An

Evaluation of the Therapeutic and Dosage Equivalence Glyburide and Glipizide Linda

A. Jaber, Pavel

PharmD,

Nancy

Komanicky,

MD,

and

J.

Wenzloff,

Edward

Effects of MPH,

PharmD,

J. Antal,

PhD

diabetic patients [ten women, nine men, aged 36-80 ± 2.7 years)] were randomized to receive either glyburide or glipizide in a double-blind crossover fashion. A 2-week washout period preceded each treatment period. The patients measured blood glucose concentrations 16 times weekly using Chemstrip-bG#{174}. The medication dosages were titrated to achieve fasting blood glucose concentrations of 6.2 mM and preprandial and postprandial concentrations of 9.0 mM, or to a total daily dose of 20 mg for glyburide and 40 mg for glipizide. Glyburide therapy resulted in a significant decline in fasting, preprandial, post pro ndial and bedtime blood glucose levels, while glipizide treatment led to a significant lowering of post prandial and bedtime blood glucose. Furthermore, fasting, preprandial and postprandial blood glucose concentrations were significantly lower during glybu ride as compared to glipizide treatment phase. Glycosylated hemoglobin levels were decreased only with glyburide. Serum C-peptide and insulin concentrations were not altered over the entire study. The mean final daily dose of glyburide (15.4 ± 1.6 mg) was markedly lower than that of glipizide(29.7± 3.1 mg). Thus, in this patient population, glyburide was twice as potent on a weight basis than glipizide. Nineteen

years

(mean

noninsulin-dependent ± SE 56.8 for 16 weeks,

R

ecently, two new oral sulfonylurea agents, glyburide and glipizide, were introduced into the U.S. market. Both agents are indicated for the treatment of noninsulin-dependent diabetes mellitus (NIDDM) unresponsive to diet therapy alone. These

agents are similar tion sulfonylureas structural changes

in efficacy to both the first-generaand to each other. However, have resulted in an increased hy-

poglycemic fonylureas fonylurea

potency as compared to the original sul(Figure 1). The theraru’itic effects of suldrugs ster’ ibility to improve

beta

function,

cell

peripheral

glucose

From the Departments of Pharmacy Practice (Drs. Jaber and Wenztoft) and internal Medicine (Dr. K#{224}manicky),Wayne State University, Detroit, Michigan, and the Division of Clinical Pharmacokinetics (Dr.

Antal), The Upjohn Company, Kalamazoo, Michigan. Supported grant from The Upjohn Company, Kalamazoo, Michigan. Presented the annual

meeting

tion for Clinical

of the Midwestern

Research,

November

(Clin Res 36:83A, 1988). Address PharmD, Department of Pharmacy Detroit, Mi 48202.

J Clin Pharmacol

section

1990;30:181-188

9-11,

of the American

1988,

Chicago,

by a

at

Federa-

Illinois

reprint requests to: Linda A. Jaber, Practice, Wayne State University,

and

to reduce

basal

hepatic

glucose

produc-

tion.8 Some authors have suggested that the relative importance of each of these actions is patientdependent and that different sulfonylureas lower plasma glucose concentrations by a differential effect via one of these mechanisms.3’4 In support of these observations research has identified some important differences in the mechanisms of actions and therapeutic effects as well as

pharmacokinetic glipizide.’3’92



ennance

uptake

properties Glyburide

lowering of fasting tions than glipizide.’3 uted to glyburide’s glucose production.14 enhances an earlier

response

glyburide and more profound

blood glucose (FBG) concentraThis difference may be attribimpressive reduction in hepatic Glipizide, on the other hand, and greater insulin secretion in

to postprandial

pared to glyburide.12’516 fect dosage requirements. Studies comparing

between causes

hyperglycemia These glyburide

as

differences and

glipizide

may

comafhave

not established fully the dosage equivalence of these agents. Blohme et al.15 compared blood glucose concentrations achieved with 4-6 weeks of glyburide 15

181

JABER

C:__

LNH_CH2_CH2___

AL

study was to determine the dosage equivalence of glyburide and glipizide following Food and Drug Administration (FDA)-approved drug package inserts recommendations. Clinic laboratory testing and self blood glucose monitoring were used to determine the glycemic response to these agents.

-rj

802_NH_LNH

ET

OCH3 Glyburide

METHODS Patients The study was conducted in a university-affiliated outpatient clinic. Thirty patients with type II diabetes mellitus were recruited from the endocrinology and family practice clinics. Of those, 19 patients completed the entire study protocol. The remaining 11 subjects (five women and six men) dropped out during the first treatment phase of the study for various reasons; four patients were lost to follow-up,

00

II

-

II

-

C.4IH-CH-CH2---c--.

H3C ---

802-NH-C-NH

Glipizide

Figure

1. Chemical

structures

of glyburide

and

four

glipizide.

mg and glipizide 15 mg. Fasting centrations and urine glucose significantly lower with glyburide

serum glucose conconcentrations were therapy. Adtuyibi

and

agents

Ogundipe17

found

the

two

to be equally

effective in lowering fasting blood glucose. However, both studies used fixed dosage regimens. Deleeuw et al.18 and Lahon and Mann19 found that higher doses

of glipizide were needed for adequate blood glucose control as compared to those of glyburide. In contrast, Vailati et al.2#{176} found no difference in blood glucose concentrations after a test dose of glyburide 2.5 mg or glipizde 2.5 mg. gation studied the long-term Other studies comparing have made no comparisons cial doses of each drug.1621 Determining the dosage

and

glipizide

will

have

However, neither investieffects of these agents. glyburide and glipizide of the maximum benefiequivalence

Other

implications

costs.

requirements The

sulfonylurea

use

are

of lower

could

often doses

prove

linked of a more

to save

costs

to medication potent

both

oral

in the

quantity of the drug purchased and in the drug administration process in institutional settings. Thus, the need for a well controlled, long-term study comparing the dosage equivalence of glyburide and gli-

pizide

is of fundamental

importance.

This paper describes a randomized, double-blind, crossover study comparing the dosage requirements of glyburide and glipizide. The objective of

182

#{149} J Clin Pharmacol

1990;30:181-188

clinic

visits

inconvenient,

two

had

nonhypoglycemic

medications,

if taken,

throughout by the Human of Wayne

were

the study. and AniState Uni-

on

both patient care and health care costs for several reasons. First, such determination will define dosing guidelines for the initiation of therapy as well as in switching from one sulfonylurea to another. Second,

dosage

the

continued and kept constant The protocol was approved mal Investigation Committee versity.

of glyburide

important

found

difficulty with self blood glucose monitoring, and one was normoglycemic during the initial washout period. Data of dropout patients were not included in the analysis. The study group consisted of ten women and nine men with a mean age of 56.8 ± 2.7 years (range 36-80 years). The duration of diabetes prior to entering the study for these patients ranged from less than I to 21 years, the mean ± SE being 6.8 ± 1.5 years. Fourteen patients had been treated with sulfonylurea agents, two with low-dose insulin (20 units or less) and three with diet alone. They had no evidence of renal, hepatic, cardiac and pulmonary disorders. All patients were instructed to continue their usual diet, exercise patterns and lifestyles.

this

Design After history

obtaining and

written physical subject. All

for each period of no antidiabetic tients were randomized

informed consent, examination were patients began with

therapy. to receive

a medical completed a 2-week

Thereafter, paeither glyburide

or glipizide in a double-blind manner for 16 weeks. The first treatment phase was followed by a 2-week washout period. Patients then were placed on the alternative medication for another 16-week treatment phase which was again followed by a 2-week washout period. At the end of the study the patients were returned to the care of their primary physicians.

DOSAGE

EQUIVALENCE

OF

Patients were individually taught self blood glucose monitoring by using Chemstrip-bG#{174} (Boehringer Mannheim Diagnostics, Indianapolis, iN). Each patient had to demonstrate the ability to perform the test according to product instructions before acceptance into the study. Use of self blood glucose monitoring allowed close assessment of blood glucose changes without requiring numerous clinic visits. Monitoring schedules detailing written instructions for specific testing times relative to fasting

and meals were provided to each patient. Each week the patient obtained four fasting, four preprandial, four postprandial and four bedtime blood glucose concentrations. Test results were recorded by the patient and the used Chemstrip-bG strips were placed in an air-tight container and then brought to the next clinic visit, where the investigators reviewed and checked the concentrations by the use of an Accu.chek#{174} meter (Boehringer Mannheim Diagnostics, Indianapolis, IN). Meter readings of the chemstrips were reported. The date and time of any hypoglycemic events as well as any other symptoms were documented along with blood glucose test results done at that time. The medication dosages were individualized according to the meter-read mean blood glucose values obtained during the preceding 7-day period. Reading of these strips is reported to be reliable for up to 7 to 14 days.22’23 However, recent research has demonstrated a consistent decay in the used Chemstrip-bG test strips despite proper storage.24 Nevertheless, the variations in blood glucose readings due to this phenomenon were similar or consistent throughout both phases of the study with both drugs. Therefore, comparisons between treatment periods should not have been affected. Identically appearing capsules containing glyburide 2.5 mg or glipizide 5 mg tablets were used. During the 16-week treatment period the medication

dose

was

with

an

titrated initial

determined

on a biweekly average

by self

FBG

blood

basis. of less

glucose

Those than

monitoring

11.2

patients mM

AND

GLIPIZIDE

per day were required, the dosage was equally divided and given half an hour before breakfast and supper. The maximum dose of glyburide (20 mg) or glipizide (40 mg) used was eight capsules per day. These capsule strengths were used so that the study regimen complied with FDA-approved dosage guidelines for glyburide and glipizide. The study time-frame selected would allow all subjects to reach either an effective dose or to receive the maximum allowable dosage ranges of both medications. Furthermore, in determining dosage equivalence, it is the final rather than the starting dosage that is assessed. On each biweekly clinic visit, patients were asked to bring their treatment medications. Capsules were counted to determine medication compliance and patients were also questioned in a nonthreatening manner regarding their medication compliance. The occurrence of side effects was determined through direct questioning. Patient weight, vital signs and results of home blood glucose monitoring were recorded. Baseline and follow-up data for glycosylated hemoglobin (GHb), blood glucose, C-peptide and insulin concentrations were collected in the fasting state at the beginning and end of each treatment and washout period and every 4 weeks during treatment.

Chemical

Analysis

Glycosylated hemoglobin was measured by Isolab affinity chromatography column (normal range 4.0-8.0%). Insulin was determined by Immuphase Insulin (1251) Radioimmunoassay Test Kit (Corning Medical and Scientific, Medfield, MA) (normal range 0-20 zU/ml). C-peptide was measured by Double Antibody Radioimmunoassay System for Human Cpeptide (Diagnostics Corporation, Los Angeles, CA) (normal range 0.8-4.0 ng/ml).

as

during

the washout period were started on one capsule per day. Those with an initial FBG of 11.2 mM or greater were started on two capsules per day. Patients 70 years old or above were started on one capsule per day regardless of their initial FBG, per recommendations of the FDA. If on a return visit, the average FBG was equal to or less than 6.2 mM and the preand postprandial blood glucose readings were equal to or less than 9.0 mM, the same dose of medication was continued. If the average FBG was greater than 6.2 mM or the preand/or postprandial blood glucose readings were above 9.0 mM, the dose was increased by one capsule per day. If greater than three capsules

MISCELLANEOUS

GLYBUIIIDE

Data Analysis An analysis of variance for complete crossover design was used to evaluate the differences in finger capillary blood glucose values obtained from the meter reading of the strips, glycosylated hemoglobin, C-peptide, and insulin concentrations and patient weight between the two treatments at the beginning and end of each treatment phase. The significance level was set at 95% (P < .05). Differences in these parameters between the specific weeks and baseline within the two treatments were evaluated by analysis of variance with “patient” and “week” as fixed effects. In all cases where “week” effects

183

JABER

were significant (P < .05), pairwise comparisons tween individual weeks and baseline were ated with a Wailer-Duncan K ratio t test.25 are expressed as a mean ± standard error

mean

(mean

±

beevaluResults of the

SEM).

RESULTS Nine patients were randomized initially to receive glyburide and ten patients to receive glipizide. The baseline blood glucose values are indicated in the Table. Upon entry into the study, all patients had

high fasting,

preprandial, postprandial and bedtime glucose concentrations, reflecting poor blood control. No statistical difference in initial

blood glucose

glucose, GHb, C-peptide, insulin and body weight values were noted between the two treatment periods, thereby allowing direct comparisons in treatment effects.

Blood The

Glucose effects

glycemic

Concentrations of

glyburide

and

glipizide

are

presented

in

control

therapy

the

Table.

on

All

TABLE Effects of 16 Weeks of Glyburide Treatment on Blood Glucose Glyburide Treatment

Fasting blood glucose (mM/L)* Baseline Final Preprandial blood glucose (mM/L)* Baseline Final

and Glipizide Control Glipizide Treatment

Pt

Value

11.6

±

0.8

.47

11.0

± 1.1

.03

13.4 ± 1.3 9.4 ± 0.71:

12.9 ± 1.2 11.3

± 1.1

.57 .02

14.1

11.9 9.1

± 1.1 ± 0.71:

15.2

±

1.3

.43

± 0.81:

11.8

±

1.Oj

.04

14.3 ± 1.2 10.5 ± 0.91:

15.0

±

1.3

.50

12.3

±

1.21:

.13

9.8

±

1.2

#{149} J Clin Pharmacol

blood glucose concentrations are presented graphically in Figure 2 as a function of treatment week and dose. Although all patients experienced improvement in blood glucose measurements, not all had achieved normoglycemia on maximum doses of both agents. The mean FBG concentration with glyburide therapy was significantly lower compared to baseline at 10, 12, 14 and 16 weeks of treatment. However, no significant changes in mean FBG occurred during the entire active treatment period with glipizide. In comparison, the mean FBG concentrations with glyburide were significantly lower at the final week of treatment than during glipizide treatment (P = .03).

The

mean

13.2 11.1

± 1.1

12.4

± 0.9

.29

± 0.7*

12.7

±

.06

1.0

1990;30:181-188

preprandial

blood

glucose

concentra-

tions were significantly lower at weeks 8 through 16 of glybu ride and weeks 10 and 14 of glipizide treatment periods compared to baseline. The mean preprandial blood glucose concentrations at the final week of treatment was significantly lower (P = .02) with glyburide as compared to glipizide. The mean postprandial blood glucose concentrations were significantly lower after weeks 2 through 16 of glyburide and weeks 4 through 16 of glipizide compared to baseline. However, the mean postprandial blood glucose concentrations at week 16 were significantly lower (P = .04) with glyburide therapy. With glyburide, the mean bedtime blood glucose concentration at weeks 4 and 8 through 16 were significantly lowered from the initial baseline value. Likewise, glipizide significantly decreased the bedtime blood glucose after weeks 4 through 16 of treatment compared to baseline. There was no significant difference in the mean bedtime blood glucose concentrations between the two groups at the final week of treatment.

Hemoglobin

Compared to baseline GHb levels, a significant decrease was found at weeks 12 and 16 of glyburide therapy. In contrast, GHb values remained unchanged over the entire glipizide treatment period. A marginal statistical difference (P = .06) was observed between GHb values at the last week of treatment with both medications.

Dosage

* Values bases on the mean of four blood glucose readings done in a 7’day period. t ANOVA results when comparing the two treatment groups. Significant decrease from baseline (P < .05).

184

AL

Glycosylated

Postprandial blood glucose (mM/L)* Baseline Final Bedtime blood glucose (mM/L)* Baseline Final Glycosylated Hemoglobin (%) Baseline Final

ET

Requirements

The doses required of each drug at the end of the treatment phases were compared. The mean final daily doses were 15.4 ± 1.6 mg/day for glyburide and 29.7 ± 3.1 mg/day for glipizide. The difference is significant (P = .0001). Twelve subjects received maximum daily dosages of glyburide and ten sub-

DOSAGE

EQUIVALENCE

OF

GLYBURIDE

AND

GLIPIZIDE

GLUCOSE #{149}-. Glipizide 17

.

Fasting

o--’o

Glyburide

*3 -I *3

0

E E

4ii Preprandial

*3

-I *3

a E

E

17

Postprandial

*3 -J a) 0

11

E E

9 7

ii

Bedtime

15 a) -j *3

0

E

11

E

9 7

MEAN MEAN

Figure

2. Blood

MISCELLANEOUS

I

I

I

I

I

I

I

WEEK

0

2

4

6

8

10

12

14

DOSE GLYBURIDE

(mg)

0

7.8

9.6

11.4

13.2

14.7

15.4

(mg)

0

3.7 7.4

5.8

DOSE GLIPIZIDE

10.8

14.2

17.6

20.8

23.7

27.4

29.7

glucose

concentrations

(mean

± SE)

as a function

of treatment

week

and

I

16

dose.

185

JABER

jects these

received patients

doses

of both

Other

maximum received

doses of glipizide. the maximum

of

agents.

Variables

There was no significant weight during glyburide kg) or glipizide (85 ± 2.7

ment

Nine allowable

periods.

Patient

change in the mean body (85 ± 2.3 kg versus 84 ± 2.4 kg versus 85 ± 3.0 kg) treat-

body

weights

were

compara-

ble

between the two treatment phases. Serum C-peptide and insulin concentrations at all weeks of glyburide or glipizide treatment periods did not differ significantly from baseline, nor did they differ between treatments at the last week. Baseline and final fasting insulin concentrations were 32.9 ± 4.8 pU/mi and 29.7 ± 2.5 pU/ml with glyburide and 28.1 ± 4.2 pU/mi and 30.3 ± 3.1 pU/ml with glipizide, respectively. Baseline and final fasting C-peptide concentrations were 1.6 ± 0.3 ng/ml and 1.7 ± 0.3 ng/ml with glyburide and 1.6 ± 0.4 ng/ml and 2.0 ± 0.5 ng/ml with glipizide, respectively. No side effects directly related to study medications were reported. One patient on glyburide and another on glipizide experienced mild symptoms of hypoglycemia on a single occasion. These events

were

not

documented

by

blood

glucose

measure-

ments. At the time symptoms were experienced, former patient did not obtain a blood glucose ple, while the latter patient’s glucose test result elevated. No nausea, vomiting, rash or elevation liver function tests were noted.

the samwas in

DISCUSSION To determine logic effects

compared.

dosage of glyburide

The

patients’

equivalence, and glipizide

baseline

the

glucose

pharmacofirst must

control

be

did

not differ between the two treatments, thereby allowing direct comparisons of treatment effects. Both treatments had resulted in improvement in glucose control, even though normoglycemia was not achieved in some patients. However, the overall glycemic control differed at the end of the glyburide and glipizide treatment phases. Glyburide therapy resulted in a significant decline in FBG, preprandial, postprandial and bedtime blood glucose concentrations. By week 16, treatment with glipizide led to a significant lowering of postprandial and bedtime blood glucose values. Furthermore, when compared, the final mean fasting, preprandial and postprandial blood glucose levels were significantly lower during glyburide treatment. The lower preprandial and

186

#{149} J Clin Pharmacol

1990;30:181-188

ET

AL

postprandial blood glucose concentrations observed during treatment with glyburide had not previously been documented in other studies comparing the two agents. Different studies have observed that maximum insulin secretion and glucose-lowering effects occur earlier and faster with glipizide compared with glyburide.151626 Based on this, the postprandial blood glucose concentrations are expected to decrease to a greater extent with glipizide. The finding of lower FBG during glyburide as compared to glipizide therapy is in agreement with other studies.12131’16’21 Glyburide seems to be an appropriate choice for patients with fasting hyperglycemia. Although these differences in the efficacy parameters are of interest, clinical significance as to their magnitude cannot be determined absolutely from this study. Glycosylated hemoglobin was measured to assess cumulative diabetic control during the study. Glycosylated hemoglobin is useful in monitoring longterm diabetes control since it is believed to reflect the average blood glucose concentrations during the preceding several weeks.27 Use of this test may present a problem since the lag time between a change in glycemic control and the corresponding change in GHb values may range from 4 weeks to 3 months. Determination of the definitive effects of drug therapy on GHb concentrations during a 16-week crossover design study may not be feasible. To minimize this problem, an equal number of patients was randomly allocated to begin the study on both drugs. In addition, repeated GHb measurements after 3 or 4 months of treatment would reflect a trend towards which glycemic control is directed. The glycemic control as assessed by GHb levels improved significantly with glyburide. In contrast, no significant change in GHb concentrations was observed during glipizide treatment. The apparent discrepancy of decreased GHb concentrations with glyburide and not with glipizide treatment despite an overall improvement in glucose control may be attributed to the significant reduction in basal hyperglycemia with glyburide; such correlation between GHb and fasting hyperglycemia had been previously reported.2829 The mean daily doses of glyburide and glipizide required were significantly different. The finding that glipizide doses were approximately 2-fold higher than those of glyburide suggests that the two drugs are not equipotent on a weight basis. The same observation had been made by other authors comparing glyburide and glipizide potency.163#{176} Due to differing therapeutic responses to the medications, a direct determination of equipotent doses could not

DOSAGE

be made.

The

data

suggest

that

EQUIVALENCE

glybu

ride

may

OF

be at

least twice as potent as glipizide on a weight basis. Changes in endogenous insulin secretion as a result of drug treatment were investigated. C-peptide and insulin are secreted from the pancreas in equimolar proportions into the portal circulation.31 Since 50 to 60% of portal insulin is extracted by the liver during first pass and only minimal amounts of Cpeptide are removed, the latter is considered a useful indicator of endogenous insulin secretion.

The

role

of improved

endogenous

insulin

secre-

tion with regard to the hypoglycemic effect of sulfonylureas is still controversial. Kolterman6 and Reaven32 demonstrated no correlation between the change in glucose tolerance and the change in insulin response. However, Falko and Osei33 and Groop and Pelkonen34 have indicated that endogenous insulin concentrations were significantly increased in the patients with response to sulfonylureas compared with nonresponders. We observed no significant change in C-peptide and insulin concentrations during either treatment period. Therefore, no correlation was documented between these parameters and the plasma glucose

response. The significant decrease in GHb coupled with no change in C-peptide and insulin concentrations with glyburide, may suggest that the improved diabetic control with this drug was due in part to an extra-

pancreatic

mechanism

such

as an

increase

in the

number and/or sensitivity of insulin receptors or by ameliorating the post-receptor defect. These findings agree with observations made by other authors who concluded that the plasma glucose control was related to an improvement in insulin actions with

glyburide. Confounding the study results diet instructions

were

instructed

factors were were

that potentially may affect examined carefully. Specific not given to the patients; they

to maintain

their

usual

dietary

habits. Since no significant weight occurred during changes in glycemic control changes in weight. Acute have elevated blood glucose; the drug dose was determined

alterations in body the treatment phases, cannot be attributed to episodes of illness may however, in all patients according to protocol

regardless

cause

of the

suspected

of hyperglycemia.

To summarize, this study demonstrates (1) the efficacious response to both agents; and (2) glyburide is twice as potent on a weight basis as glipizide in its ability to decrease blood glucose concentrations. The need for a lower dose of glyburide may prove to be advantageous with regard to lower medication costs.

MISCELLANEOUS

GLYBUR

IDE

AND

GLIPIZIDE

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A, Tolppanen

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#{149} .1 Clin Pharmacol

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An evaluation of the therapeutic effects and dosage equivalence of glyburide and glipizide.

Nineteen noninsulin-dependent diabetic patients [ten women, nine men, aged 36-80 years (mean +/- SE 56.8 +/- 2.7 years)] were randomized to receive ei...
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