R EVIEWS _F T HERAPEUTICS

Sulfonylurea Treatment of Type 2 Diabetes Mellitus:

Focus on Glimepiride
Mary T. Korytkowski, M.D.
Sulfonylureas, which have evolved through two generations since their
introduction nearly 50 years ago, remain the most frequently prescribed oral
agents for treatment of patients with type 2 diabetes mellitus. Glyburide,
glipizide, and glimepiride, the newest sulfonylureas, are as effective at
lowering plasma glucose concentrations as first-generation agents but are
more potent, better tolerated, and associated with a lower risk of adverse
effects. Differences in their binding affinity to the b-cell sulfonylurea receptor
have been described, with preservation of cardioprotective responses to
ischemia with glimepiride. Clinical studies have shown glimepiride to be safe
and effective in reducing fasting and postprandial glucose levels, as well as
glycosylated hemoglobin concentrations, with dosages of 18 mg/day. In
comparative trials, glimepiride was as effective in lowering glucose levels as
glyburide and glipizide, but glimepiride was associated with a reduced
likelihood of hypoglycemia and a smaller increase in fasting insulin and Cpeptide levels than glyburide, and a more rapid lowering of fasting plasma
glucose levels than glipizide. Glimepiride also improves first-phase insulin
secretion, which plays an important role in reducing postprandial
hyperglycemia. Insulin secretagogues, specifically glimepiride, merit
consideration as first-line therapy for patients with type 2 diabetes.
Key Words: insulin secretagogues, diabetes mellitus, drug therapy,
sulfonylureas, glimepiride.
(Pharmacotherapy 2004;24(5):606620)
OUTLINE
Evolution of Insulin Secretagogues
Impairments in b-Cell Function in Type 2 Diabetes
Importance of First-Phase Insulin Secretion
Pharmacologic Profile of Glimepiride
Animal Studies
Human Studies
Cardiovascular Effects of Insulin Secretagogues
Efficacy and Safety Studies with Glimepiride
Placebo-Controlled Trials
Comparisons with Other Sulfonylureas
From the Center for Diabetes and Endocrinology, and the
Division of Endocrinology, Department of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania.
Address reprint requests to Mary T. Korytkowski, M.D.,
Division of Endocrinology, Department of Medicine,
University of Pittsburgh, Falk Building, Room 588, 3601
Fifth Avenue, Pittsburgh, PA 15213; e-mail: korytkowski@msx.
dept-med.pitt.edu.

Combination Therapy
Safety
Nonsulfonylurea Insulin Secretagogues
Repaglinide
Nateglinide
Combination Therapy with Other Agents
Summary
Insulin Secretagogues: First-Line Agents in Managing
Type 2 Diabetes
Combination Therapy
Specific Clinical Scenarios
Conclusion

Since their introduction in the 1950s, the

sulfonylureas have remained the most frequently
used drugs for management of type 2 diabetes
mellitus,1, 2 a heterogeneous disorder resulting
from the interaction of impaired pancreatic b-cell

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

function (insulin secretion) and insulin
resistance. 3 The sulfonylureas lower blood
glucose levels by stimulating insulin release
through a direct action on b cells. These agents
bind to a specific receptor, called the sulfonylurea
receptor, on the b-cell surface (SUR1). The SUR1
is a component of the adenosine triphosphate
(ATP)dependent potassium (K ATP ) channel.
Binding of a sulfonylurea to SUR1 promotes
closure of potassium channels, depolarization of
the cell membrane, and subsequent voltagedependent opening of cell-surface calcium
channels.
Influx of calcium from the
extracellular to the intracellular compartment of
the b cell triggers insulin release (Figure 1).1, 2, 46

membranes more easily, accounting for their

increased potency.7, 8
Second-generation sulfonylureas have similar
efficacy in reducing hyperglycemia to firstgeneration sulfonylureas (e.g., tolbutamide,
acetohexamide, chlorpropamide). However,
second-generation sulfonylureas are preferred for
their greater potency and generally more
favorable safety profiles. It should be noted that
significant differences in safety exist even among
the second-generation sulfonylureas. For
example, therapy with glyburide results in
similar rates of hypoglycemia to those observed
with chlorpropamide. 1, 2, 4 First-generation
agents are associated with more hypoglycemia,
weight gain, and water retention than generally is
seen with second-generation agents. 5, 9 In
addition, differences in binding to circulating
plasma proteins exist between the two
generations of agents and can contribute to
potential unfavorable drug interactions. Firstgeneration sulfonylureas bind ionically to plasma
proteins and thus have a higher likelihood of
drug interactions with other ionically bound
drugs, such as salicylates and sulfonamides. The
second-generation agents, which are nonionically
bound to plasma proteins, cause fewer problems
with drug interactions.5

Evolution of Insulin Secretagogues

The sulfonylureas share a common core
structure consisting of a benzene ring plus a
sulfonylurea group. The pharmacokinetic and
pharmacodynamic differences among the
available sulfonylureas are a consequence of
substitutions at the para position of the benzene
ring and on a urea nitrogen (Figure 2).5, 7 Firstgeneration sulfonylureas have relatively small,
polar, hydrophilic substitutions. Secondgeneration sulfonylureas have large, nonpolar,
lipophilic substitutions that penetrate cell

Ca+ +

ATP-sensitive
potassium channel

Voltage-dependent
calcium channel

(+)
Depolarization
K+

()

607

bb cell
cell
[ATP]
[ADP]

Free
Ca++

Postprandial glucose
excursions are
targeted by the
restoration of
early-phase
insulin secretion

Metabolism
Sulfonylurea receptor

Glucose
Insulin release

Significant glucose-dependency
lowers the risk of hypoglycemia
Figure 1. Mechanism of action of the sulfonylureas and the nonsulfonylurea insulin secretagogues. Binding to b-cell
membrane receptors causes closure of adenosine triphosphate (ATP)dependent potassium channels, followed by cell
membrane depolarization, influx of calcium ions into the b cell, and triggering of insulin secretion. ADP = adenosine
diphosphate, Ca++ = calcium ion; K+ = potassium ion. (Reprinted with permission from reference 6.)

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PHARMACOTHERAPY Volume 24, Number 5, 2004

glucose in individuals with type 2 diabetes that is
in good to fair control.7, 11 Thus, glimepiride may
improve early postprandial as well as late
postprandial hyperglycemia (Figure 3).12, 13
Postprandial hyperglycemia precedes the
development of fasting hyperglycemia as an
individual progresses from normal glucose
tolerance to diabetes. 1315 With the onset of
diabetes, postprandial hyperglycemia contributes
significantly to total hyperglycemia and A1C and,

All sulfonylureas induce increases in fasting

and late postprandial insulin responses that are
associated with clinically meaningful decreases in
blood glucose levels and glycosylated hemoglobin
(A1C).2, 4, 10, 11 Glimepiride is the most potent of
the second-generation sulfonylureas, causing the
greatest reduction in blood glucose levels with
the lowest indicated dosage (Table 1).1, 7 Unlike
other available sulfonylureas, glimepiride also
improves early or first-phase insulin response to

O
R1

Sulfonylurea general structure:

SO 2NHCNH

R1

R2
R2

First-generation agents
Tolbutamide
Chlorpropamide
Tolazamide

H3 C

C4H9

Cl

C3 H7

H3 C

Acetohexamide

H3CCO

Second-generation agents

Cl

Glyburide, glibenclamide

CONH(CH 2) 2
OCH3
N

Glipizide

H3 O

CONH(CH 2) 2
N

H3C
N

Glimepiride
H3C2

Nonsulfonylureas

CH3
Nateglinide

CH

C-NH-CH-CH2

CH3
CH3
Repaglinide

CH3

CONH(CH 2) 2

CO 2H
O
CH-CH2-CH-NH-C-CH2

CH3

CO2H
O
CH2
CH
CH3

Figure 2. Molecular structures of insulin secretagogues. The general sulfonylurea formula is shown together with the
substitutions present in first- and second-generation agents. The structures of the nonsulfonylurea insulin secretagogues
nateglinide (a D-phenylalanine derivative) and repaglinide (a derivative of the nonsulfonylurea portion of glyburide) are also
shown.

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

609

Table 1. Currently Available Insulin Secretagogues

Drug
Sulfonylureas
Glyburide
Glipizide
Glipizide,
extended release
Glimepiride
Nonsulfonylureas
Repaglinide
Nateglinide

Duration of
Action (hrs)

Daily Dose
1.2520 mg, single or two divided doses
2.540 mg, single or two divided doses
on an empty stomach

Up to 24
612

Up to 20 mg, single dose

18 mg, single dose

Up to 24
Up to 24

4 mg, 23 divided doses, 15 min before meals;

maximum daily dose 16 mg
60 or 120 mg 3 times/day before meals

3
1.5

Adapted from reference 1.

ultimately, the risk for diabetes-related

complications. This has led to the introduction
of agents that target postprandial insulin
secretion.2, 6, 1618 These agents, repaglinide and
nateglinide, are short-acting nonsulfonylurea
insulin secretagogues with a more rapid insulin
response to a meal and shorter duration of action
than the sulfonylureas. These characteristics
translate clinically to lower postmeal glucose
excursions and reduced potential for hypoglycemia.
The nonsulfonylurea insulin secretagogues are
taken before each meal and have a mechanism of
action similar to that of the sulfonylureas, but
they differ in their affinity for and binding
kinetics to b-cell sulfonylurea receptors.2, 19
Impairments in b-Cell Function in Type 2
Diabetes Mellitus

Glucose-Stimulated
Insulin Secretion

Insulin secretory defects in type 2 diabetes

include blunting of early insulin responses to
glucose or a meal, absence of a first-phase insulin

1st Phase

2nd Phase
Basal
State

Response

Time
Figure 3. Schematic representation of normal first and
second phases of insulin release in response to a meal.
(Adapted with permission from reference 13.)

response to intravenous glucose, alteration in

insulin pulsatility, and excess circulating
proinsulin and glucagon.20 These abnormalities
in insulin secretion contribute to deterioration of
both fasting and postprandial glycemic regulation, resulting in progression of the disorder. An
impairment in first-phase insulin release is
evident in individuals with impaired glucose
tolerance as well as in those at risk for type 2
diabetes based on an affected first-degree
relative.2022
Importance of First-Phase Insulin Secretion
Several excellent reviews have discussed the
importance of first-phase insulin secretion.20, 23, 24
First-phase insulin secretion is important in
blunting the rise in glucose levels after a meal.
This process is due partly to suppression of
endogenous glucose production (EGP).20 In one
study of patients with type 2 diabetes, infusion of
insulin to simulate a first-phase insulin response
resulted in a 25-mg/dl decrease in peak plasma
glucose responses to an intravenous glucose
bolus.25 This defect in insulin secretion, with its
pathogenic role in postprandial hyperglycemia,
suggests that agents targeting early as well as late
insulin secretion may be advantageous in the
therapy of type 2 diabetes.23, 26
Several clinical studies have investigated the
impact of insulin secretagogues on first-phase
insulin release.17, 27, 28 Tolbutamide, a short-acting
sulfonylurea, improved first-phase insulin
secretion in patients with type 2 diabetes who
had severe hyperglycemia. However, it did not
provide this benefit in patients with type 2
diabetes who had only mild hyperglycemia.27
Nateglinide improved early insulin responsiveness
to both oral and intravenously administered

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PHARMACOTHERAPY Volume 24, Number 5, 2004

glucose,17 but it had less of an effect on fasting

glucose levels. 17 Glipizide and glyburide
increased both first- and late-phase insulin
responsiveness in nondiabetic, but not diabetic,
volunteers.29 Thus, glimepiride may be unique
among the available insulin secretagogues in that
it improves first-phase insulin response, a
characteristic of the meglitinides and of
nateglinide, as well as improving basal and late
insulin responses traditionally characteristic of
the sulfonylureas.11

absorptive EGP without a change in insulin

sensitivity was observed in the euglycemic clamp
studies. The reduction in EGP correlated with
observed reductions in FPG levels. Results from
the hyperglycemic clamp study demonstrated
significant improvements in first and second
(steady-state) phases of insulin secretion with
glimepiride. Additional measures of first-phase
insulin response, including maximal insulin
response during the first 10 minutes after the
glucose bolus and incremental first-phase Cpeptide responses supported this finding.

Pharmacologic Profile of Glimepiride

Animal Studies
Studies in animal models of diabetes mellitus
have shown that at pharmacologic concentrations,
glimepiride stimulates insulin release in a
biphasic pattern, with a discrete first-phase peak
and a prolonged second phase. 30 One study
showed that in addition to increasing the total
amount of insulin released, glimepiride resulted
in persistence of the biphasic pattern of first and
second phases of insulin secretion as the glucose
infusion increased. 30 Using the same model,
tolbutamide also promoted biphasic insulin
release. 31 However, a more rapid decline in
second-phase insulin secretion was observed with
this short-acting, first-generation sulfonylurea.
Glyburide, another second-generation sulfonylurea,
produced a delayed monophasic insulin response
and did not elicit any change in first-phase
insulin response.31, 32 In summary, the pattern of
insulin secretion with glimepiride differed from
tolbutamide in that the secondary phase of
insulin release was prolonged, and from
glyburide in that the first-phase insulin release
was present.3032
Human Studies
Glimepirides beneficial effects on the first and
second phases of insulin secretion have been
documented in humans as well as in animals.11, 30
In one recent study, 11 obese patients with type 2
diabetes
underwent
euglycemic
and
hyperglycemic clamp studies before and after a 4month treatment period with glimepiride to
determine the potential effects of this agent on
insulin sensitivity and b-cell function.11 A group
of nondiabetic individuals, matched for age and
body mass index, served as controls. The
glimepiride dosage started at 2 mg/day and was
titrated to achieve fasting plasma glucose (FPG)
levels of 90160 mg/dl. A reduction in post-

Cardiovascular Effects of Insulin Secretagogues

The University Group Diabetes Program
(UGDP) published in 1970 raised the concern
that sulfonylureas might increase the risk of
cardiovascular death.33, 34 In the UGDP, a greater
than 2-fold increase in cardiovascular mortality
was observed in the group randomized to receive
tolbutamide. The significance of these results
has been the subject of ongoing debate.
Discovery of a sulfonylurea receptor (SUR) as a
component of KATP channels within both b cells
(SUR1) and myocardial cells (SUR2A) opened
scientific inquiry into a potential link between
sulfonylurea agents and cardiovascular risk. 35
The binding of sulfonylureas to SUR2A offers a
potential physiologic explanation for the
increased cardiovascular mortality associated
with tolbutamide in the controversial UGDP.33 34
Both cardiac and vascular smooth muscle contain
SURs with KATP channels.35 These receptors play
a role in ischemic preconditioning, which can
protect myocardial cells from a prolonged
ischemic insult. 35, 36 Binding to cardiac K ATP
channels by a sulfonylurea may theoretically
interfere with ischemic preconditioning, thus
increasing the likelihood and severity of a
myocardial infarction. Differences in binding
characteristics among the sulfonylureas suggest
that the second-generation sulfonylurea
glimepiride may bind more selectively to b-cell
KATP channels than other agents in this class.36
Ischemic preconditioning refers to the
protective effect of repetitive brief periods of
myocardial ischemia that ultimately serve a
protective function within the myocardium by
decreasing infarct size resulting from more
prolonged periods of ischemia.36, 37 Cardiac KATP
channels are activated during periods of
ischemia, thus playing a role in ischemic
preconditioning. Drugs that bind to K ATP
channels and prevent their activation can

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

Table 2. Summary of Selected Studies of Glimepiride
No. of
Study
Patients
Study Design
Duration
Treatment Arms
30445

Results of Glimepiride-Treated Patients

vs Comparator Group

14 wks

57743

Placebocontrolled
Placebocontrolled
Placebocontrolled
Comparator

12 mo

Glimepiride 1, 4, 8 mg
vs placebo
Glimepiride 8, 16 mg
vs placebo
Glimepiride titrated to 8 mg
vs placebo
Glimepiride vs glyburide

104444

Comparator

12 mo

Glimepiride vs glyburide

41642
24946

14 wks
12 wksa

611

FPG 4347 mg/dl; PPPG 6394 mg/dl;

A1C 1.21.9%
FPG 5668 mg/dl; A1C 1.7%
FPG 46 mg/dl; PPPG 86 mg/dl;
A1C 1.4%
Lower rate of hypoglycemia
(1.7% vs 5% at 1 mo; 12% vs 17% at 12 mo)
Lower fasting insulin level (-0.92 U/ml, p=0.04);
lower C-peptide level (-0.14 ng/ml; p=0.03);
similar glycemic control (8.4% vs 8.3%);
lower rate of hypoglycemia (105 vs 150 episodes)

FPG = fasting plasma glucose level; PPPG = peak postprandial glucose level; A1C = glycosylated hemoglobin.
a
Preceded by 10 weeks titration.

interfere with this protective response.36, 37

Glyburide has been shown to interfere with
this protective response to ischemia in both
animal and human studies. 36, 38 In a recent
clinical trial investigating the effects of glyburide
and glimepiride on the preconditioning response
to ischemia, glimepiride did not interfere with
the preconditioning response in either patients
with diabetes or nondiabetic volunteers. 36
Glyburide, on the other hand, inhibited the
ischemic preconditioning response in both
groups.
These observed differences may reflect the
binding characteristics of these agents to K ATP
channels. Although both glyburide and
glimepiride bind to cell-surface KATP channels,
only glyburide binds to mitochondrial channels
within myocardial cells, which are responsible for
mediating this protective response.38 The impact
of other sulfonylureas, such as glipizide, and the
short-acting insulin secretagogues on this
protective response to ischemia has not been
tested. However, these differences between the
available sulfonylureas should not undermine the
clinical potential and safety of the drug class in
general. The United Kingdom Prospective
Diabetes Study (UKPDS) demonstrated that
reductions in A1C and myocardial infarction with
the sulfonylureas glyburide and chlorpropamide
were similar to those achieved with insulin,
although the sulfonylureas caused less hypoglycemia and less weight gain than insulin. 39
Other studies also support the safety profiles of
the sulfonylureas.40, 41
In summary, based on available data, it is
probably incorrect to assume therapeutic

equivalence among the available sulfonylureas.

Although the efficacy and safety profiles of the
second-generation sulfonylureas are excellent,
glimepiride may have theoretic advantages over
other members of this class.
Efficacy and Safety Studies with Glimepiride
Placebo-Controlled Trials
Evidence that glimepiride restores some degree
of first-phase as well as second-phase insulin
release is supported by trials evaluating measures
of fasting and postprandial glycemia as well as
overall glycemic control (Table 2).4246 Glimepiride
significantly reduces fasting and postprandial
plasma glucose levels, as well as A1C, in patients
with type 2 diabetes when compared with
placebo.42, 45 In one double-blind, multicenter
trial, 304 patients with type 2 diabetes were
randomized to receive 1, 4, or 8 mg of
glimepiride once/day for 14 weeks.45 Reductions
in fasting and 2-hour postprandial plasma
glucose levels and A1C concentrations were
observed with both the 4-mg and 8-mg doses.
Levels of FPG decreased by 43.2 mg/dl with the
1-mg/day dosage, 70.2 mg/dl with the 4-mg/day
dosage, and 73.8 mg/dl with the 8-mg dosage,
compared with placebo (p<0.01 for all
comparisons). Postprandial plasma glucose
levels were reduced by 63.0 mg/dl, 91.8 mg/dl,
and 93.6 mg/dl after administration of 1-mg, 4mg, and 8-mg doses, respectively (p<0.01).
Finally, A1C concentrations in the treatment
groups were 1.2%, 1.8%, and 1.9% lower,
respectively, than in the placebo arm of the study
(p<0.001).

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PHARMACOTHERAPY Volume 24, Number 5, 2004

The efficacy of glimepiride over placebo was

demonstrated in a 14-week study comparing
treatment with glimepiride 8 mg/day or 16
mg/day in 416 randomized patients.42 The FPG
levels were reduced from 223232 mg/dl at
baseline to 155176 mg/dl (p0.001), and 2-hour
postprandial plasma glucose level was
significantly decreased from the baseline range of
283297 mg/dl to 203221 mg/dl (p<0.001) with
glimepiride. Both glimepiride regimens also
decreased 2-hour postprandial glucose levels
significantly more than did placebo (-61 mg/dl
and -94 mg/dl vs +25.0 mg/dl, p0.001).
Improvements in A1C from baseline were
consistently greater with the active treatment
regimens than with placebo, reducing absolute
A1C by 0.1-0.8% to a final end point of 7.4-7.6%
(p0.001). There were no clinically meaningful
differences in efficacy between the glimepiride
once-daily and twice-daily regimens, or between
treatment with dosages of 8 mg/day and 16
mg/day
A placebo-controlled study in 249 patients
with type 2 diabetes mellitus that was poorly
controlled with diet and exercise confirmed the
efficacy of glimepiride. 46 Glimepiride was
titrated over 10 weeks to a daily dose of 18 mg.
After a 12-week treatment period, patients
treated with glimepiride showed a significant
improvement in median FPG levels (from 153
mg/dl at baseline to 107 mg/dl). This was
significantly greater than the improvement seen
in the placebo group (p<0.001). The same
pattern of improvement from baseline with
glimepiride was also observed for median A1C
(from 9.1% to 6.4%) and median 2-hour
postprandial plasma glucose levels (from 297
mg/dl to 174 mg/dl, a 72-mg/dl change when
compared with placebo). Finally, A1C values of
7.2% or less were achieved by 69% of patients in
the active group, versus only 32% of those in the
placebo group.
In these studies, the groups receiving
glimepiride monotherapy were similar to the
placebo groups in regard to the rate of adverse
events. Headache, dizziness, and digestive
system disturbances were the most commonly
reported events. Reports of symptomatic
hypoglycemia by patients were considered not
severe by investigators or were few in number. In
addition, no cases of laboratory-confirmed
hypoglycemia (plasma glucose levels < 60 mg/dl)
were reported.42, 45, 46 The number of patients
discontinuing glimepiride due to symptomatic
hypoglycemia was very small (two patients46 and

four patients42; < 1% in either trial), and most

patients in the glimepiride arms completed the
studies.
Comparison with Other Sulfonylureas
Studies comparing glimepiride with other
sulfonylureas have focused primarily on
comparisons with glyburide. Two activecontrolled trials demonstrated similar glucoselowering effects for glimepiride and glyburide,
with a reduced likelihood of hypoglycemia and
possibly a more rapid response with glimepiride
(Table 2). 43, 44 In these studies, doses were
titrated over 12 weeks to achieve FPG levels of
90150 mg/dl and were then continued for 12
months.
One of these studies evaluated the efficacy and
safety of glimepiride and glyburide in 577
patients previously treated with diet or
sulfonylureas. 43 No patients had a history of
primary or secondary drug failure. The two
treatments were similar in terms of the amount of
reduction in fasting and postprandial plasma
glucose levels and A1C concentrations, as well as
in the time to these reductions. However,
glimepiride was associated with a significantly
lower incidence of hypoglycemia than glyburide
(1.7% cumulative incidence of symptomatic
hypoglycemia in the first month of the study in
the glimepiride group, compared with 5.0% in
the glyburide group [p=0.015]). This trend
continued over time, with a cumulative incidence
at 12 months of 12% for glimepiride and 17% for
glyburide (p=0.069). Most subjects were
receiving the maximum dosage of either
glimepiride (116 mg/day) or glyburide (1.2520
mg/day).
The second, larger study reported similar
results after randomizing 1044 patients to receive
glimepiride with dosage titration to 8 mg/day
(524 patients) or glyburide with dosage titration
to 20 mg/day (520 patients). 44 No clinically
significant differences in mean concentrations of
A1C or fasting blood glucose levels were
observed between treatment groups. However,
treatment with glimepiride was associated with
smaller increases in median fasting insulin levels
(1.27 U/ml vs 2.2 U/ml, p=0.041) and Cpeptide concentrations (0.28 ng/ml vs 0.47
ng/ml, p=0.03) than glyburide. These differences
were small, but the authors considered them
potentially important, given the known
association between hyperinsulinemia and
hypertension. The two treatment groups had

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

similar safety profiles. Patients treated with
glimepiride experienced fewer episodes of
hypoglycemia (60 patients, 105 episodes) than
those who received glyburide (74 patients, 150
episodes). At the end point, 51% of subjects
reached the maximum glimepiride dosage of 8
mg/day, and 42% of subjects reached the
maximum glyburide dosage of 20 mg/day.
Combination Therapy
Glimepiride has been evaluated in combination
with both metformin and insulin. Metformin
and glimepiride are coadministered to address
defects in both insulin secretory capacity and
insulin resistance in individuals with type 2
diabetes. In one study of 372 patients with type
2 diabetes who had failed monotherapy with
metformin, the addition of glimepiride to
metformin was associated with a mean reduction
in A1C of 0.74 0.08%, fasting glucose level of
43 4 mg/dl, and postprandial plasma glucose
level of 46.8 5 mg/dl (p<0.001). 47 No
significant deterioration in any of these
parameters was observed in the glimepiride or
metformin monotherapy groups; however,
glimepiride monotherapy was significantly more
effective than metformin monotherapy in
reducing postprandial plasma glucose levels
(p=0.029). This is consistent with evidence that
glimepiride stimulates early postprandial insulin
secretion.
When combination therapy with oral agents
does not maintain desirable levels of A1C in
patients with type 2 diabetes, insulin frequently
is added to, rather than substituted for, an oral
hypoglycemic regimen. Glimepiride is the only
sulfonylurea that carries an indication for use in
combination with insulin. In one study, 208
patients with uncontrolled diabetes mellitus
receiving a sulfonylurea alone were switched to
glimepiride, which was titrated to 8 mg
twice/day.48 Subjects with persistence of fasting
hyperglycemia (i.e., plasma glucose level
180300 mg/dl) were randomized to receive
either placebo or glimepiride in combination
with insulin for 24 weeks. Insulin (70% neutral
protamine Hagedorn [NPH]-30% regular)
administered at bedtime was started at a dosage
of 10 U/day and titrated upward until the FPG
level reached a target of 100120 mg/dl. The
FPG levels and A1C values improved to a similar
extent in both treatment groups (136 39 mg/dl
and 7.7 1.0%, respectively, for patients
receiving insulin with placebo, and 138 33

613

mg/dl and 7.6 0.8%, respectively, for those

receiving insulin with glimepiride). The declines
in FPG level and A1C were more rapid in the
glimepiride group until week 12, at which time
both treatment groups approached the target
level and remained there until the end of the
study. The mean insulin dosage needed to
control glucose levels was significantly lower
with glimepiride than with placebo (49 U/day vs
78 U/day, p<0.001). Fourteen percent of patients
treated with placebo required insulin dosages in
excess of 100 U/day, versus only 6% of patients
receiving glimepiride. A single daily injection of
insulin combined with glimepiride was sufficient
to restore glycemic control in patients whose
glucose levels were not controlled by glimepiride
alone, and control was established more quickly
and with lower insulin doses when glimepiride
therapy was continued.
In an open-label, 9-month, single-center
clinical practice study, 27 insulin-naive patients
previously treated with either glimepiride alone
or with the combination of glimepiride and
metformin received a daily single injection of
basal insulin glargine.49 Addition of bedtime
insulin resulted in improved glycemic control as
measured by A1C concentrationfrom 8.8%
before treatment to 7.3% after treatment (p<0.01).
Safety
Hypoglycemia and weight gain are the two
most common adverse effects of sulfonylurea
therapy in patients with type 2 diabetes mellitus.
These adverse effects, particularly the occurrence
of hypoglycemia, often limit the usefulness of
sulfonylureas. A large population-based
prospective study (30,768 patients) in Germany
collected data on the incidence of severe
hypoglycemia in patients with type 2 diabetes
who received either glimepiride or glyburide.50
Glimepiride was associated with fewer episodes
of severe hypoglycemia than glyburide (6 vs 38
events). The incidence of severe hypoglycemia
was 0.86/1000 person-years with glimepiride and
5.6/1000 person-years with glyburide. A greater
suppression of EGP by glyburide as compared
with glimepiride was suggested as a potential
explanation for the higher rates of hypoglycemia
observed with glyburide.
Glimepiride also does not appear to be
associated with significant weight gain. A
meta-analysis of four pivotal studies that
compared glimepiride with an active control drug
in 1444 patients revealed no significant weight

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PHARMACOTHERAPY Volume 24, Number 5, 2004

change from baseline at 1 year after the start of

glimepiride therapy (p=0.81).51
In a comparative trial with glyburide,
glimepiride was found to decrease serum insulin
and C-peptide levels significantly during
exercise, while glyburide had no effect.52 This
information may have practical applications in
that individuals with type 2 diabetes who are
treated with an insulin secretagogue fail to
normally suppress endogenous insulin during
exercise, placing them at higher risk for a
hypoglycemic event. This study demonstrated a
more physiologic response to exercise with
glimepiride in well-controlled type 2 diabetics.
Since exercise is an integral part of diabetic
therapy for weight loss, glycemic control, and
cardiovascular fitness, glimepiride may be
preferable to other sulfonylureas in this regard.
Nonsulfonylurea Insulin Secretagogues
Repaglinide and nateglinide, the two available
nonsulfonylurea insulin secretagogues, have a
mechanism of action that is similar to that of the
sulfonylureas.2 These agents are also comparable
to the sulfonylureas in regard to efficacy in
reducing A1C and plasma glucose levels (both
fasting and postprandial).4, 18, 53, 54
The nonsulfonylurea insulin secretagogues are
structurally unrelated to sulfonylurea agents.
They have short metabolic half-lives and have
high affinity, with rapid association-dissociation
kinetic activity at the KATP b cell, resulting in
relatively brief modulations of insulin secretion.19
Consequently, these agents augment early insulin
secretion in response to glucose or a meal and
reduce postprandial glucose peaks.55, 56 They are
rapidly absorbed, with mean time to peak
concentration between 0.52 hours after
administration. Their short duration of action
therefore does not affect FPG level, which also
reduces the risk of hypoglycemia between
meals. 57 These compounds are metabolized
primarily in the liver and excreted through the
renal system, with an average elimination halflife of 1.5 hours.2 Metabolism in the liver occurs
primary by the cytochrome P450 3A4 and 2C9
pathways. Therefore, this class of drugs poses a
risk for potential drug interactions with any
inducers or inhibitors of those pathways.4, 6
Repaglinide
The hypoglycemic effect of repaglinide, a
benzoic acid derivative, begins within 45 minutes
and lasts for 46 hours. Insulin concentrations

peak at 12 hours and return to fasting levels by

6 hours.2
In a placebo-controlled study of 99 subjects
with type 2 diabetes mellitus, 4 months of
repaglinide therapy was associated with absolute
reductions in A1C of 1.7% (p<0.0001), FPG level
of 3.4 mmol/l (61.2 mg/dl), and postprandial
plasma glucose level of 8 mmol/l (104.4 mg/dl)
(p<0.05) compared with placebo.54 Repaglinide
was started at a dosage of 0.25 mg given 3
times/day before meals and titrated to a maximal
dosage of 8 mg 3 times/day according to results
of FPG readings. At the end of the study, 37% of
participants were taking repaglinide 4 mg 3
times/day and 14% were taking 8 mg 3 times/day.
Another trial compared repaglinide with
glyburide.57 Repaglinide was associated with a
mean A1C reduction of 1.3% in treatment-nave
patients and a mean A1C reduction of 0.08% for
the entire cohort. Patients receiving glyburide
exhibited a mean A1C reduction of 0.10%.
Levels of FPG were comparable between the two
treatment groups. In this study, 55% of those
randomized to repaglinide and 56% of those
randomized to glyburide received maximal doses.
Nateglinide
Nateglinide, a D -phenylalanine derivative,
stimulates early insulin secretion and reduces
blood glucose levels within 3090 minutes, with
a low frequency of hypoglycemia.2, 6, 58 In one
study, nateglinide produced rapid, transient,
dose-related increases in circulating insulin
concentrations (1329 U/ml) and reductions in
postprandial plasma glucose levels (1428 mg/dl)
during the first 4 hours after doses of 30120 mg
given preprandially.55
Combination Therapy with Other Agents
Nateglinide has been evaluated in combination
with metformin. In a 24-week study, 701
patients inadequately controlled with diet alone
were randomized to nateglinide monotherapy
(120 mg before meals), metformin monotherapy
(500 mg 3 times/day), combination therapy, or
placebo.56 At the end of the study, A1C and FPG
levels were reduced in all three active-treatment
arms. The effects of combination therapy were
additive, with significantly greater changes in
A1C (-1.4%, p0.01) and FPG levels (-43.2
mg/dl, p0.01) in the combination therapy group
than in either monotherapy group. After an oral
glucose challenge, nateglinide produced a greater
reduction in glucose levels than either metformin

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

or placebo (p0.0001), and the response to
combination therapy did not differ significantly
from that observed with nateglinide monotherapy.
Thus, the decrease in A1C reflected the additive
effects of nateglinide and metformin, although
improvements in postprandial glucose level were
a direct result of the improvement in early insulin
secretion with nateglinide.
Summary
Although no trials have compared efficacy or
insulin secretory patterns between the shortacting insulin secretagogues and glimepiride,
compliance with drugs requiring multiple daily
dosing is often lower than that with single daily
dosing.59 Both nateglinide and repaglinide have a
more rapid time of onset of inhibition of K ATP
than the sulfonylureas. Nateglinide also differs
from the sulfonylureas in that it has a more rapid
reversal of inhibition.19
Insulin Secretagogues: First-Line Agents in
Managing Type 2 Diabetes Mellitus
Although insulin resistance is present in most
individuals with type 2 diabetes, it is the
impairment in insulin secretion by b cells that
leads to development of hyperglycemia. For this
reason, impaired insulin secretion can be viewed
as the primary metabolic abnormality in lean as
well as obese patients with type 2 diabetes,
providing a rationale for early use of an insulin
secretagogue in the pharmacologic management
of this disorder.20, 26
Guidelines for glycemic control to prevent or
delay progression of diabetic complications are
based on data from randomized trials, including
the Diabetes Control and Complications Trial for
people with type 1 diabetes mellitus and the
UKPDS for people with type 2 diabetes. 39, 60, 61
Neither of these trials identified a threshold for
A1C at which the risk of diabetes complications
was halted. Nevertheless, the trials confirmed
that reductions in A1C are associated with fewer
long-term microvascular complications, with a
relative risk reduction of 1530% for each 1%
decrease in A1C concentration. An epidemiologic
analysis of UKPDS data demonstrated a 14%
reduction in all-cause mortality and myocardial
infarction with each 1% reduction in A1C.61
The contribution of the postprandial glucose
level to cardiovascular risk independent of
elevated FPG level has been reported in
epidemiologic studies. 14, 62 The American
Diabetes Association (ADA) established

615

Table 3. Glycemic Treatment Goals for Individuals with

Diabetes Mellitus
ADA Goals
AACE Goals
Preprandial plasma
90130
110
glucose level (mg/dl)
Peak postprandial plasma
< 180
140
glucose level (mg/dl)
A1C (%)
< 7a
6.5
ADA = American Diabetes Association; AACE = American
Association of Clinical Endocrinologists; A1C = glycosylated
hemoglobin.
a
Referenced to a nondiabetic range of 4.06.0% using an assay
based on the Diabetes Control and Complications Trial.60
Adapted from reference 63 and 64.

treatment goals for individuals with diabetes as

summarized in Table 3.63, 64 These goals were
revised in 2003 to include targets for
postprandial as well as fasting glucose level.63
The current ADA target for a 2-hour postprandial
glucose level is less than 180 mg/dl.
Medical nutrition therapy, increased exercise,
and patient education remain the central
elements for management of type 2 diabetes.63, 64
Weight reduction is the primary goal of medical
nutrition therapy in obese patients with mild
hyperglycemia. If treatment goals are not met
after a trial of diet and exercise alone,
pharmacotherapy should be added to the
treatment regimen. Several classes of oral agents
are available for reducing hyperglycemia in
patients with type 2 diabetes. These include
insulin secretagogues (sulfonylureas, repaglinide,
and nateglinide), insulin sensitizers (the
biguanide metformin and the thiazolidinediones),
and a-glucosidase inhibitors.4
A suggested algorithm illustrating glycemic
control therapy for adult patients with type 2
diabetes is presented in Figure 4.65 Evaluation of
individual patient characteristics will aid
selection of the best oral agent for initial
monotherapy as well as for later combination
therapy. Patients with marked symptomatic
hyperglycemia, defined as a fasting glucose level
above 300 mg/dl with evidence of ketonuria or
ketonemia, may be candidates for early
introduction of insulin treatment to reduce
glucotoxicity before the start of oral therapy.66, 67
Careful consideration of patient clinical
characteristics and the availability of diabetes
self-management education (including dietary
control and exercise prescriptions) during
sulfonylurea treatment can lead to the successful
management of type 2 diabetes in as many as
7580% of patients.8 Based on findings of the
UKPDS, a sulfonylurea is recommended as initial

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PHARMACOTHERAPY Volume 24, Number 5, 2004

pharmacologic therapy for nonobese individuals

with newly diagnosed or untreated type 2
diabetes, while metformin is recommended as
initial therapy for obese individuals who have no
contraindications to its use.4, 67 The short-acting
nonsulfonylurea secretagogues may be preferred
in individuals whose meal schedules are irregular
or who experience hypoglycemia with longacting agents. 4 While the a-glucosidase
inhibitors and thiazolidinediones may be
acceptable choices for first-line therapy in
individuals with type 2 diabetes, no outcome
studies support their use over the insulin
secretagogues or metformin, as demonstrated in
the UKPDS.
Most patients with type 2 diabetes mellitus are
obese. Obese individuals may benefit from initial
therapy with metformin as observed in the
UKPDS.68 However, the progressive decline in bcell function documented in people with type 2

diabetes implies the need for add-on therapy with

a drug such as a sulfonylurea to maintain desired
levels of glycemic control over time.68 An evaluation
in 28 normal-weight and morbidly obese patients
with type 2 diabetes demonstrated a similar
pharmacokinetic profile for glimepiride in both
patient groups.69 The maximum concentration
was significantly lower in obese individuals, but
other pharmacokinetic parameters (e.g., time of
maximum concentration, area under the
concentration-time curve, clearance, half-life)
were similar.
Combination Therapy
Dosing recommendations for the available
sulfonylurea and nonsulfonylurea insulin
secretagogues are summarized in Table 1. The
UKPDS showed that by 9 years, 24% of patients
randomized to a sulfonylurea alone and 13% of

Initial intervention:
Education, nutrition, and exercisea
Goal: FPG < 130 mg/dl, SMBG < 120 mg/dl, A1C < 7.0%

Goals met
Follow-up every 36 months

Therapy adequate
FPG < 130 mg/dl, SMBG < 120 mg/dl,
A1C < 7.0%

FPG and SMBG goals not met after 1 month

Consider initial monotherapy
or early dual therapyb with
sulfonylurea and/or metformin

Therapy inadequate after 3 months

FPG 130 mg/dl, SMBGb 120 mg/dl,
A1Cb 7.0%

Continue therapy,
check A1C every 36 months

Combine
sulfonylurea with metformin

Combination therapy adequate

FPG < 130 mg/dl, SMBG < 120 mg/dl,
A1C < 7.0%
Continue combination therapy,
check A1C every 36 months

Other initial monotherapy options:

Pioglitazone or rosiglitazone,
nateglinide, repaglinide,
acarbose or miglitol,
insulin or insulin analog

Other combination options:

Metformin or a sulfonylurea +
pioglitazone or rosiglitazone,
or acarbose or miglitol,
metformin + nateglinide or
repaglinide; or insulin or insulin
analog (as mono- or combination
therapy)

Combination therapy inadequate after 36 months

FPG 130 mg/dl, SMBG 120 mg/dl,
A1C 7.0%
Add intermediate-acting bedtime NPH insulin or glargine, add intermediateacting regular insulin or lispro/aspart mixture before supper, add third
oral agent, or switch to split-dose insulin or insulin-analog therapy.
Consider referral to endocrinologist.

Figure 4. Glycemic control algorithm for type 2 diabetes mellitus in children and adults. Goals and therapies must be
individualized. Normal range for glycosylated hemoglobin (A1C) is 46%, normal fasting plasma glucose (FPG) level is
< 110 mg/dl, and impaired fasting glucose level range is 110125 mg/dl. SMBG = self-monitored blood glucose; NPH = neutral
protamine Hagedorn. aIf a symptomatic patient has an initial FPG level of 300 mg/dl or above, consider insulin or insulin
analog as initial intervention; if initial FPG level is 210 mg/dl or above, or A1C is 9% or above, consider dual oral therapy (e.g.,
metformin + sulfonylurea). bIf initial dual oral therapy is started, clinicians should consider add-on therapy within 36 months
if glycemic goals are not met. (Adapted from reference 65 with permission.)

TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

those randomized to metformin alone were able
to maintain glycemic control, with an A1C less
than 7.0%.68 These data emphasize the need to
address both defects in insulin secretion and
sensitivity in individuals with type 2 diabetes. In
addition, these findings refute the concern that
early use of sulfonylureas contributes to b-cell
exhaustion and failure in individuals with type 2
diabetes. In fact, b-cell function was improved
by early sulfonylurea use, with a rate of decline
that did not differ from metformin.
In nonobese patients, sulfonylureas are
generally successful in reducing glucose levels to
target. After FPG levels no longer can be
maintained below 120 mg/dl with near-maximal
doses of a sulfonylurea, addition of an insulinsensitizing agent (metformin or a thiazolidinedione) often will succeed in reestablishing
control.67
If glycemic control is not achieved with the use
of two oral agents, a third class of oral agents can
be added. This third agent may be either an
insulin sensitizer or an a-glucosidase inhibitor.
There is limited information on the success of
this practice.7074 In one study, 42% of patients
given triple therapy reached an A1C of 7% (vs
14% of patients receiving dual therapy), and the
number of patients reaching a final A1C of 6.5%
was four times higher in the triple-therapy group
than in the dual-therapy group (18% vs 4%).72
However, the triple-therapy group had a higher
risk of hypoglycemia (22.1% vs 3.3%). The
success seen in lowering A1C levels was
considered to outweigh the risk of hypoglycemia.
In patients with prolonged, severe
hyperglycemia, glucose toxicity worsens insulin
resistance and b-cell responsiveness. Insulin
therapy can lower glucose levels, reduce insulin
resistance, and improve b-cell function, thereby
improving the response to therapy with oral
agents.15, 66 Patients who continue to receive oral
agents can be given a single daily dose of an
intermediate-acting insulin such as NPH or lente,
or they may take a long-acting preparation such
as insulin glargine or ultralente. Another option
is to substitute a basal and bolus insulin
component for oral agents (Figure 4).65
A recent placebo-controlled study evaluated
the dosage of insulin required to control blood
glucose levels in patients who received
metformin 2550 mg/day and/or glimepiride 8
mg/day and had A1C values above 8%.75 Insulin
(70-30) was started at 10 U (before supper) and
titrated by 5 U/week until the FPG level declined
below 8 mmol/L (144 mg/dl). Achieved A1C

617

concentrations were less than 7% in all treatment

groups. The total daily insulin requirement was
lower in all three active-treatment arms than in
the placebo group (metformin, 50 U; glimepiride
40 U; combination, 23 U; placebo, 82 U). The
insulin-sparing effect was greater in patients
receiving glimepiride monotherapy (p<0.05) and
in those receiving combination therapy
(p<0.001) than in those assigned to metformin
monotherapy. Thus, glimepiride may have more
insulin-sparing activity than metformin, and it
appears to have a synergistic effect with
metformin in lowering insulin requirements
when used in combination.
Specific Clinical Scenarios
Glyburide, glipizide, and gliclazide should be
used cautiously in patients with renal or hepatic
disease because reduced excretion of either the
parent molecule or its metabolites can lead to
hypoglycemia. Glimepiride, however, has shown
favorable pharmacokinetic data related to
elimination half-life and drug clearance and a
good safety profile in patients with both diabetes
and renal impairment76 and in patients with liver
disease.41 A study of glimepiride pharmacokinetics
in 31 patients categorized by creatinine clearance
(> 50 ml/min, 2050 ml/min, and < 20 ml/min)
demonstrated that mean relative total clearance
and mean volume of distribution increased in
proportion to the degree of renal impairment.
Thus, glimepiride is effectively cleared in patients
with renal disease. The active M1 metabolite of
glimepiride, which had an increased maximum
concentration and elimination half-life in
patients with lower creatinine clearance, may
have contributed to the pharmacologic activity of
this drug; therefore, drug dosage does not need to
be increased. Terminal half-life and mean time of
concentration did not change with renal
impairment, which may be related to an
increased displacement of glimepiride from
plasma proteins in individuals with renal disease.
This effect has no apparent impact on efficacy. In
12 of 16 patients with impaired renal function
who received glimepiride over 3 months, dosages
of 14 mg/day stabilized glucose levels with no
drug-related adverse events.76 The remaining
four patients required higher dosages of
glimepiride to maintain glycemic control (up to 8
mg/day).
Limited data are available on the pharmacokinetics of glimepiride in patients with type 2
diabetes who have liver disease. This was

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PHARMACOTHERAPY Volume 24, Number 5, 2004

addressed in a study in which 11 patients with

liver disease (periportal fibrosis, mononuclear
infiltration with connective tissue, fat metamorphosis with bridging necrosis, or connective
tissue infiltration) received a single 1-mg dose of
glimepiride. 41 The resulting pharmacokinetic
profile of glimepiride was similar with regard to
maximum concentration, time of maximum
concentration, and area under the concentrationtime curve to that seen in 24 healthy
volunteers.76
Although advanced age is not a contraindication
to the use of insulin secretagogues, therapy in
elderly patients should be started at a low dose
and titrated slowly to avoid severe hypoglycemia,
which can have devastating consequences in the
presence of other comorbid conditions. The use
of agents such as glipizide, glimepiride, or the
short-acting insulin secretagogues, which are less
likely than other drugs to cause severe
hypoglycemia, is recommended.
Conclusion
Glimepiride is a second-generation sulfonylurea
that exerts its hypoglycemic effect by stimulating
basal, first, and second phases of insulin release
and by reducing postabsorptive rates of EGP.
Thus, glimepiride targets two of the pathophysiologic mechanisms that contribute to hyperglycemia in individuals with diabetes mellitus.
The efficacy of single daily dosing, the low risk of
hypoglycemia in comparison with glyburide,
together with its demonstrated selectivity for
pancreatic KATP channels and lack of affinity for
cardiac receptors may make glimepiride an
acceptable first choice as an oral agent for
treatment of type 2 diabetes.
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