catherine only
R E V I E W S F T H E R A P E U T I C S_
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 1–8 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 C- peptide levels than glyburide, and a more rapid lowering of fasting plasma glucose levels than glipizide. Glimepiride also improves first-phase insulin s e c re t i o n , w h i c h p l a y s a n i m p o rt a n t ro l e i n re d u c i n g p o s t p r a n d i a l 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):606–620)
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
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
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.
TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski
f u n c t i o n ( i n s u l i n s e c re t i o n ) a n d i n s u l i n 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 (KATP) channel. Binding of a sulfonylurea to SUR1 promotes closure of potassium channels, depolarization of the cell membrane, and subsequent voltage- dependent opening of cell-surface calcium c h a n n e l s . I n f l u x o f c a l c i u m f ro m t h e extracellular to the intracellular compartment of the b cell triggers insulin release (Figure 1).1, 2, 4–6
Evolution of Insulin Secretagogues
T h e s u l f o n y l u re a s s h a re a c o m m o n c o re structure consisting of a benzene ring plus a sulfonylurea group. The pharmacokinetic and p h a r m a c o d y n a m i c d i ff e re n c e s a m o n g t h e available sulfonylureas are a consequence of substitutions at the para position of the benzene ring and on a urea nitrogen (Figure 2).5, 7 First- generation sulfonylureas have relatively small, p o l a r, h y d ro p h i l i c s u b s t i t u t i o n s . S e c o n d - generation sulfonylureas have large, nonpolar, lipophilic substitutions that penetrate cell
membranes more easily, accounting for their increased potency.7, 8
Second-generation sulfonylureas have similar efficacy in reducing hyperglycemia to first- generation sulfonylureas (e.g., tolbutamide, acetohexamide, chlorpropamide). However, second-generation sulfonylureas are preferred for t h e i r g re a t e r p o t e n c y a n d g e n e r a l l y m o re favorable safety profiles. It should be noted that significant differences in safety exist even among t h e s e c o n d - g e n e r a t i o n s u l f o n y l u re a s . F o r 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 p l a s m a p ro t e i n s e x i s t b e t w e e n t h e t w o generations of agents and can contribute to potential unfavorable drug interactions. First- generation 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
607
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.)
Ca+ Voltage-dependent
calcium channel
Free Ca++
b cell
Metabolism
(+)
(–)
Depolarization
Sulfonylurea receptor
[ATP] [ADP]
Significant glucose-dependency lowers the risk of hypoglycemia
Glucose Insulin release
Postprandial glucose excursions are targeted by the restoration of early-phase
insulin secretion
+
Free Ca++
Metabolism
(+)
(–)
Depolarization
[ATP] [ADP]
K+
b cell
ATP-sensitive potassium channel
PHARMACOTHERAPY Volume 24, Number 5, 2004
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
glucose in individuals with type 2 diabetes that is in good to fair control.7, 11 Thus, glimepiride may i m p ro v e e a r l y p o s t p r a n d i a l a s w e l l a s l a t e postprandial hyperglycemia (Figure 3).12, 13
Postprandial hyperglycemia precedes the development of fasting hyperglycemia as an individual progresses from normal glucose tolerance to diabetes.13–15 With the onset of diabetes, postprandial hyperglycemia contributes significantly to total hyperglycemia and A1C and,
608
First-generation agents
Tolbutamide
Chlorpropamide
Tolazamide
Acetohexamide
Second-generation agents
Glyburide, glibenclamide
Glipizide
Glimepiride
Nonsulfonylureas
Nateglinide
Repaglinide
H3C C4H9
Sulfonylurea general structure:
Cl C3H7
H3C N
H3CCO
SO2NHCNHR1 R2
R1 R2
O
C-NH-CH-CH2CH
CH3
CH3
O
CO2H
CH-CH2-CH-NH-C-CH2
CH3
CH3
CO2H
N O
CH2
CH3
O
CONH(CH 2)2
Cl
OCH3
CONH(CH 2) 2H3O N
N
CH3CONH(CH 2) 2N
H3C
H3C2 O
H3C C4H9H3C C4H9
Cl C3H7Cl C3H7
H3C NH3C N
H3CCOH3CCO
SO2NHCNHR1 R2
R1 R2
O
C-NH-CH-CH2CH
CH3
CH3
O
CO2H
CH-CH2-CH-NH-C-CH2
CH3
CH3
CO2H
N O
CH2 CH
3
O
CONH(CH 2)2
Cl
OCH3
CONH(CH 2)2
Cl
OCH3
CONH(CH 2) 2H3O N
N CONH(CH 2) 2H3O
N
N
CH3CONH(CH 2) 2N
H3C
H3C2 O
CH3CONH(CH 2) 2N
H3C
H3C2 O
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
u l t i m a t e l y, t h e r i s k f o r d i a b e t e s - re l a t e d complications. This has led to the introduction o f a g e n t s t h a t t a rg e t p o s t p r a n d i a l i n s u l i n secretion.2, 6, 16–18 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
Insulin secretory defects in type 2 diabetes include blunting of early insulin responses to glucose or a meal, absence of a first-phase insulin
response to intravenous glucose, alteration in i n s u l i n p u l s a t i l i t y, a n d e x c e s s c i rc u l a t i n g proinsulin and glucagon.20 These abnormalities in insulin secretion contribute to deterioration of both fasting and postprandial glycemic regula- tion, 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 d i a b e t e s b a s e d o n a n a ff e c t e d f i r s t - d e g re e relative.20–22
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
609
Table 1. Currently Available Insulin Secretagogues
Duration of Drug Daily Dose Action (hrs) Sulfonylureas
Glyburide 1.25–20 mg, single or two divided doses Up to 24 Glipizide 2.5–40 mg, single or two divided doses 6–12
on an empty stomach Glipizide,
extended release Up to 20 mg, single dose Up to 24 Glimepiride 1–8 mg, single dose Up to 24
Nonsulfonylureas Repaglinide 4 mg, 2–3 divided doses, 15 min before meals; 3
maximum daily dose 16 mg Nateglinide 60 or 120 mg 3 times/day before meals 1.5
Adapted from reference 1.
Figure 3. Schematic representation of normal first and second phases of insulin release in response to a meal. (Adapted with permission from reference 13.)
1st Phase
2nd Phase
Response
Basal State
1st Phase
2nd Phase
Response
Basal StateG
lu c o
se -S
ti m
u la
te d
In su
lin S
e c re
ti o
n
Time
PHARMACOTHERAPY Volume 24, Number 5, 2004
glucose,17 but it had less of an effect on fasting g l u c o s e l e v e l s . 17 G l i p i z i d e a n d g l y b u r i d e 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 c h a r a c t e r i s t i c o f t h e m e g l i t i n i d e s a n d o f nateglinide, as well as improving basal and late insulin responses traditionally characteristic of the sulfonylureas.11
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 i n s u l i n re l e a s e w a s p ro l o n g e d , a n d f ro m glyburide in that the first-phase insulin release was present.30–32
Human Studies
Glimepiride’s 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 d i a b e t e s u n d e r w e n t e u g l y c e m i c a n d hyperglycemic clamp studies before and after a 4- month 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, ser ved as controls. The glimepiride dosage started at 2 mg/day and was titrated to achieve fasting plasma glucose (FPG) levels of 90–160 mg/dl. A reduction in post-
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 C- peptide responses supported this finding.
Cardiovascular Effects of Insulin Secretagogues
T h e U n i v e r s i t y G ro u p D i a b e t e s P ro g r a m (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 p o t e n t i a l p h y s i o l o g i c e x p l a n a t i o n f o r t h e 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 KATP 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 t h a t t h e s e c o n d - g e n e r a t i o n s u l f o n y l u re a glimepiride may bind more selectively to b-cell KATP channels than other agents in this class.
36
I s c h e m i c p re c o n d i t i o n i n g re f e r s t o t h e 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 c h a n n e l s a re a c t i v a t e d d u r i n g p e r i o d s o f i s c h e m i a , t h u s p l a y i n g a ro l e i n i s c h e m i c p re c o n d i t i o n i n g . D r u g s t h a t b i n d t o K AT P c h a n n e l s a n d p re v e n t t h e i r a c t i v a t i o n c a n
610
TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski
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 KATP c h a n n e l s . A l t h o u g h b o t h g l y b u r i d e a n d 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 s h o rt - a c t i n g i n s u l i n s e c re t a g o g u e s o n t h i s 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 hypo- glycemia 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 p ro b a b l y i n c o r re c t t o a s s u m e t h e r a p e u t i c
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).42–46 Glimepiride significantly reduces fasting and postprandial plasma glucose levels, as well as A1C, in patients w i t h t y p e 2 d i a b e t e s w h e n c o m p a re d w i t h placebo.42, 45 In one double-blind, multicenter trial, 304 patients with type 2 diabetes were r a n d o m i z e d t o re c e i v e 1 , 4 , o r 8 m g o f 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, c o m p a re d w i t h p l a c e b o ( p < 0 . 0 1 f o r a l l 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, 4- mg, and 8-mg doses, respectively (p<0.01). Finally, A1C concentrations in the treatment g ro u p s w e re 1 . 2 % , 1 . 8 % , a n d 1 . 9 % l o w e r, respectively, than in the placebo arm of the study (p<0.001).
611
Table 2. Summary of Selected Studies of Glimepiride
No. of Study Results of Glimepiride-Treated Patients Patients Study Design Duration Treatment Arms vs Comparator Group
30445 Placebo- 14 wks Glimepiride 1, 4, 8 mg ↓ FPG 43–47 mg/dl; ↓ PPPG 63–94 mg/dl; controlled vs placebo ↓ A1C 1.2–1.9%
41642 Placebo- 14 wks Glimepiride 8, 16 mg ↓ FPG 56–68 mg/dl; ↓ A1C 1.7% controlled vs placebo
24946 Placebo- 12 wksa Glimepiride titrated to 8 mg ↓ FPG 46 mg/dl; ↓ PPPG 86 mg/dl; controlled vs placebo ↓ A1C 1.4%
57743 Comparator 12 mo Glimepiride vs glyburide Lower rate of hypoglycemia (1.7% vs 5% at 1 mo; 12% vs 17% at 12 mo)
104444 Comparator 12 mo Glimepiride vs glyburide Lower fasting insulin level (-0.92 µU/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. aPreceded by 10 weeks’ titration.
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 223–232 mg/dl at baseline to 155–176 mg/dl (p≤0.001), and 2-hour p o s t p r a n d i a l p l a s m a g l u c o s e l e v e l w a s significantly decreased from the baseline range of 283–297 mg/dl to 203–221 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 a n d - 9 4 m g / d l v s + 2 5 . 0 m g / d l , p≤0 . 0 0 1 ) . I m p ro v e m e n t s i n A 1 C f ro m b a s e l i n e w e re 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% (p≤0.001). 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 1–8 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 ( f ro m 9 . 1 % t o 6 . 4 % ) a n d m e d i a n 2 - h o u r 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.
I n t h e s e s t u d i e s , t h e g ro u p s re c e i v i n g 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 re p o rt e d e v e n t s . R e p o rt s o f s y m p t o m a t i c 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 s u l f o n y l u re a s h a v e f o c u s e d p r i m a r i l y o n c o m p a r i s o n s w i t h g l y b u r i d e . Tw o a c t i v e - controlled trials demonstrated similar glucose- lowering 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 90–150 mg/dl and were then continued for 12 months.
One of these studies evaluated the efficacy and safety of glimepiride and glyburide in 577 p a t i e n t s p re v i o u s l y t re a t e d w i t h d i e t o r 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 g l y b u r i d e ( p = 0 . 0 6 9 ) . M o s t s u b j e c t s w e re re c e i v i n g t h e m a x i m u m d o s a g e o f e i t h e r glimepiride (1–16 mg/day) or glyburide (1.25–20 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 A 1 C o r f a s t i n g b l o o d g l u c o s e l e v e l s w e re observed between treatment groups. However, treatment with glimepiride was associated with smaller increases in median fasting insulin levels (1.27 µU/ml vs 2.2 µU/ml, p=0.041) and C- peptide concentrations (0.28 ng/ml vs 0.47 ng/ml, p=0.03) than glyburide. These differences were small, but the authors considered them p o t e n t i a l l y i m p o rt a n t , g i v e n t h e k n o w n association between hyperinsulinemia and hypertension. The two treatment groups had
612
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 m g / d a y, a n d 4 2 % o f s u b j e c t s re a c h e d t h e 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 m e t f o r m i n , t h e a d d i t i o n o f g l i m e p i r i d e t o 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 l e v e l o f 4 6 . 8 ± 5 m g / d l ( p < 0 . 0 0 1 ) . 47 N o s i g n i f i c a n t d e t e r i o r a t i o n i n a n y o f t h e s e parameters was observed in the glimepiride or m e t f o r m i n m o n o t h e r a p y g ro u p s ; h o w e v e r, glimepiride monotherapy was significantly more e ff e c t i v e t h a n m e t f o r m i n m o n o t h e r a p y i n 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 g l i m e p i r i d e , w h i c h w a s t i t r a t e d t o 8 m g twice/day.48 Subjects with persistence of fasting h y p e rg l y c e m i a ( i . e . , p l a s m a g l u c o s e l e v e l 180–300 mg/dl) were randomized to receive either placebo or glimepiride in combination with insulin for 24 weeks. Insulin (70% neutral p ro t a m i n e H a g e d o r n [ N P H ] - 3 0 % re g u l a r ) administered at bedtime was started at a dosage of 10 U/day and titrated upward until the FPG level reached a target of 100–120 mg/dl. The FPG levels and A1C values improved to a similar extent in both treatment groups (136 ± 39 mg/dl a n d 7 . 7 ± 1 . 0 % , re s p e c t i v e l y, f o r p a t i e n t s receiving insulin with placebo, and 138 ± 33
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 concentration—from 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 s u l f o n y l u re a s . A l a rg e p o p u l a t i o n - b a s e d prospective study (30,768 patients) in Germany c o l l e c t e d d a t a o n t h e i n c i d e n c e o f s e v e re 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.
G l i m e p i r i d e a l s o d o e s n o t a p p e a r t o b e associated with significant weight gain. A m e t a - a n a l y s i s o f f o u r p i v o t a l s t u d i e s t h a t compared glimepiride with an active control drug in 1444 patients revealed no significant weight
613
PHARMACOTHERAPY Volume 24, Number 5, 2004
change from baseline at 1 year after the start of glimepiride therapy (p=0.81).51
I n a c o m p a r a t i v e t r i a l w i t h g l y b u r i d e , glimepiride was found to decrease serum insulin a n d C - p e p t i d e l e v e l s s i g n i f i c a n t l y d u r i n g 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 r a p i d l y a b s o r b e d , w i t h m e a n t i m e t o p e a k c o n c e n t r a t i o n b e t w e e n 0 . 5 – 2 h o u r s a f t e r 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 half- life 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 4–6 hours. Insulin concentrations
peak at 1–2 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-naïve 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 30–90 minutes, with a low frequency of hypoglycemia.2, 6, 58 In one study, nateglinide produced rapid, transient, dose-related increases in circulating insulin concentrations (13–29 µU/ml) and reductions in postprandial plasma glucose levels (14–28 mg/dl) during the first 4 hours after doses of 30–120 mg given preprandially.55
Combination Therapy with Other Agents
Nateglinide has been evaluated in combination w i t h m e t f o r m i n . I n a 2 4 - w e e k s t u d y, 7 0 1 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%, p≤0.01) and FPG levels (-43.2 mg/dl, p≤0.01) 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
614
TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski
or placebo (p≤0.0001), 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 short- acting 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 KATP 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 i n d i v i d u a l s w i t h t y p e 2 d i a b e t e s , i t i s t h e 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 15–30% 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 e l e v a t e d F P G l e v e l h a s b e e n re p o rt e d i n e p i d e m i o l o g i c s t u d i e s . 1 4 , 6 2 T h e A m e r i c a n D i a b e t e s A s s o c i a t i o n ( A D A ) e s t a b l i s h e d
treatment goals for individuals with diabetes as summarized in Table 3.63, 64 These goals were re v i s e d i n 2 0 0 3 t o i n c l u d e t a rg e t s f o r 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, a n d p a t i e n t e d u c a t i o n re m a i n t h e c e n t r a l 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 a f t e r a t r i a l o f d i e t a n d e x e rc i s e a l o n e , p h a r m a c o t h e r a p y s h o u l d b e a d d e d t o t h e treatment regimen. Several classes of oral agents are available for reducing hyperglycemia in patients with type 2 diabetes. These include insulin secretagogues (sulfonylureas, repaglinide, a n d n a t e g l i n i d e ) , i n s u l i n s e n s i t i z e r s ( t h e 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 i n d i v i d u a l p a t i e n t c h a r a c t e r i s t i c s w i l l a i d s e l e c t i o n o f t h e b e s t o r a l a g e n t f o r i n i t i a l 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 k e t o n e m i a , m a y b e c a n d i d a t e s f o r e a r l y 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 75–80% of patients.8 Based on findings of the UKPDS, a sulfonylurea is recommended as initial
615
Table 3. Glycemic Treatment Goals for Individuals with Diabetes Mellitus
ADA Goals AACE Goals Preprandial plasma 90–130 ≤ 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. aReferenced to a nondiabetic range of 4.0–6.0% using an assay based on the Diabetes Control and Complications Trial.60
Adapted from reference 63 and 64.
PHARMACOTHERAPY Volume 24, Number 5, 2004
pharmacologic therapy for nonobese individuals w i t h n e w l y d i a g n o s e d o r u n t re a t e d t y p e 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 long- a c t i n g a g e n t s . 4 W h i l e t h e a- g l u c o s i d a s e i n h i b i t o r s a n d t h i a z o l i d i n e d i o n e s m a y b e acceptable choices for first-line therapy in individuals with type 2 diabetes, no outcome s t u d i e s s u p p o rt t h e i r u s e o v e r t h e i n s u l i n 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 b- cell 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 m a x i m u m c o n c e n t r a t i o n , a re a u n d e r t h e concentration-time curve, clearance, half-life) were similar.
Combination Therapy
Dosing recommendations for the available s u l f o n y l u re a a n d n o n s u l f o n y l u re a i n s u l i n secretagogues are summarized in Table 1. The UKPDS showed that by 9 years, 24% of patients randomized to a sulfonylurea alone and 13% of
616
Goal: FPG < 130 mg/dl, SMBG < 120 mg/dl, A1C < 7.0%
Goals met FPG and SMBG goals not met after 1 month
Consider initial monotherapy or early dual therapyb with
sulfonylurea and/or metformin
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)
Therapy adequate FPG < 130 mg/dl, SMBG < 120 mg/dl,
A1C < 7.0%
Continue therapy, check A1C every 3–6 months
Therapy inadequate after 3 months FPG ≥ 130 mg/dl, SMBGb ≥ 120 mg/dl,
A1Cb ≥ 7.0%
Combine sulfonylurea with metformin
Combination therapy adequate FPG < 130 mg/dl, SMBG < 120 mg/dl,
A1C < 7.0%
Continue combination therapy, check A1C every 3–6 months
Combination therapy inadequate after 3–6 months FPG ≥ 130 mg/dl, SMBG ≥ 120 mg/dl,
A1C ≥ 7.0%
Add intermediate-acting bedtime NPH insulin or glargine, add intermediate- acting 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.
Follow-up every 3–6 months
Initial intervention: Education, nutrition, and exercisea
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 4–6%, normal fasting plasma glucose (FPG) level is < 110 mg/dl, and impaired fasting glucose level range is 110–125 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 3–6 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.
I n n o n o b e s e p a t i e n t s , s u l f o n y l u re a s a re generally successful in reducing glucose levels to t a rg e t . A f t e r F P G l e v e l s n o l o n g e r c a n b e maintained below 120 mg/dl with near-maximal doses of a sulfonylurea, addition of an insulin- sensitizing agent (metformin or a thiazolidine- dione) 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.70–74 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 s u c c e s s s e e n i n l o w e r i n g A 1 C l e v e l s w a s considered to outweigh the risk of hypoglycemia.
I n p a t i e n t s w i t h p ro l o n g e d , s e v e re 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 i s t o s u b s t i t u t e a b a s a l a n d b o l u s i n s u l i n component for oral agents (Figure 4).65
A recent placebo-controlled study evaluated the dosage of insulin required to control blood g l u c o s e l e v e l s i n p a t i e n t s w h o re c e i v e d 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
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 i n t h o s e re c e i v i n g c o m b i n a t i o n t h e r a p y (p<0.001) than in those assigned to metformin monotherapy. Thus, glimepiride may have more insulin-sparing activity than metformin, and it a p p e a r s t o h a v e a s y n e rg i s t i c e ff e c t w i t h 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 f a v o r a b l e p h a r m a c o k i n e t i c d a t a re l a t e d t o 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, 20–50 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 c o n c e n t r a t i o n a n d e l i m i n a t i o n h a l f - l i f e i n 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 c o n c e n t r a t i o n d i d n o t c h a n g e w i t h re n a l i m p a i r m e n t , w h i c h m a y b e re l a t e d t o a n 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 1–4 mg/day stabilized glucose levels with no drug-related adverse events.76 The remaining f o u r p a t i e n t s re q u i re d h i g h e r d o s a g e s o f glimepiride to maintain glycemic control (up to 8 mg/day).
Limited data are available on the pharmaco- kinetics of glimepiride in patients with type 2 diabetes who have liver disease. This was
617
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 meta- morphosis 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 concentration- t i m e c u r v e t o t h a t s e e n i n 2 4 h e a l t h y 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 l i k e l y t h a n o t h e r d r u g s t o c a u s e s e v e re 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 pathophysio- logic mechanisms that contribute to hyper- glycemia 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.
References 1. Masharani U, Karam JH. Diabetes mellitus and hypoglycemia.
In: Tierney LMJ, McPhee SJ, Papadakis MA, eds. 2002 current medical diagnosis and treatment: adult ambulatory and inpatient management. New York: McGraw-Hill, 2002: 1203–50.
2. Perfetti R, Ahmad A. Novel sulfonylurea and non-sulfonylurea drugs to promote the secretion of insulin. Trends Endocrinol Metab 2000;11:218–23.
3. DeFronzo RA. The triumvirate: b cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988;37:667–87.
4. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360–72.
5. Gerich JE . O r a l h y p o g l y c e m i c a g e n t s . N E n g l J M e d 1989;321:1231–45.
6. Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001;358:1709–16.
7. Campbell RK. Glimepiride: role of a new sulfonylurea in the treatment of type 2 diabetes mellitus. Ann Pharmacother 1998;32:1044–52.
8. Tal A. Oral hypoglycemic agents in the treatment of type II
diabetes. Am Fam Physician 1993;48:1089–95. 9. Harrower AD. Comparative tolerability of sulphonylureas in
diabetes mellitus. Drug Safety 2000;22:313–20. 10. Lebovitz HE. Oral therapies for diabetic hyperglycemia.
Endocrinol Metab Clin North Am 2001;30:909–33. 11. Korytkowski M, Thomas A, Reid L, Tedesco MB, Gooding
WE, Gerich J. Glimepiride improves both first and second phases of insulin secretion in type 2 diabetes. Diabetes Care 2002;25:1607–11.
12. Sonnenberg GE, Garg DC, Weidler DJ, et al. Short-term comparison of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent diabetes mellitus. Ann Pharmacother 1997;31:671–6.
13. Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med 1981;70:579–88.
14. DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999;354:617–21.
15. Edelman SV, Henry RR. Diagnosis and management of type 2 diabetes, 4th ed. Caddo, OK: Professional Communications, Inc, 2001.
16. Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care 1997;20: 1822–6.
17. Hollander PA, Schwartz SL, Gatlin MR, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 2001;24:983–8.
18. Damsbo P, Clauson P, Marbury TC, Windfeld K. A double- blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. Diabetes Care 1999;22:789–94.
19. Hu S, Wang S, Fanelli B, et al. Pancreatic b-cell KATP channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther 2000;293:444–52.
20. Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes. Diabetes Metab Res Rev 2001;17:164–74.
21. Pimenta W, Mitrakou A, Jensen T, Yki-Järvinen H, Daily G, Gerich J. Insulin secretion and insulin sensitivity in people with impaired glucose tolerance. Diabet Med 1996;13:S33–6.
22. Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 1976;42:222–9.
23. Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release a n d m e t a b o l i c re g u l a t i o n i n t y p e 2 d i a b e t e s . D i a b e t e s 2002;51(suppl 1):S109–16.
24. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia 2001;44:929–45.
25. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW . Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes 1988;37:736–44.
26. Basu A, Alzaid A, Dinneen S, Caumo A, Cobelli C, Rizza RA. Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance. J Clin Invest 1996;97:2351–61.
27. Pfeifer MA, Halter JB, Beard JC, Porte D Jr. Differential effects of tolbutamide on first and second phase insulin secretion in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1981;53:1256–62.
28. Schmitz O, Lund S, Andersen PH, Jønler M, Pørksen N. Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide. Diabetes Care 2002;25:342–6.
29. Groop LC, Ratheiser K, Luzi L, et al. Effect of sulphonylurea on glucose-stimulated insulin secretion in healthy and non-
618
TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski
insulin dependent diabetic subjects: a dose-response study. Acta Diabetol 1991;28:162–8.
30. Gregorio F, Ambrosi F, Cristallini S, Filipponi P, Santeusanio F. Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations. Acta Diabetol 1996;33:25–9.
31. Gregorio F, Ambrosi F, Filipponi P, Cristallini S, Santeusanio F. Glucose modulates the amount, but not the kinetics, of insulin released by sulfonylureas. J Diabetes Complications 1994;8:204–12.
32. Gregorio F, Ambrosi F, Cristallini S, Pedetti M, Filipponi P, Santeusanio F. Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic a- and b-cell function. Diabetes Res Clin Pract 1992;18:197–206.
33. Kilo C, Miller JP, Williamson JR. The crux of the UGDP: spurious results and biologically inappropriate data analysis. Diabetologia 1980;18:179–85.
34. Kilo C, Miller JP, Williamson JR. The Achilles heel of the University Group Diabetes Program. JAMA 1980;243:450–7.
35. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP- sensitive potassium channels in humans. Diabetologia 1996;39:1083–90.
36. Lee T-M, Chou T-F. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab 2003;88: 531–7.
37. O’Rourke B. Myocardial KATP channels in preconditioning. Circ Res 2000;87:845–55.
38. Buffington CK, Kitabchi AE . A c t i v a t i o n o f p y r u v a t e dehydrogenase complex (PDC) of rat heart mitochondria by glyburide. Biochem Biophys Res Commun 1984;123:202–9.
39. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352: 837–53.
40. Jollis JG, Simpson RJ Jr, Cascio WE, Chowdhury MK, Crouse JR III, Smith SC Jr. Relation between sulfonylurea therapy, complications, and outcome for elderly patients with acute myocardial infarction. Am Heart J 1999;138:S376–80.
41. Rosenkranz B. Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients. Horm Metab Res 1996;28:434–9.
42. Rosenstock J, Samols E, Muchmore DB, Schneider J, for the Glimepiride Study Group. Glimepiride, a new once-daily sulfonylurea: a double-blind placebo-controlled study of NIDDM patients. Diabetes Care 1996;19:1194–9.
43. Dills DG, Schneider J, for the Glimepiride/Glyburide Research Group. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 1996;28:426–9.
44. Draeger KE, Wernicke-Panten K, Lomp H-J, Schüler E, Roßkamp R. Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl®): a double-blind comparison with glibenclamide. Horm Metab Res 1996;28:419–25.
45. Goldberg RB, Holvey SM, Schneider J, for the Glimepiride Protocol #201 Study Group. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. Diabetes Care 1996;19:849–56.
46. Schade DS, Jovanovic L, Schneider JA. Placebo-controlled, randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. J Clin Pharmacol 1998;38:636–41.
47. Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin m o n o t h e r a p y i n t y p e 2 d i a b e t i c p a t i e n t s . D i a b e t M e d 2001;18:828–34.
48. Riddle MC, Schneider J, for the Glimepiride Combination Group. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Diabetes Care 1998;21:1052–7.
49. Schreiber SA, Russmann A. Improved metabolic control with a favorable weight profile in patients with type 2 diabetes treated with insulin glargine in clinical practice [abstr]. Diabetes 2002;51(suppl 2):A114.
50. Holstein A, Plaschke A, Egberts E-H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001;17:467–73.
51. Bugos C, Austin M, Atherton T, Viereck C. Long-term treatment of type 2 diabetes mellitus with glimepiride is weight neutral: a meta-analysis [abstr]. Diabetes Res Clin Pract 2000;50(suppl 1):S47.
52. Massi-Benedetti M, Herz M, Pfeiffer C. The effects of acute exercise on metabolic control in type II diabetic patients treated with glimepiride or glibenclamide. Horm Metab Res 1996;28: 451–5.
53. Kalbag JB, Walter YH, Nedelman JR, McLeod JF. Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo. Diabetes Care 2001;24:73–7.
54. Goldberg RB, Einhorn D, Lucas CP, et al. A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabetes Care 1998;21:1897–903.
55. Walter YH, Spratt DI, Garreffa S, McLeod JF. Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus. Eur J Clin Pharmacol 2000;56:129–33.
56. Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000;23:1660–5.
57. Marbury T, Huang W-C, Strange P, Lebovitz H. Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract 1999;43:155–66.
58. Levien TL, Baker DE, Campbell RK, White JR Jr. Nateglinide therapy for type 2 diabetes mellitus. Ann Pharmacother 2001;35:1426–34.
59. Dailey G, Kim MS, Lian JF. Patient compliance and persistence with anti-hyperglycemic therapy: evaluation of a population of type 2 diabetic patients. J Int Med Res 2002;30:71–9.
60. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–86.
61. Stratton IM, Adler AI, Neil HAW, et al, on behalf of the UK Prospective Diabetes Study Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–12.
62. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in type II diabetes: the epidemiological evidence. Diabetologia 2001;44:2107–14.
63. American Diabetes Association. Clinical practice recommen- dations 2003. Diabetes Care 2003;26(suppl 1):S1–156.
64. American College of Endocrinology, American Association of Clinical Endocrinologists. Consensus statement on guidelines for glycemic control. Endocr Pract 2002;8(suppl 1):5–11.
65. Texas Diabetes Council. Glycemic control algorithm for type 2 diabetes mellitus in children and adults. Last update 2003. Available from http://www.tdh.state.tx.us/diabetes/pdf/ algorithms/pharm2.pdf. Accessed July 14, 2003.
66. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: application, benefits, and risks. Diabetes Reviews 1995;3:308–34.
67. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281–303.
68. Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005–12.
69. Shukla U, Chi E, Lehr KH. Comparison of glimepiride (Amaryl®) pharmacokinetics in normal weight and obese
619
PHARMACOTHERAPY Volume 24, Number 5, 2004
patients with type 2 diabetes [abstr]. Diabetes 2001;50(suppl 2):A444.
70. Bell DS. Combination therapy for type 2 diabetes [editorial]. Am Fam Physician 2001;64:1812–14.
71. Bell DS, Ovalle F. Long-term efficacy of triple oral therapy for type 2 diabetes mellitus. Endocr Pract 2002;8:271–5.
72. Bruce S, Lee H, Goldstein BJ. Incidence of hypoglycemia following addition of rosiglitazone to glyburide/metformin tablets in patients with type 2 diabetes [abstr]. Diabetes 2002;51(suppl 2):A466.
73. Goldstein BJ, Bruce S, Lee H, Fiedorek FT. Rosiglitazone
added to glyburide/metformin tablets: glycemic effects [abstr]. Diabetes 2002;51(suppl 2):A98.
74. Ovalle F, Bell DSH. Triple oral antidiabetic therapy in type 2 diabetes mellitus. Endocr Pract 1998;4:146–7.
75. Kabadi UM, Kabadi MM. Daily insulin dose in combination with metformin or/and glimepiride in type 2 diabetes mellitus [abstr]. Diabetes 2002;51(suppl 2):A102.
76. Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V. Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment. Diabetologia 1996;39:1617–24.
620