be included in
the study.
 They will undergo glucometer tests, pre and post prandial sugar level to confirm the
diabetic, by comparing with normal blood sugar level and also other related procedures
as specified in the inclusive criteria to screen the patients for the study.
 A fasting sugar level was measured at 8 AM of the day of testing, with 10 hr gap of the
overnight dinner meal and postprandial administration of glucometer.
 The blood sugar readings were noted along with normal diet and anti diabetic drug doses
prescribed by the physician.
 The outcome variables measured were noted. The results will be documented in a form.
 Patients were given anti diabetic drugs like metformin (M) alone in a 15 number of
diabetic patients for a period of 45 days continuous therapy at a rational drug dose.
 The same treatment was discontinued on the 46 th day and kept those people in
observation for 15 days without any antidiabetic as a wash out period and started the
second trail viz glibenclamide (GLIBEN) alone on 61 day and continued the same
procedure for 45 days from the day of second trail, and also tried with pioglitazone along
with glibenclamide plus metformin (P-GLIBEN-M) rational combination on 121 th day
and followed the same procedure.
 Glucometers were calibrated daily and therapeutic response of the anti diabetic drug(s)
under trial was noted every day in all patients while in sitting position.

15. DM HT TB Epilepsy Asthma
DM &
HT
Miscellaneous Total
320 234 5 14 147 175 237 1132
Tab 1. Number of Diseases

16. Fig I. Number of Diseases
5
14
147
175
237
1132
234
320
0
200
400
600
800
1000
1200
DM
HT
TB
Epilepsy
Asthma
DM&HT
Miscellaneous
Total
Name of the Disease
NumberofPatients

17. Male Female Total
155 165 320
Tab 2.Demographic Data Based on Sex

18. Fig 2. Demographic Data Based on Sex
(n=320)
155
165
320
0
50
100
150
200
250
300
350
Male Female Total
Sex
PercentageofPatients

19. Age in
years 20-29 30-39 40-49 50-59 >60
Number
of Patients
2 17 71 101 129
Tab 3.Demographic Data Based on Age

20. Fig 3. Demographic Data Based on Age
(n=320)
2
17
71
101
129
0
20
40
60
80
100
120
140
20-29 30-39 40-49 50-59 >60
Age in Years
%ofPatients

21. Tab 4. Demographic Data Based on Education
Education Illiterates Middle School High School College Higher
Number of
Patients
103 73 77 57 19

22. Fig 4.Demographic Data Based on Education
(n=320)
103
73
77
57
19
0
20
40
60
80
100
120
Illeterates Middle School High School College Higher
Education
%ofPatients

23. Occupation Employee
House
wife
Cultivation Unemployed
Number of
Patients
163 140 2 15
Tab 5. Demographic Data Based on Occupation

24. Fig 5. Demographic Data Based on Occupation
Employee, 163,
50%
House wife, 140,
44%
Cultivation, 2, 1%
Unemployee, 15,
5%

25. Fig 6. Demographic Data Based on Smoking
(n=320)
35
285
0
50
100
150
200
250
300
Yes No
Smoking
%ofPatients

26. Fig 7. Demographic Data Based on Alcohol
(n=320)
37
283
0
50
100
150
200
250
300
Yes No
Alcohol
%ofPatients

27. Causes of Diabetics Genetic Sedentary Obesity Drug Induced
Total Diabetics 89 67 48 1
Tab 7. Demographic Data Based on Causes of Diabetes

28. Fig 8. Risk Factor - BMI
Obesity, 36
(17%)
Overweight 85
(40%)
Normal, 89
( 43%)

29. Tab 8. % Change of glycemic value of per oral Anti Diabetics drug(s)
(N=15)
Drug
Mean Baseline
FBS
(mg/dl)
Mean Base line
PPBS
(mg/dl)
Mean Follow-up
FBS
(mg/dl)
Mean Follow up
PPBS
(mg/dl)
Mean%
Change
FBS
(mg/dl)
Mean%
Chan
gePP
BS
(mg/
dl)
M alone 168.25+3.35 230.75+32.54 54.5+34.35 210.5+5.04 22.61 31.56
Gliben
alone
168.25+3.35 230.75+32.54 142.2+3.33 198.9+3.0 12.85 24.31
P +
GLI
BEN
+ M
168.25+3.35 230.75+32.54 120+0.1 174+17 -4.76 8.75
Retrospective study
Met +
Pioz
+
Acar
110 172 94 160 -25.396 0
Met +
Pioz
+
glimipride
153 150 138 115 -8.8235 -39.133

30. Fig:9 Pharmacodynamic response of Metformin HCl
alone
126
168.25
154.4160
230.75
210.5
0
50
100
150
200
250
normal base line the response
Blood sugar parameters
GlycemicResponse(mg/dl)
fbs
ppbs

31. Fig:10 Pharmacodynamic response of Glibenclamide HCl
alone
126
168.25
142.2
160
230.75
198.9
0
50
100
150
200
250
normal base line the.response
Blood sugar parameters
GlycemicResponse(mg/dl)
fbs
ppbs

32. Fig:11 Pharmacodynamic response of
P+Glibenclamide+Met
126
168.25
120
160
230.75
174
0
50
100
150
200
250
normal base line the.response
Blood sugar parameters
Glycemic
Response(mg/dl)
fbs
ppbs

33. Fig:12 Glycemic responses of peroral rational anti diabetic drug(s)
22.61
12.85
-4.76
-25.396
-8.8235
31.56
24.31
8.75
0
-39.133
-50
-40
-30
-20
-10
0
10
20
30
40
met gliben p+gli+met p+met+acar p+met+glimer
Rational Blood samples
%changeinglycemicresponse
fbs(mg/dl)
ppbs(mg/dl)

34. Complications Hypo/Hyper
Risk of
Infections
Diabetic
Retinopathy
Total Diabetics 6 13 20
Diabetics using
M + Gliben+p
4 11 0
Tab 9. Complications of Diabetes

35. 6
13
20
4
11
0
0
5
10
15
20
25
Hypo/Hyper Risk of Infections Diabetic Retinopathy
Diabetic complication
No.ofPatients
Total Diabetics
Diabetics using
Metformin+Gliben+p

36. Tab 10. Adverse Drug Reactions of Anti diabetic Drugs
ADR
Hypo/
hyper
Sweating Appetite Asthenia
Diarrhoe
a
Tremors Malaise
Total
Diabetic
Patients
47 93 111 120 4 44 54

37. 47
93
111
120
4
44
54
0
20
40
60
80
100
120
140
Hypo/Hyper Sweating Appetite Asthenia Diarrhoea Tremors Malaise
Adverse drug reactions
No.ofPatients
Total Diabetics

38. Conclusion
 It was concluded that the addition of pioglitazone to metformin plus
glibenclamide in Type 2 diabetic patients inadequately controlled by
metformin alone resulted in superior glycemic control compared with
glibenclamide or metformin monotherapy have a complementary mechanisms
of action.
 It was also concluded that Glimepride, pioglitazone and metformin or
Acarbose, pioglitazone and metformin have a complementary mechanisms of
action combination therapy with these agents result in improved glycemic
control and improved tolerability at lower doses of individual agents
(retrospective study).
 It was also shown that oral antidaibetic drug combination therapy will also
postpone the usage of parenteral insulin therapy.
 Diabetes is more common in overweight or obese persons.
Finally it was conclude that, right diagnosis of diabetes, a rationale
combination of right oral anti diabetic drugs, changes in diet and lifestyle
makes to achieve good glycemic control.

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