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

toSRI VENKATESWARA UNIVERSITY,TIRUPATHI

In partial fulfillment for the award of degree inMASTER OF PHARMACY

PHARMACOLOGY

ByD.SUKANYA

Reg; No.2800762009

Under the Guidance Sri K V GOPINATHPHARMACY DIVISION

SRI VENKATESWARA UNIVERSITYTIRUPATI- 517502,(A.P),INDIA

APRIL - 2008

AIM &

OBJECTIVE

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 .

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.

Design of studyparallel case study design & retrospective study

Study CriteriaInclusion 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.

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.

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

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.

Materials & Methodology

Study SiteThe study was conducted at TTD central hospital, Tirupati, Andhra Pradesh.

Sample SizeTotal 36 patients were screened and enrolled in the study, but only 15 diabetic

patients were satisfying the inclusion criteria

Drugs Glibenclamide, Metformin, pioglitazone

Drug profilesGlibenclamide Systematic (IUPAC) name: 5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl) phenyl]ethyl]-2-

methoxy-benzamide

Chemical data Formula: C23H28ClN3O5S Mol. mass: 494.004 g/molPharmacokinetic data Protein binding: Extensive Metabolism: Hepatic hydroxylation (CYP2C9-mediated) Half life: 10 hours Excretion: Renal and biliaryTherapeutic 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”.

Metformin Systematic (IUPAC) name: N,N-dimethylimidodicarbonimidic diamideChemical 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 OCT2Therapeutic considerations Routes: Oral

pioglitazone Systematic (IUPAC) name: 5-((4-(2-(5-ethyl-2-pyridinyl)

ethoxy)phenyl)methyl)-,(+-)-2,4-thiazolidinedioneChemical data Formula:C19H20N2O3S Mol. mass: 356.44 g/mol Brand name: Actos,GlustinPharmacokinetic data Protein binding:>99% Metabolism:liver (CYP2C8) Half life: 3–7 hours Excretion:in bile Routes: oral

Instruments Glucometer (Life Scan, INC, Milpitas, CA 95035, USA, made in China), hemocytometer, six-channel ECG machine, sphygmomanometer, and UV spectrophotometer

Duration of Study6 months

Main Sources of Data Patient interview Patient case notes Personnel medication record Glucometer tests results

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.

DM HT TB Epilepsy Asthma DM & HT Miscellaneous Total

320 234 5 14 147 175 237 1132

Tab 1. Number of Diseases

Fig I. Number of Diseases

5 14

147

175 23

7

1132

23432

0

0

200

400

600

800

1000

1200

DM HT

TB

Epi

leps

y

Ast

hma

DM

& H

T

Mis

cella

neou

s

Tota

l

Name of the Disease

Num

ber o

f Pat

ient

s

Male Female Total

155 165 320

Tab 2.Demographic Data Based on Sex

Fig 2. Demographic Data Based on Sex(n=320)

155165

320

0

50

100

150

200

250

300

350

Male Female Total

Sex

Per

cent

age

of P

atie

nts

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

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

% o

f Pat

ient

s

Tab 4. Demographic Data Based on Education

Education Illiterates Middle School High School College Higher

Number of Patients

103 73 77 57 19

Fig 4.Demographic Data Based on Education(n=320)

103

7377

57

19

0

20

40

60

80

100

120

Illeterates Middle School High School College Higher

Education

% o

f Pat

ient

s

Occupation Employee House wife Cultivation Unemployed

Number of Patients 163 140 2 15

Tab 5. Demographic Data Based on Occupation

Fig 5. Demographic Data Based on Occupation

Employee, 163, 50%House wife, 140,

44%

Cultivation, 2, 1%

Unemployee, 15, 5%

Fig 6. Demographic Data Based on Smoking (n=320)

35

285

0

50

100

150

200

250

300

Yes No

Smoking

% o

f Pat

ient

s

Fig 7. Demographic Data Based on Alcohol(n=320)

37

283

0

50

100

150

200

250

300

Yes No

Alcohol

% o

f Pat

ient

s

Causes of Diabetics Genetic Sedentary Obesity Drug Induced

Total Diabetics 89 67 48 1

Tab 7. Demographic Data Based on Causes of Diabetes

Fig 8. Risk Factor - BMI

Obesity, 36 (17%)

Overweight 85 (40%)

Normal, 89( 43%)

Tab 8. % Change of glycemic value of per oral Anti Diabetics drug(s)(N=15)

DrugMean 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% ChangePPBS

(mg/dl)

M alone 168.25+3.35 230.75+32.54 54.5+34.35 210.5+5.04 22.61 31.56

Glibenalone 168.25+3.35 230.75+32.54 142.2+3.33 198.9+3.0 12.85 24.31

P + GLIBEN+ 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

Fig:9 Pharmacodynamic response of Metformin HCl alone

126

168.25154.4160

230.75210.5

0

50

100

150

200

250

normal base line the response

Blood sugar parameters

Glyc

emic

Resp

onse

(mg/

dl)

fbsppbs

Fig:10 Pharmacodynamic response of Glibenclamide HCl alone

126

168.25142.2

160

230.75198.9

0

50

100

150

200

250

normal base line the.response

Blood sugar parameters

Gly

cem

ic R

espo

nse(

mg/

dl)

fbsppbs

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

Gly

cem

ic

Res

po

nse

(mg

/dl)

fbsppbs

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

%ch

ange

in g

lyce

mic

resp

onse

fbs(mg/dl)ppbs(mg/dl)

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

6

13

20

4

11

00

5

10

15

20

25

Hypo/Hyper Risk of Infections Diabetic Retinopathy

Diabetic complication

No.

of P

atie

nts

Total Diabetics

Diabetics usingMetformin+Gliben+p

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

47

93

111120

4

4454

0

20

40

60

80

100

120

140

Hypo/Hyper Sweating Appetite Asthenia Diarrhoea Tremors Malaise

Adverse drug reactions

No.

of P

atie

nts

Total Diabetics

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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