jurnal amaryl fix

15
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 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 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):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.

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Page 1: Jurnal Amaryl Fix

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 theirintroduction nearly 50 years ago, remain the most frequently prescribed oralagents for treatment of patients with type 2 diabetes mellitus. Glyburide,glipizide, and glimepiride, the newest sulfonylureas, are as effective atlowering plasma glucose concentrations as first-generation agents but aremore potent, better tolerated, and associated with a lower risk of adverseeffects. Differences in their binding affinity to the b-cell sulfonylurea receptorhave been described, with preservation of cardioprotective responses toischemia with glimepiride. Clinical studies have shown glimepiride to be safeand effective in reducing fasting and postprandial glucose levels, as well asglycosylated hemoglobin concentrations, with dosages of 1–8 mg/day. Incomparative trials, glimepiride was as effective in lowering glucose levels asglyburide and glipizide, but glimepiride was associated with a reducedlikelihood of hypoglycemia and a smaller increase in fasting insulin and C-peptide levels than glyburide, and a more rapid lowering of fasting plasmaglucose levels than glipizide. Glimepiride also improves first-phase insulinsecretion, which plays an important role in reducing postprandialhyperglycemia. Insulin secretagogues, specifically glimepiride, meritconsideration 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 SecretagoguesImpairments in b-Cell Function in Type 2 Diabetes

Importance of First-Phase Insulin SecretionPharmacologic Profile of Glimepiride

Animal StudiesHuman Studies

Cardiovascular Effects of Insulin SecretagoguesEfficacy and Safety Studies with Glimepiride

Placebo-Controlled TrialsComparisons with Other Sulfonylureas

Combination TherapySafety

Nonsulfonylurea Insulin SecretagoguesRepaglinideNateglinideCombination Therapy with Other AgentsSummary

Insulin Secretagogues: First-Line Agents in ManagingType 2 DiabetesCombination TherapySpecific Clinical Scenarios

Conclusion

Since their introduction in the 1950s, thesulfonylureas have remained the most frequentlyused drugs for management of type 2 diabetesmellitus,1, 2 a heterogeneous disorder resultingfrom the interaction of impaired pancreatic b-cell

From the Center for Diabetes and Endocrinology, and theDivision 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, 3601Fifth Avenue, Pittsburgh, PA 15213; e-mail: [email protected].

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TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

function (insulin secretion) and insulinresistance.3 The sulfonylureas lower bloodglucose levels by stimulating insulin releasethrough a direct action on b cells. These agentsbind to a specific receptor, called the sulfonylureareceptor, on the b-cell surface (SUR1). The SUR1is a component of the adenosine triphosphate(ATP)–dependent potassium (KATP) channel.Binding of a sulfonylurea to SUR1 promotesclosure of potassium channels, depolarization ofthe cell membrane, and subsequent voltage-dependent opening of cell-surface calciumchannels. Influx of calcium from theextracellular to the intracellular compartment ofthe b cell triggers insulin release (Figure 1).1, 2, 4–6

Evolution of Insulin Secretagogues

The sulfonylureas share a common corestructure consisting of a benzene ring plus asulfonylurea group. The pharmacokinetic andpharmacodynamic differences among theavailable sulfonylureas are a consequence ofsubstitutions at the para position of the benzenering and on a urea nitrogen (Figure 2).5, 7 First-generation sulfonylureas have relatively small,polar, hydrophilic substitutions. Second-generation sulfonylureas have large, nonpolar,lipophilic substitutions that penetrate cell

membranes more easily, accounting for theirincreased potency.7, 8

Second-generation sulfonylureas have similarefficacy in reducing hyperglycemia to first-generation sulfonylureas (e.g., tolbutamide,acetohexamide, chlorpropamide). However,second-generation sulfonylureas are preferred fortheir greater potency and generally morefavorable safety profiles. It should be noted thatsignificant differences in safety exist even amongthe second-generation sulfonylureas. Forexample, therapy with glyburide results insimilar rates of hypoglycemia to those observedwith chlorpropamide.1, 2, 4 First-generationagents are associated with more hypoglycemia,weight gain, and water retention than generally isseen with second-generation agents.5, 9 Inaddition, differences in binding to circulatingplasma proteins exist between the twogenerations of agents and can contribute topotential unfavorable drug interactions. First-generation sulfonylureas bind ionically to plasmaproteins and thus have a higher likelihood ofdrug interactions with other ionically bounddrugs, such as salicylates and sulfonamides. Thesecond-generation agents, which are nonionicallybound to plasma proteins, cause fewer problemswith drug interactions.5

607

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

Ca+Voltage-dependent

calcium channel

FreeCa++

b cell

Metabolism

(+)

(–)

Depolarization

Sulfonylurea receptor

[ATP][ADP]

Significant glucose-dependencylowers the risk of hypoglycemia

GlucoseInsulin release

Postprandial glucoseexcursions aretargeted by therestoration ofearly-phase

insulin secretion

+

FreeCa++

Metabolism

(+)

(–)

Depolarization

[ATP][ADP]

K+

b cell

ATP-sensitivepotassium channel

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PHARMACOTHERAPY Volume 24, Number 5, 2004

All sulfonylureas induce increases in fastingand late postprandial insulin responses that areassociated with clinically meaningful decreases inblood glucose levels and glycosylated hemoglobin(A1C).2, 4, 10, 11 Glimepiride is the most potent ofthe second-generation sulfonylureas, causing thegreatest reduction in blood glucose levels withthe lowest indicated dosage (Table 1).1, 7 Unlikeother available sulfonylureas, glimepiride alsoimproves early or first-phase insulin response to

glucose in individuals with type 2 diabetes that isin good to fair control.7, 11 Thus, glimepiride mayimprove early postprandial as well as latepostprandial hyperglycemia (Figure 3).12, 13

Postprandial hyperglycemia precedes thedevelopment of fasting hyperglycemia as anindividual progresses from normal glucosetolerance to diabetes.13–15 With the onset ofdiabetes, postprandial hyperglycemia contributessignificantly 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(CH2)2

Cl

OCH3

CONH(CH2)2H3ON

N

CH3CONH(CH2)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

CH3

O

CONH(CH2)2

Cl

OCH3

CONH(CH2)2

Cl

OCH3

CONH(CH2)2H3ON

NCONH(CH2)2H3O

N

N

CH3CONH(CH2)2N

H3C

H3C2 O

CH3CONH(CH2)2N

H3C

H3C2 O

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

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ultimately, the risk for diabetes-relatedcomplications. This has led to the introductionof agents that target postprandial insulinsecretion.2, 6, 16–18 These agents, repaglinide andnateglinide, are short-acting nonsulfonylureainsulin secretagogues with a more rapid insulinresponse to a meal and shorter duration of actionthan the sulfonylureas. These characteristicstranslate clinically to lower postmeal glucoseexcursions and reduced potential for hypoglycemia.The nonsulfonylurea insulin secretagogues aretaken before each meal and have a mechanism ofaction similar to that of the sulfonylureas, butthey differ in their affinity for and bindingkinetics to b-cell sulfonylurea receptors.2, 19

Impairments in b-Cell Function in Type 2Diabetes Mellitus

Insulin secretory defects in type 2 diabetesinclude blunting of early insulin responses toglucose or a meal, absence of a first-phase insulin

response to intravenous glucose, alteration ininsulin pulsatility, and excess circulatingproinsulin and glucagon.20 These abnormalitiesin insulin secretion contribute to deterioration ofboth fasting and postprandial glycemic regula-tion, resulting in progression of the disorder. Animpairment in first-phase insulin release isevident in individuals with impaired glucosetolerance as well as in those at risk for type 2diabetes based on an affected first-degreerelative.20–22

Importance of First-Phase Insulin Secretion

Several excellent reviews have discussed theimportance of first-phase insulin secretion.20, 23, 24

First-phase insulin secretion is important inblunting the rise in glucose levels after a meal.This process is due partly to suppression ofendogenous glucose production (EGP).20 In onestudy of patients with type 2 diabetes, infusion ofinsulin to simulate a first-phase insulin responseresulted in a 25-mg/dl decrease in peak plasmaglucose responses to an intravenous glucosebolus.25 This defect in insulin secretion, with itspathogenic role in postprandial hyperglycemia,suggests that agents targeting early as well as lateinsulin secretion may be advantageous in thetherapy of type 2 diabetes.23, 26

Several clinical studies have investigated theimpact of insulin secretagogues on first-phaseinsulin release.17, 27, 28 Tolbutamide, a short-actingsulfonylurea, improved first-phase insulinsecretion in patients with type 2 diabetes whohad severe hyperglycemia. However, it did notprovide this benefit in patients with type 2diabetes who had only mild hyperglycemia.27

Nateglinide improved early insulin responsivenessto both oral and intravenously administered

609

Table 1. Currently Available Insulin Secretagogues

Duration ofDrug Daily Dose Action (hrs)Sulfonylureas

Glyburide 1.25–20 mg, single or two divided doses Up to 24Glipizide 2.5–40 mg, single or two divided doses 6–12

on an empty stomachGlipizide,

extended release Up to 20 mg, single dose Up to 24Glimepiride 1–8 mg, single dose Up to 24

NonsulfonylureasRepaglinide 4 mg, 2–3 divided doses, 15 min before meals; 3

maximum daily dose 16 mgNateglinide 60 or 120 mg 3 times/day before meals 1.5

Adapted from reference 1.

Figure 3. Schematic representation of normal first andsecond 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

luco

se-S

timul

ated

Insu

lin S

ecre

tion

Time

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PHARMACOTHERAPY Volume 24, Number 5, 2004

glucose,17 but it had less of an effect on fastingglucose levels.17 Glipizide and glyburideincreased both first- and late-phase insulinresponsiveness in nondiabetic, but not diabetic,volunteers.29 Thus, glimepiride may be uniqueamong the available insulin secretagogues in thatit improves first-phase insulin response, acharacteristic of the meglitinides and ofnateglinide, as well as improving basal and lateinsulin responses traditionally characteristic ofthe sulfonylureas.11

Pharmacologic Profile of Glimepiride

Animal Studies

Studies in animal models of diabetes mellitushave shown that at pharmacologic concentrations,glimepiride stimulates insulin release in abiphasic pattern, with a discrete first-phase peakand a prolonged second phase.30 One studyshowed that in addition to increasing the totalamount of insulin released, glimepiride resultedin persistence of the biphasic pattern of first andsecond phases of insulin secretion as the glucoseinfusion increased.30 Using the same model,tolbutamide also promoted biphasic insulinrelease.31 However, a more rapid decline insecond-phase insulin secretion was observed withthis short-acting, first-generation sulfonylurea.Glyburide, another second-generation sulfonylurea,produced a delayed monophasic insulin responseand did not elicit any change in first-phaseinsulin response.31, 32 In summary, the pattern ofinsulin secretion with glimepiride differed fromtolbutamide in that the secondary phase ofinsulin release was prolonged, and fromglyburide in that the first-phase insulin releasewas present.30–32

Human Studies

Glimepiride’s beneficial effects on the first andsecond phases of insulin secretion have beendocumented in humans as well as in animals.11, 30

In one recent study, 11 obese patients with type 2diabetes underwent euglycemic andhyperglycemic clamp studies before and after a 4-month treatment period with glimepiride todetermine the potential effects of this agent oninsulin sensitivity and b-cell function.11 A groupof nondiabetic individuals, matched for age andbody mass index, served as controls. Theglimepiride dosage started at 2 mg/day and wastitrated to achieve fasting plasma glucose (FPG)levels of 90–160 mg/dl. A reduction in post-

absorptive EGP without a change in insulinsensitivity was observed in the euglycemic clampstudies. The reduction in EGP correlated withobserved reductions in FPG levels. Results fromthe hyperglycemic clamp study demonstratedsignificant improvements in first and second(steady-state) phases of insulin secretion withglimepiride. Additional measures of first-phaseinsulin response, including maximal insulinresponse during the first 10 minutes after theglucose bolus and incremental first-phase C-peptide responses supported this finding.

Cardiovascular Effects of Insulin Secretagogues

The University Group Diabetes Program(UGDP) published in 1970 raised the concernthat sulfonylureas might increase the risk ofcardiovascular death.33, 34 In the UGDP, a greaterthan 2-fold increase in cardiovascular mortalitywas observed in the group randomized to receivetolbutamide. The significance of these resultshas been the subject of ongoing debate.

Discovery of a sulfonylurea receptor (SUR) as acomponent of KATP channels within both b cells(SUR1) and myocardial cells (SUR2A) openedscientific inquiry into a potential link betweensulfonylurea agents and cardiovascular risk.35

The binding of sulfonylureas to SUR2A offers apotential physiologic explanation for theincreased cardiovascular mortality associatedwith tolbutamide in the controversial UGDP.33 34

Both cardiac and vascular smooth muscle containSURs with KATP channels.35 These receptors playa role in ischemic preconditioning, which canprotect myocardial cells from a prolongedischemic insult.35, 36 Binding to cardiac KATPchannels by a sulfonylurea may theoreticallyinterfere with ischemic preconditioning, thusincreasing the likelihood and severity of amyocardial infarction. Differences in bindingcharacteristics among the sulfonylureas suggestthat the second-generation sulfonylureaglimepiride may bind more selectively to b-cellKATP channels than other agents in this class.36

Ischemic preconditioning refers to theprotective effect of repetitive brief periods ofmyocardial ischemia that ultimately serve aprotective function within the myocardium bydecreasing infarct size resulting from moreprolonged periods of ischemia.36, 37 Cardiac KATPchannels are activated during periods ofischemia, thus playing a role in ischemicpreconditioning. Drugs that bind to KATPchannels and prevent their activation can

610

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TREATMENT OF TYPE 2 DIABETES MELLITUS: FOCUS ON GLIMEPIRIDE Korytkowski

interfere with this protective response.36, 37

Glyburide has been shown to interfere withthis protective response to ischemia in bothanimal and human studies.36, 38 In a recentclinical trial investigating the effects of glyburideand glimepiride on the preconditioning responseto ischemia, glimepiride did not interfere withthe preconditioning response in either patientswith diabetes or nondiabetic volunteers.36

Glyburide, on the other hand, inhibited theischemic preconditioning response in bothgroups.

These observed differences may reflect thebinding characteristics of these agents to KATPchannels. Although both glyburide andglimepiride bind to cell-surface KATP channels,only glyburide binds to mitochondrial channelswithin myocardial cells, which are responsible formediating this protective response.38 The impactof other sulfonylureas, such as glipizide, and theshort-acting insulin secretagogues on thisprotective response to ischemia has not beentested. However, these differences between theavailable sulfonylureas should not undermine theclinical potential and safety of the drug class ingeneral. The United Kingdom ProspectiveDiabetes Study (UKPDS) demonstrated thatreductions in A1C and myocardial infarction withthe sulfonylureas glyburide and chlorpropamidewere 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 ofthe sulfonylureas.40, 41

In summary, based on available data, it isprobably incorrect to assume therapeutic

equivalence among the available sulfonylureas.Although the efficacy and safety profiles of thesecond-generation sulfonylureas are excellent,glimepiride may have theoretic advantages overother members of this class.

Efficacy and Safety Studies with Glimepiride

Placebo-Controlled Trials

Evidence that glimepiride restores some degreeof first-phase as well as second-phase insulinrelease is supported by trials evaluating measuresof fasting and postprandial glycemia as well asoverall glycemic control (Table 2).42–46 Glimepiridesignificantly reduces fasting and postprandialplasma glucose levels, as well as A1C, in patientswith type 2 diabetes when compared withplacebo.42, 45 In one double-blind, multicentertrial, 304 patients with type 2 diabetes wererandomized to receive 1, 4, or 8 mg ofglimepiride once/day for 14 weeks.45 Reductionsin fasting and 2-hour postprandial plasmaglucose levels and A1C concentrations wereobserved with both the 4-mg and 8-mg doses.Levels of FPG decreased by 43.2 mg/dl with the1-mg/day dosage, 70.2 mg/dl with the 4-mg/daydosage, and 73.8 mg/dl with the 8-mg dosage,compared with placebo (p<0.01 for allcomparisons). Postprandial plasma glucoselevels 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 treatmentgroups were 1.2%, 1.8%, and 1.9% lower,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 PatientsPatients 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.

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PHARMACOTHERAPY Volume 24, Number 5, 2004

The efficacy of glimepiride over placebo wasdemonstrated in a 14-week study comparingtreatment with glimepiride 8 mg/day or 16mg/day in 416 randomized patients.42 The FPGlevels were reduced from 223–232 mg/dl atbaseline to 155–176 mg/dl (p≤0.001), and 2-hourpostprandial plasma glucose level wassignificantly decreased from the baseline range of283–297 mg/dl to 203–221 mg/dl (p<0.001) withglimepiride. Both glimepiride regimens alsodecreased 2-hour postprandial glucose levelssignificantly more than did placebo (-61 mg/dland -94 mg/dl vs +25.0 mg/dl, p≤0.001).Improvements in A1C from baseline wereconsistently greater with the active treatmentregimens than with placebo, reducing absoluteA1C by 0.1-0.8% to a final end point of 7.4-7.6%(p≤0.001). There were no clinically meaningfuldifferences in efficacy between the glimepirideonce-daily and twice-daily regimens, or betweentreatment with dosages of 8 mg/day and 16mg/day

A placebo-controlled study in 249 patientswith type 2 diabetes mellitus that was poorlycontrolled with diet and exercise confirmed theefficacy of glimepiride.46 Glimepiride wastitrated over 10 weeks to a daily dose of 1–8 mg.After a 12-week treatment period, patientstreated with glimepiride showed a significantimprovement in median FPG levels (from 153mg/dl at baseline to 107 mg/dl). This wassignificantly greater than the improvement seenin the placebo group (p<0.001). The samepattern of improvement from baseline withglimepiride was also observed for median A1C(from 9.1% to 6.4%) and median 2-hourpostprandial plasma glucose levels (from 297mg/dl to 174 mg/dl, a 72-mg/dl change whencompared with placebo). Finally, A1C values of7.2% or less were achieved by 69% of patients inthe active group, versus only 32% of those in theplacebo group.

In these studies, the groups receivingglimepiride monotherapy were similar to theplacebo groups in regard to the rate of adverseevents. Headache, dizziness, and digestivesystem disturbances were the most commonlyreported events. Reports of symptomatichypoglycemia by patients were considered notsevere by investigators or were few in number. Inaddition, no cases of laboratory-confirmedhypoglycemia (plasma glucose levels < 60 mg/dl)were reported.42, 45, 46 The number of patientsdiscontinuing glimepiride due to symptomatichypoglycemia was very small (two patients46 and

four patients42; < 1% in either trial), and mostpatients in the glimepiride arms completed thestudies.

Comparison with Other Sulfonylureas

Studies comparing glimepiride with othersulfonylureas have focused primarily oncomparisons with glyburide. Two active-controlled trials demonstrated similar glucose-lowering effects for glimepiride and glyburide,with a reduced likelihood of hypoglycemia andpossibly a more rapid response with glimepiride(Table 2).43, 44 In these studies, doses weretitrated over 12 weeks to achieve FPG levels of90–150 mg/dl and were then continued for 12months.

One of these studies evaluated the efficacy andsafety of glimepiride and glyburide in 577patients previously treated with diet orsulfonylureas.43 No patients had a history ofprimary or secondary drug failure. The twotreatments were similar in terms of the amount ofreduction in fasting and postprandial plasmaglucose levels and A1C concentrations, as well asin the time to these reductions. However,glimepiride was associated with a significantlylower incidence of hypoglycemia than glyburide(1.7% cumulative incidence of symptomatichypoglycemia in the first month of the study inthe glimepiride group, compared with 5.0% inthe glyburide group [p=0.015]). This trendcontinued over time, with a cumulative incidenceat 12 months of 12% for glimepiride and 17% forglyburide (p=0.069). Most subjects werereceiving the maximum dosage of eitherglimepiride (1–16 mg/day) or glyburide (1.25–20mg/day).

The second, larger study reported similarresults after randomizing 1044 patients to receiveglimepiride with dosage titration to 8 mg/day(524 patients) or glyburide with dosage titrationto 20 mg/day (520 patients).44 No clinicallysignificant differences in mean concentrations ofA1C or fasting blood glucose levels wereobserved between treatment groups. However,treatment with glimepiride was associated withsmaller 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 0.47ng/ml, p=0.03) than glyburide. These differenceswere small, but the authors considered thempotentially important, given the knownassociation between hyperinsulinemia andhypertension. The two treatment groups had

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similar safety profiles. Patients treated withglimepiride experienced fewer episodes ofhypoglycemia (60 patients, 105 episodes) thanthose who received glyburide (74 patients, 150episodes). At the end point, 51% of subjectsreached the maximum glimepiride dosage of 8mg/day, and 42% of subjects reached themaximum glyburide dosage of 20 mg/day.

Combination Therapy

Glimepiride has been evaluated in combinationwith both metformin and insulin. Metforminand glimepiride are coadministered to addressdefects in both insulin secretory capacity andinsulin resistance in individuals with type 2diabetes. In one study of 372 patients with type2 diabetes who had failed monotherapy withmetformin, the addition of glimepiride tometformin was associated with a mean reductionin A1C of 0.74 ± 0.08%, fasting glucose level of43 ± 4 mg/dl, and postprandial plasma glucoselevel of 46.8 ± 5 mg/dl (p<0.001).47 Nosignificant deterioration in any of theseparameters was observed in the glimepiride ormetformin monotherapy groups; however,glimepiride monotherapy was significantly moreeffective than metformin monotherapy inreducing postprandial plasma glucose levels(p=0.029). This is consistent with evidence thatglimepiride stimulates early postprandial insulinsecretion.

When combination therapy with oral agentsdoes not maintain desirable levels of A1C inpatients with type 2 diabetes, insulin frequentlyis added to, rather than substituted for, an oralhypoglycemic regimen. Glimepiride is the onlysulfonylurea that carries an indication for use incombination with insulin. In one study, 208patients with uncontrolled diabetes mellitusreceiving a sulfonylurea alone were switched toglimepiride, which was titrated to 8 mgtwice/day.48 Subjects with persistence of fastinghyperglycemia (i.e., plasma glucose level180–300 mg/dl) were randomized to receiveeither placebo or glimepiride in combinationwith insulin for 24 weeks. Insulin (70% neutralprotamine Hagedorn [NPH]-30% regular)administered at bedtime was started at a dosageof 10 U/day and titrated upward until the FPGlevel reached a target of 100–120 mg/dl. TheFPG levels and A1C values improved to a similarextent in both treatment groups (136 ± 39 mg/dland 7.7 ± 1.0%, respectively, for patientsreceiving insulin with placebo, and 138 ± 33

mg/dl and 7.6 ± 0.8%, respectively, for thosereceiving insulin with glimepiride). The declinesin FPG level and A1C were more rapid in theglimepiride group until week 12, at which timeboth treatment groups approached the targetlevel and remained there until the end of thestudy. The mean insulin dosage needed tocontrol glucose levels was significantly lowerwith glimepiride than with placebo (49 U/day vs78 U/day, p<0.001). Fourteen percent of patientstreated with placebo required insulin dosages inexcess of 100 U/day, versus only 6% of patientsreceiving glimepiride. A single daily injection ofinsulin combined with glimepiride was sufficientto restore glycemic control in patients whoseglucose levels were not controlled by glimepiridealone, and control was established more quicklyand with lower insulin doses when glimepiridetherapy was continued.

In an open-label, 9-month, single-centerclinical practice study, 27 insulin-naive patientspreviously treated with either glimepiride aloneor with the combination of glimepiride andmetformin received a daily single injection ofbasal insulin glargine.49 Addition of bedtimeinsulin resulted in improved glycemic control asmeasured by A1C concentration—from 8.8%before treatment to 7.3% after treatment (p<0.01).

Safety

Hypoglycemia and weight gain are the twomost common adverse effects of sulfonylureatherapy in patients with type 2 diabetes mellitus.These adverse effects, particularly the occurrenceof hypoglycemia, often limit the usefulness ofsulfonylureas. A large population-basedprospective study (30,768 patients) in Germanycollected data on the incidence of severehypoglycemia in patients with type 2 diabeteswho received either glimepiride or glyburide.50

Glimepiride was associated with fewer episodesof severe hypoglycemia than glyburide (6 vs 38events). The incidence of severe hypoglycemiawas 0.86/1000 person-years with glimepiride and5.6/1000 person-years with glyburide. A greatersuppression of EGP by glyburide as comparedwith glimepiride was suggested as a potentialexplanation for the higher rates of hypoglycemiaobserved with glyburide.

Glimepiride also does not appear to beassociated with significant weight gain. Ameta-analysis of four pivotal studies thatcompared glimepiride with an active control drugin 1444 patients revealed no significant weight

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change from baseline at 1 year after the start ofglimepiride therapy (p=0.81).51

In a comparative trial with glyburide,glimepiride was found to decrease serum insulinand C-peptide levels significantly duringexercise, while glyburide had no effect.52 Thisinformation may have practical applications inthat individuals with type 2 diabetes who aretreated with an insulin secretagogue fail tonormally suppress endogenous insulin duringexercise, placing them at higher risk for ahypoglycemic event. This study demonstrated amore physiologic response to exercise withglimepiride in well-controlled type 2 diabetics.Since exercise is an integral part of diabetictherapy for weight loss, glycemic control, andcardiovascular fitness, glimepiride may bepreferable to other sulfonylureas in this regard.

Nonsulfonylurea Insulin Secretagogues

Repaglinide and nateglinide, the two availablenonsulfonylurea insulin secretagogues, have amechanism of action that is similar to that of thesulfonylureas.2 These agents are also comparableto the sulfonylureas in regard to efficacy inreducing A1C and plasma glucose levels (bothfasting and postprandial).4, 18, 53, 54

The nonsulfonylurea insulin secretagogues arestructurally unrelated to sulfonylurea agents.They have short metabolic half-lives and havehigh affinity, with rapid association-dissociationkinetic activity at the KATP b cell, resulting inrelatively brief modulations of insulin secretion.19

Consequently, these agents augment early insulinsecretion in response to glucose or a meal andreduce postprandial glucose peaks.55, 56 They arerapidly absorbed, with mean time to peakconcentration between 0.5–2 hours afteradministration. Their short duration of actiontherefore does not affect FPG level, which alsoreduces the risk of hypoglycemia betweenmeals.57 These compounds are metabolizedprimarily in the liver and excreted through therenal system, with an average elimination half-life of 1.5 hours.2 Metabolism in the liver occursprimary by the cytochrome P450 3A4 and 2C9pathways. Therefore, this class of drugs poses arisk for potential drug interactions with anyinducers or inhibitors of those pathways.4, 6

Repaglinide

The hypoglycemic effect of repaglinide, abenzoic acid derivative, begins within 45 minutesand lasts for 4–6 hours. Insulin concentrations

peak at 1–2 hours and return to fasting levels by6 hours.2

In a placebo-controlled study of 99 subjectswith type 2 diabetes mellitus, 4 months ofrepaglinide therapy was associated with absolutereductions in A1C of 1.7% (p<0.0001), FPG levelof 3.4 mmol/l (61.2 mg/dl), and postprandialplasma glucose level of 8 mmol/l (104.4 mg/dl)(p<0.05) compared with placebo.54 Repaglinidewas started at a dosage of 0.25 mg given 3times/day before meals and titrated to a maximaldosage of 8 mg 3 times/day according to resultsof FPG readings. At the end of the study, 37% ofparticipants were taking repaglinide 4 mg 3times/day and 14% were taking 8 mg 3 times/day.

Another trial compared repaglinide withglyburide.57 Repaglinide was associated with amean A1C reduction of 1.3% in treatment-naïvepatients and a mean A1C reduction of 0.08% forthe entire cohort. Patients receiving glyburideexhibited a mean A1C reduction of 0.10%.Levels of FPG were comparable between the twotreatment groups. In this study, 55% of thoserandomized to repaglinide and 56% of thoserandomized to glyburide received maximal doses.

Nateglinide

Nateglinide, a D-phenylalanine derivative,stimulates early insulin secretion and reducesblood glucose levels within 30–90 minutes, witha low frequency of hypoglycemia.2, 6, 58 In onestudy, nateglinide produced rapid, transient,dose-related increases in circulating insulinconcentrations (13–29 µU/ml) and reductions inpostprandial plasma glucose levels (14–28 mg/dl)during the first 4 hours after doses of 30–120 mggiven preprandially.55

Combination Therapy with Other Agents

Nateglinide has been evaluated in combinationwith metformin. In a 24-week study, 701patients inadequately controlled with diet alonewere randomized to nateglinide monotherapy(120 mg before meals), metformin monotherapy(500 mg 3 times/day), combination therapy, orplacebo.56 At the end of the study, A1C and FPGlevels were reduced in all three active-treatmentarms. The effects of combination therapy wereadditive, with significantly greater changes inA1C (-1.4%, p≤0.01) and FPG levels (-43.2mg/dl, p≤0.01) in the combination therapy groupthan in either monotherapy group. After an oralglucose challenge, nateglinide produced a greaterreduction in glucose levels than either metformin

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or placebo (p≤0.0001), and the response tocombination therapy did not differ significantlyfrom that observed with nateglinide monotherapy.Thus, the decrease in A1C reflected the additiveeffects of nateglinide and metformin, althoughimprovements in postprandial glucose level werea direct result of the improvement in early insulinsecretion with nateglinide.

Summary

Although no trials have compared efficacy orinsulin secretory patterns between the short-acting insulin secretagogues and glimepiride,compliance with drugs requiring multiple dailydosing is often lower than that with single dailydosing.59 Both nateglinide and repaglinide have amore rapid time of onset of inhibition of KATPthan the sulfonylureas. Nateglinide also differsfrom the sulfonylureas in that it has a more rapidreversal of inhibition.19

Insulin Secretagogues: First-Line Agents inManaging Type 2 Diabetes Mellitus

Although insulin resistance is present in mostindividuals with type 2 diabetes, it is theimpairment in insulin secretion by b cells thatleads to development of hyperglycemia. For thisreason, impaired insulin secretion can be viewedas the primary metabolic abnormality in lean aswell as obese patients with type 2 diabetes,providing a rationale for early use of an insulinsecretagogue in the pharmacologic managementof this disorder.20, 26

Guidelines for glycemic control to prevent ordelay progression of diabetic complications arebased on data from randomized trials, includingthe Diabetes Control and Complications Trial forpeople with type 1 diabetes mellitus and theUKPDS for people with type 2 diabetes.39, 60, 61

Neither of these trials identified a threshold forA1C at which the risk of diabetes complicationswas halted. Nevertheless, the trials confirmedthat reductions in A1C are associated with fewerlong-term microvascular complications, with arelative risk reduction of 15–30% for each 1%decrease in A1C concentration. An epidemiologicanalysis of UKPDS data demonstrated a 14%reduction in all-cause mortality and myocardialinfarction with each 1% reduction in A1C.61

The contribution of the postprandial glucoselevel to cardiovascular risk independent ofelevated FPG level has been reported inepidemiologic studies.14, 62 The AmericanDiabetes Association (ADA) established

treatment goals for individuals with diabetes assummarized in Table 3.63, 64 These goals wererevised in 2003 to include targets forpostprandial as well as fasting glucose level.63

The current ADA target for a 2-hour postprandialglucose level is less than 180 mg/dl.

Medical nutrition therapy, increased exercise,and patient education remain the centralelements for management of type 2 diabetes.63, 64

Weight reduction is the primary goal of medicalnutrition therapy in obese patients with mildhyperglycemia. If treatment goals are not metafter a trial of diet and exercise alone,pharmacotherapy should be added to thetreatment regimen. Several classes of oral agentsare available for reducing hyperglycemia inpatients with type 2 diabetes. These includeinsulin secretagogues (sulfonylureas, repaglinide,and nateglinide), insulin sensitizers (thebiguanide metformin and the thiazolidinediones),and a-glucosidase inhibitors.4

A suggested algorithm illustrating glycemiccontrol therapy for adult patients with type 2diabetes is presented in Figure 4.65 Evaluation ofindividual patient characteristics will aidselection of the best oral agent for initialmonotherapy as well as for later combinationtherapy. Patients with marked symptomatichyperglycemia, defined as a fasting glucose levelabove 300 mg/dl with evidence of ketonuria orketonemia, may be candidates for earlyintroduction of insulin treatment to reduceglucotoxicity before the start of oral therapy.66, 67

Careful consideration of patient clinicalcharacteristics and the availability of diabetesself-management education (including dietarycontrol and exercise prescriptions) duringsulfonylurea treatment can lead to the successfulmanagement of type 2 diabetes in as many as75–80% of patients.8 Based on findings of theUKPDS, a sulfonylurea is recommended as initial

615

Table 3. Glycemic Treatment Goals for Individuals withDiabetes Mellitus

ADA Goals AACE GoalsPreprandial plasma 90–130 ≤ 110glucose level (mg/dl)

Peak postprandial plasma < 180 ≤ 140glucose level (mg/dl)

A1C (%) < 7a ≤ 6.5ADA = American Diabetes Association; AACE = AmericanAssociation of Clinical Endocrinologists; A1C = glycosylatedhemoglobin.aReferenced to a nondiabetic range of 4.0–6.0% using an assaybased on the Diabetes Control and Complications Trial.60

Adapted from reference 63 and 64.

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pharmacologic therapy for nonobese individualswith newly diagnosed or untreated type 2diabetes, while metformin is recommended asinitial therapy for obese individuals who have nocontraindications to its use.4, 67 The short-actingnonsulfonylurea secretagogues may be preferredin individuals whose meal schedules are irregularor who experience hypoglycemia with long-acting agents.4 While the a-glucosidaseinhibitors and thiazolidinediones may beacceptable choices for first-line therapy inindividuals with type 2 diabetes, no outcomestudies support their use over the insulinsecretagogues or metformin, as demonstrated inthe UKPDS.

Most patients with type 2 diabetes mellitus areobese. Obese individuals may benefit from initialtherapy with metformin as observed in theUKPDS.68 However, the progressive decline in b-cell function documented in people with type 2

diabetes implies the need for add-on therapy witha drug such as a sulfonylurea to maintain desiredlevels of glycemic control over time.68 An evaluationin 28 normal-weight and morbidly obese patientswith type 2 diabetes demonstrated a similarpharmacokinetic profile for glimepiride in bothpatient groups.69 The maximum concentrationwas significantly lower in obese individuals, butother pharmacokinetic parameters (e.g., time ofmaximum concentration, area under theconcentration-time curve, clearance, half-life)were similar.

Combination Therapy

Dosing recommendations for the availablesulfonylurea and nonsulfonylurea insulinsecretagogues are summarized in Table 1. TheUKPDS showed that by 9 years, 24% of patientsrandomized 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 monotherapyor 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 adequateFPG < 130 mg/dl, SMBG < 120 mg/dl,

A1C < 7.0%

Continue therapy,check A1C every 3–6 months

Therapy inadequate after 3 monthsFPG ≥ 130 mg/dl, SMBGb ≥ 120 mg/dl,

A1Cb ≥ 7.0%

Combinesulfonylurea with metformin

Combination therapy adequateFPG < 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 monthsFPG ≥ 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 beindividualized. 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 = neutralprotamine Hagedorn. aIf a symptomatic patient has an initial FPG level of 300 mg/dl or above, consider insulin or insulinanalog 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 monthsif glycemic goals are not met. (Adapted from reference 65 with permission.)

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those randomized to metformin alone were ableto maintain glycemic control, with an A1C lessthan 7.0%.68 These data emphasize the need toaddress both defects in insulin secretion andsensitivity in individuals with type 2 diabetes. Inaddition, these findings refute the concern thatearly use of sulfonylureas contributes to b-cellexhaustion and failure in individuals with type 2diabetes. In fact, b-cell function was improvedby early sulfonylurea use, with a rate of declinethat did not differ from metformin.

In nonobese patients, sulfonylureas aregenerally successful in reducing glucose levels totarget. After FPG levels no longer can bemaintained below 120 mg/dl with near-maximaldoses of a sulfonylurea, addition of an insulin-sensitizing agent (metformin or a thiazolidine-dione) often will succeed in reestablishingcontrol.67

If glycemic control is not achieved with the useof two oral agents, a third class of oral agents canbe added. This third agent may be either aninsulin sensitizer or an a-glucosidase inhibitor.There is limited information on the success ofthis practice.70–74 In one study, 42% of patientsgiven triple therapy reached an A1C of 7% (vs14% of patients receiving dual therapy), and thenumber of patients reaching a final A1C of 6.5%was four times higher in the triple-therapy groupthan in the dual-therapy group (18% vs 4%).72

However, the triple-therapy group had a higherrisk of hypoglycemia (22.1% vs 3.3%). Thesuccess seen in lowering A1C levels wasconsidered to outweigh the risk of hypoglycemia.

In patients with prolonged, severehyperglycemia, glucose toxicity worsens insulinresistance and b-cell responsiveness. Insulintherapy can lower glucose levels, reduce insulinresistance, and improve b-cell function, therebyimproving the response to therapy with oralagents.15, 66 Patients who continue to receive oralagents can be given a single daily dose of anintermediate-acting insulin such as NPH or lente,or they may take a long-acting preparation suchas insulin glargine or ultralente. Another optionis to substitute a basal and bolus insulincomponent for oral agents (Figure 4).65

A recent placebo-controlled study evaluatedthe dosage of insulin required to control bloodglucose levels in patients who receivedmetformin 2550 mg/day and/or glimepiride 8mg/day and had A1C values above 8%.75 Insulin(70-30) was started at 10 U (before supper) andtitrated by 5 U/week until the FPG level declinedbelow 8 mmol/L (144 mg/dl). Achieved A1C

concentrations were less than 7% in all treatmentgroups. The total daily insulin requirement waslower in all three active-treatment arms than inthe placebo group (metformin, 50 U; glimepiride40 U; combination, 23 U; placebo, 82 U). Theinsulin-sparing effect was greater in patientsreceiving glimepiride monotherapy (p<0.05) andin those receiving combination therapy(p<0.001) than in those assigned to metforminmonotherapy. Thus, glimepiride may have moreinsulin-sparing activity than metformin, and itappears to have a synergistic effect withmetformin in lowering insulin requirementswhen used in combination.

Specific Clinical Scenarios

Glyburide, glipizide, and gliclazide should beused cautiously in patients with renal or hepaticdisease because reduced excretion of either theparent molecule or its metabolites can lead tohypoglycemia. Glimepiride, however, has shownfavorable pharmacokinetic data related toelimination half-life and drug clearance and agood safety profile in patients with both diabetesand renal impairment76 and in patients with liverdisease.41 A study of glimepiride pharmacokineticsin 31 patients categorized by creatinine clearance(> 50 ml/min, 20–50 ml/min, and < 20 ml/min)demonstrated that mean relative total clearanceand mean volume of distribution increased inproportion to the degree of renal impairment.Thus, glimepiride is effectively cleared in patientswith renal disease. The active M1 metabolite ofglimepiride, which had an increased maximumconcentration and elimination half-life inpatients with lower creatinine clearance, mayhave contributed to the pharmacologic activity ofthis drug; therefore, drug dosage does not need tobe increased. Terminal half-life and mean time ofconcentration did not change with renalimpairment, which may be related to anincreased displacement of glimepiride fromplasma proteins in individuals with renal disease.This effect has no apparent impact on efficacy. In12 of 16 patients with impaired renal functionwho received glimepiride over 3 months, dosagesof 1–4 mg/day stabilized glucose levels with nodrug-related adverse events.76 The remainingfour patients required higher dosages ofglimepiride to maintain glycemic control (up to 8mg/day).

Limited data are available on the pharmaco-kinetics of glimepiride in patients with type 2diabetes who have liver disease. This was

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addressed in a study in which 11 patients withliver disease (periportal fibrosis, mononuclearinfiltration with connective tissue, fat meta-morphosis with bridging necrosis, or connectivetissue infiltration) received a single 1-mg dose ofglimepiride.41 The resulting pharmacokineticprofile of glimepiride was similar with regard tomaximum concentration, time of maximumconcentration, and area under the concentration-time curve to that seen in 24 healthyvolunteers.76

Although advanced age is not a contraindicationto the use of insulin secretagogues, therapy inelderly patients should be started at a low doseand titrated slowly to avoid severe hypoglycemia,which can have devastating consequences in thepresence of other comorbid conditions. The useof agents such as glipizide, glimepiride, or theshort-acting insulin secretagogues, which are lesslikely than other drugs to cause severehypoglycemia, is recommended.

Conclusion

Glimepiride is a second-generation sulfonylureathat exerts its hypoglycemic effect by stimulatingbasal, first, and second phases of insulin releaseand 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 ofhypoglycemia in comparison with glyburide,together with its demonstrated selectivity forpancreatic KATP channels and lack of affinity forcardiac receptors may make glimepiride anacceptable first choice as an oral agent fortreatment of type 2 diabetes.

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