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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