REVIEW ARTICLE

Clin Pharmacokinet 2004; 43 (2): 97-120 0312-5963/04/0002-0097/$31.00/0 © 2004 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics of Nateglinide A Rapidly-Absorbed, Short-Acting Insulinotropic Agent James F. McLeod Novartis Pharmaceuticals, East Hanover, New Jersey, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 1. Pharmacology of Nateglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 2. Clinical Pharmacokinetics of Nateglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 2.1 Absorption, Distribution, Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 2.2 Dose-Pharmacokinetic Relationship and Multiple-Dose Pharmacokinetics . . . . . . . . . . . . . . . . . 101 2.3 Drug-Food Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2.4 Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.5 Drug-Demographic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.6 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.6.1 Renally Impaired . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.6.2 Hepatically Impaired . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3. Clinical Pharmacodynamics of Nateglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.1 Effects on Plasma Glucose, Insulin and Glycated Haemoglobin . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.2 Synergy of Nateglinide and Meal Ingestion on Insulin Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 3.3 Stimulation of Early Phase of Insulin Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 3.4 Glucose Dependence of Insulinotropic Effect of Nateglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 3.5 Inhibition of Hepatic Glucose Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 3.6 Nateglinide in Combination with Other Antidiabetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3.6.1 Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3.6.2 Troglitazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.6.3 Glibenclamide (Glyburide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.7 Pharmacodynamic Effects in Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4. Comparison of Nateglinide with Other Antidiabetic Agents: Pharmacokinetics and Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.1 Repaglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.2 Glibenclamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 5. Pharmacokinetic-Pharmacodynamic Relationships of Nateglinide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 5.1 Plasma Nateglinide Concentrations and Plasma Insulin, Glucose and Glycated Haemoglobin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 5.2 Pharmacokinetic-Pharmacodynamic Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 5.3 Pharmacokinetics and the Incidence of Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 6. Therapeutic Use of Nateglinide in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

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Abstract

McLeod

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic β-cells, facilitating insulin secretion. Nateglinide sensitises β-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0–30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60–240mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic β-cell function.

The prevalence of type 2 diabetes mellitus is increasing dramatically, with an estimated prevalence of 2–5% of adults in Western societies in 1997.[1] The worldwide prevalence of diabetes is predicted to increase from 124 million cases in 1997 to over 221 million by the year 2010, 97% of these being type 2 diabetes.[1] Studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of type 2 diabetes as they move to urban or non-traditional situations, often with 5- to 10-fold increases in the prevalence of the disease.[2] In the US, the prevalence of diabetes (type 1 or 2) rose from 4.9% in 1990 to 6.5% in © 2004 Adis Data Information BV. All rights reserved.

1998, representing an increase of 33%, which was observed in both sexes, all ages, all ethnic groups, all education levels and nearly all parts of the country.[3] In the year 2000, a further increase in diabetes incidence to 7.3% has been reported.[4] Insulin resistance, impaired insulin secretion and increased hepatic glucose output are believed to be the major pathogenetic factors in type 2 diabetes,[5-8] but the disease often does not produce symptoms for years.[9,10] The UK Prospective Diabetes Study observed that over 50% of type 2 diabetes patients already have diabetes-related tissue damage (i.e. retinopathy, proteinuria, neuropathy) upon diagClin Pharmacokinet 2004; 43 (2)

Nateglinide

nosis.[11,12] Secondary sequelae, including coronary artery disease, stroke and peripheral vascular disease, account for 75% of the diabetes-associated direct medical expenditures in the US,[13] which were estimated at $US44.1 billion in 1997. An additional $US54.1 billion in indirect costs from death and disability brought the total US diabetes-related costs to $US98.2 billion in 1997. Since 90% of patients with diabetes have type 2 diabetes,[9] these figures underscore the obvious need for earlier diagnosis and more effective approaches to its treatment. The importance of tight control of postprandial hyperglycaemia in type 2 diabetes has become increasingly recognised.[14] The Diabetes Intervention Study showed that adequate control of postprandial serum glucose, blood pressure and triglycerides was associated with a decreased incidence of coronary artery disease and mortality.[15] The UK Prospective Diabetes Study confirmed that intensive control of fasting plasma glucose and glycated haemoglobin (HbA1c) using sulfonylureas or insulin for more than 10 years decreased the risk of microvascular complications but not of macrovascular complications or diabetes-related mortality.[11] Furthermore, recent studies have shown that 2-hour post-challenge hyperglycaemia is associated with increased total mortality,[16-18] cardiovascular disease mortality[18,19] and coronary heart disease mortality.[17,20] Antidiabetic agents that reduce postprandial hyperglycaemia may therefore be of benefit in reducing type 2 diabetes-related mortality. In recent years, new non-sulfonylurea β-cellactivating insulinotropic agents have become available for the treatment of type 2 diabetes.[21] These new agents, including the phenylalanine derivative nateglinide, have a more rapid onset and a shorter duration of hypoglycaemic action than the sulfonylureas. Following preprandial administration, these drugs make insulin more readily available during and just after a meal, reducing postprandial hyperglycaemia.[21] The purpose of this article is to provide a comprehensive review of the clinical pharmacokinetics of nateglinide in order to facilitate © 2004 Adis Data Information BV. All rights reserved.

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its appropriate clinical use in the treatment of type 2 diabetes. 1. Pharmacology of Nateglinide The meglitinide family of insulinotropic agents has been named more for their functional than their structural relationship. Although they all have a similar mechanism of action and interact with the same receptor, none are chemically related to the sulfonylureas, and each has been derived from a distinct chemical entity (figure 1).[5,22] Meglitinide is the non-sulfonylurea portion of the glibenclamide (glyburide) molecule, whereas nateglinide was derived from the amino acid D-phenylalanine, with structural name (–)-N-[(trans-4-isopropylcyclohexane) carbonyl]-D-phenylalanine. Repaglinide was derived from meglitinide and mitiglinide from succinate.[21,22] Nateglinide is believed to enhance insulin secretion by reducing K+ efflux via ATP-dependent K+ channels in pancreatic β-cells, hence depolarising the cells and opening voltage-sensitive Ca2+ channels. The resultant increase in cytoplasmic Ca2+ triggers insulin release.[5,21,23] Differences exist in the pharmacodynamic actions of insulinotropic agents and will be discussed subsequently in section 4. 2. Clinical Pharmacokinetics of Nateglinide 2.1 Absorption, Distribution, Metabolism and Excretion

Pharmacokinetic parameters for single oral and intravenous doses of nateglinide given to healthy subjects are provided in table I.[24] A single 120mg oral dose of [14C] nateglinide was rapidly (half-time of absorption 0.22 hours) and nearly completely (approximately 90%) absorbed, with an absolute bioavailability of 73%, indicating only a modest first-pass effect. Maximum plasma concentrations appeared within approximately 1 hour. The steadyClin Pharmacokinet 2004; 43 (2)

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McLeod

a

CI O

O

C

NH

CH2 CH2

NH

CH2

O

O S

NH

C

NH

OCH3 b

CI O C

CO2H

CH2

OCH2 c

O

CH3 CH

NH

C

CH3

CH

CH2

CO2H O

d CH3

CH

CH3

CH2

CH

NH

C

CH2

N

CO2H

O CH2 CH3

e

H N

C O

H

CH2

CH

CH2

CO2H

Fig. 1. Chemical structures of (a) a sulfonylurea, glibenclamide (glyburide); (b) the non-sulfonylurea moiety of glibenclamide, meglitinide; (c) a D-phenylalanine derivative, nateglinide; (d) a meglitinide analogue, repaglinide; (e) a meglitinide analogue, mitiglinide.[5]

state volume of distribution of nateglinide was estimated in plasma to be 10.5L after intravenous administration, suggesting only limited distribution beyond the plasma volume (which averages 3L in the normal adult). Unchanged nateglinide was the major circulating component in plasma. Nateglinide binds extensively (98%) to serum proteins, primarily albumin. The extent of serum protein binding is independent of drug concentration over the test range of 0.1–10 mg/L.[25] Peak nateglinide concentrations (Cmax) reported in plasma are approximately 3–20 μmol/L (as previously published[24,26-29] and from unpublished data). © 2004 Adis Data Information BV. All rights reserved.

One major monohydroxylated metabolite and at least eight other metabolites have been identified in plasma and urine,[24] only one of the latter (M1) having significant pharmacological activity (approximately as active as nateglinide).[35] Overall exposure to this active metabolite was less than 5% of that to nateglinide, so essentially all of the pharmacological activity is attributed to the parent compound. Nateglinide was rapidly eliminated from plasma after either intravenous or oral administration (elimination half-life of 1.5–1.7 hours). Plasma clearance was 7.4 L/h. Of the administered radioactivity, 84–87% (oral and intravenous doses) was excreted in the urine and another 8–10% in the Clin Pharmacokinet 2004; 43 (2)

Nateglinide

101

faeces by 120 hours postdose. Only 16% of the radioactivity recovered in the urine was unchanged drug, suggesting that metabolism plays a more important role in nateglinide clearance from plasma than renal elimination. In vitro experiments with human liver microsomes and cytochrome P450 (CYP) isozymes point primarily to CYP2C9 (70%) and less so to CYP3A4 (30%) as the main catalysts of oxidative metabolism of nateglinide.[24,25]

type 2 diabetes. Also, no apparent differences were noted in the pharmacokinetics of nateglinide following morning and evening doses at steady state. The pharmacokinetic profiles in healthy subjects and in patients with type 2 diabetes are very similar overall, with Cmax generally occurring within 1 hour and decaying with an average elimination half-life of 1.5 hours.[25] 2.3 Drug-Food Interaction

2.2 Dose-Pharmacokinetic Relationship and Multiple-Dose Pharmacokinetics

When intravenous doses ranging from 15 to 120mg are administered to healthy subjects[36] or oral doses ranging from 30 to 240mg administered to either healthy subjects[29] or to patients with type 2 diabetes (as previously published[25,26,37] and from unpublished data), Cmax (1.2–18 mg/L for oral doses and 2.0–16.2 mg/L for intravenous doses) and drug exposure (area under the concentration-time curve to 4 hours [AUC0–4] 2.1–28.7 mg • h/L for oral doses and AUC to infinity [AUC∞] 2.0–17.7 mg • h/L for intravenous doses) are dose-proportional, whereas the time to Cmax (tmax) of 0.5–1.9 hours for oral doses is independent of dose. As expected from the short elimination half-life of nateglinide, no accumulation has been noted with multiple oral doses of up to 240mg (twice the recommended therapeutic dose) three times daily for up to 7 days (as previously published[25] and from unpublished data) or with administration of 60mg three times daily for 3 months[38] in patients with

When nateglinide was given to healthy subjects 10 minutes before ingestion of a high-fat meal, the rate of absorption was increased relative to when it was given during a continued fast, as evidenced by a 12% increase in Cmax and a 52% decrease in tmax.[29] When the drug was given just after ingestion of a meal, a 34% decrease in Cmax and a 22% increase in tmax were observed relative to fasting conditions. Total absorption (AUC) was similar under all three sets of conditions. Another study testing the effects of administration of nateglinide to healthy subjects at different times (–10, –1 and +10 minutes) relative to the start of a meal showed that nateglinide Cmax was significantly higher and tmax was significantly shorter when the drug was given 10 minutes prior to meal ingestion (3.3 mg/L at 0.7 hours) as compared with 10 minutes after the meal was started (2.5 mg/L at 1.9 hours).[28] Administration of nateglinide at 1 minute prior to meal ingestion gave an intermediate response (2.8 mg/L at 1.4 hours). Total drug exposure, however, was not affected by the timing of the dose relative to the meal, and meal composi-

Table I. Pharmacokinetics of nateglinide and other oral insulinotropic agents[23-25,30-34] Parameter and unit

Nateglinide

Repaglinide

Glibenclamide (glyburide)

Time to peak concentration (h)

≤1

≤1

2–4

Bioavailability (%)

73

56

100a

Volume of distribution (L)

10

31

9–40

Plasma clearance (L/h)

7.4

38

4

Elimination half-life (h)

1.5

1

1.5–10

Protein binding (%)

98

>98

99

Fraction excreted unchanged in urine (%)

16

8

0

Food effect

Yes

Yes

No

a

For micronised formulation.

© 2004 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2004; 43 (2)

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tion (i.e. relative percentage of carbohydrate, fat and protein) had no effect on any pharmacokinetic parameters. Studies assessing the effect of pre-meal dose timing on nateglinide pharmacokinetics have been conducted in patients with type 2 diabetes mellitus. Whether nateglinide was administered 30 minutes pre-meal[39] to up to 1 minute pre-meal,[27] its pharmacokinetic parameters were similar. When it was given after starting a meal, however, its absorption was somewhat delayed (by approximately 15%) and its Cmax reduced (by approximately 25%). It was concluded from these observations that the precise timing of a nateglinide dose is not crucial, so long as it is taken prior to a meal, and the prescribing information in the US indicates that patients should be instructed to take the drug 1–30 minutes before ingesting a meal.[25] It is of interest to note that if nateglinide is administered 10 minutes prior to a liquid meal as compared with a solid meal, Cmax is significantly reduced.[25] Additionally, nateglinide does not affect gastric emptying in healthy subjects as assessed by paracetamol (acetaminophen) testing.[25] 2.4 Drug-Drug Interactions

In vitro evaluation of nateglinide metabolism and its capacity to inhibit the metabolism of cytochrome-specific substrates identified those cytochromes likely to be involved in nateglinide metabolism (CYP2C9 and CYP3A4) and potential drugdrug interactions. CYP2C9 is the major CYP isoform responsible for nateglinide metabolism, and possible interactions with substrates of CYP2C9 might be anticipated for nateglinide. In vitro, nateglinide has been found to inhibit the metabolism of tolbutamide (a CYP2C9 substrate), but no inhibition of CYP3A4 metabolic reactions has been detected.[25] The 50% inhibitory concentration (IC50) for nateglinide inhibition of metabolism by isolated human CYP enzymes for specific CYP2C9 substrates ranges from 25 to 50 μmol/L,[39] which approaches the Cmax reported in plasma (approxi© 2004 Adis Data Information BV. All rights reserved.

mately 3–20 μmol/L) [as previously published[24,26-29] and from unpublished data]. Nevertheless, drug-drug interaction studies in healthy subjects have shown no interaction between nateglinide and a single 75mg dose of diclofenac[25,40,41] (a substrate for CYP2C9[42]) or a single 30mg dose of warfarin[43] (a substrate for CYP3A4 and CYP2C9[44]) when nateglinide was administered at 120mg before meals (after two meals in the diclofenac study and after each meal for 2 days in the warfarin study).[25] Based on these substrates, the potential for nateglinide to inhibit the metabolism of other drugs is small. Similarly, the potential for other drugs to increase nateglinide concentrations is limited, although clinical studies with a CYP2C9 inhibitor would be required to fully explore the primary metabolic pathway of nateglinide. Other drugs of interest for possible interaction with nateglinide include those that are likely to be prescribed in patients with type 2 diabetes. As older patients with diabetes are at increased risk for developing congestive heart failure, and digoxin is the most commonly prescribed cardiac glycoside in congestive heart failure, a possible interaction with digoxin has been studied.[45] No drug interaction was reported, however, between nateglinide and a single 1mg dose of digoxin in a study in which nateglinide 120mg was given three times daily before meals to healthy subjects for 2 days and digoxin 1mg was given on the first day.[45] As oral hypoglycaemic drugs are often used in combination in diabetes treatment, nateglinide has been studied for possible interactions with several of these agents. When nateglinide 120mg was administered three times daily before meals for 1 day in combination with metformin 500mg three times daily (which was given for 3 weeks before the day of combination treatment) in patients with type 2 diabetes, there were no significant alterations in the pharmacokinetics of either agent[46] (their pharmacodynamic interactions are discussed in section 3.6). Similar results were obtained when nateglinide 120mg before meals for 1 day was administered in Clin Pharmacokinet 2004; 43 (2)

Nateglinide

combination with glibenclamide 10mg once daily for 3 weeks[25] or troglitazone (a CYP3A4 inducer) 600mg once daily for 3 weeks.[47] As nateglinide is highly bound to plasma proteins, this may be a potential site of drug-drug interactions. In vitro displacement studies have shown no influence of highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, glibenclamide, metformin, phenytoin, warfarin, aspirin, tolbutamide and pravastatin on serum protein binding of nateglinide. Conversely, no influence by nateglinide has been detected on protein binding of propranolol, nicardipine, glibenclamide, phenytoin, warfarin, aspirin and tolbutamide.[25]

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ences in nateglinide pharmacokinetics when diabetic patients in the renally impaired group were compared with matched healthy subjects (tmax 0.8 vs 0.7 hours; Cmax 7.4 vs 10.0 mg/L; AUCt 18.3 vs 17.5 mg • h/L; elimination half-life 2.8 vs 1.9 hours; renally impaired vs healthy subjects, respectively). Renal clearance of unchanged nateglinide was 3% in the renally impaired subjects versus 11% in the matched healthy subjects. There was no correlation between creatinine clearance and systemic nateglinide exposure (r2 = 0.01).[25] No special recommendations for dosage adjustment have been made in the US prescribing information for patients with type 2 diabetes with renal impairment. Further clinical data from this patient population are needed to confirm these early observations.

2.5 Drug-Demographic Interactions 2.6.2 Hepatically Impaired

Results of population pharmacokinetic analyses in the pooled healthy subjects and in the pooled patients with type 2 diabetes studied in clinical trials indicate that there are no significant effects of age, sex or race (including Caucasian, Black and other ethnic origins) on the pharmacokinetics of nateglinide. No dosage adjustments are considered necessary based on age, sex or race.[25] 2.6 Special Populations 2.6.1 Renally Impaired

Nateglinide pharmacokinetic parameters have been studied in patients with type 2 diabetes and impaired renal function. In a study in which eight inpatients with type 2 diabetes and renal impairment (creatinine clearance of 41.8 ± 16.2 mL/min) were given nateglinide 90mg three times daily before meals for 6 days,[48] nateglinide exposure, as indicated by AUC of plasma nateglinide, bore no relationship (r = 0.08) to creatinine clearance. No accumulation of nateglinide was noted. In a study of patients with type 1 or type 2 diabetes with impaired renal function (creatinine clearance 15–50 mL/min/ 1.73m2; n = 10) or with renal failure undergoing dialysis (n = 10),[49] there were no significant differ© 2004 Adis Data Information BV. All rights reserved.

Nateglinide Cmax and total exposure after a single dose of 120mg was given to non-diabetic subjects with cirrhosis were significantly increased by 38% and 30%, respectively, as compared with matched healthy subjects.[50] Although no dosage adjustment is advised in patients with mild hepatic insufficiency, caution is advised when nateglinide is administered in patients with moderate to severe chronic liver disease, as these patients have not yet been studied.[25] 3. Clinical Pharmacodynamics of Nateglinide

3.1 Effects on Plasma Glucose, Insulin and Glycated Haemoglobin

Single and multiple dose studies have been conducted in healthy volunteers and in patients with type 2 diabetes to characterise the insulinotropic action of nateglinide and to determine its effects on mealtime glucose control. Nateglinide treatment has been found to be effective in decreasing fasting plasma glucose[25,37,51,52] and HbA1c[25,51,53,54] in patients with type 2 diabetes. Clin Pharmacokinet 2004; 43 (2)

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The most prominent pharmacodynamic effects of nateglinide are on postprandial glucose regulation. Nateglinide has been consistently found in clinical studies to increase insulin secretion associated with a meal or oral glucose challenge and, therefore, to decrease related glucose excursions in patients with type 2 diabetes.[26,27,37,51,52,55-58] Peak insulin levels generally occur at 0.5–2 hours postdose and return to near placebo levels by approximately 3–4 hours postdose.[26,27,37,51,57,58] Figure 2 shows plasma insulin (a) and glucose (b) concentrations measured over a 24-hour period after 7 days of treatment with either nateglinide 30–120mg or placebo taken 10 minutes prior to meals (three times daily, or four times daily to include a fourth 120mg dose after an evening snack) in ten patients with type 2 diabetes.[56] All treatments significantly (p < 0.05) increased the average plasma insulin over placebo during the 0–4 hour, 0–11 hour and 0–24 hour intervals. The 120mg three times daily (average plasma insulin 79.1 ± 12.0, 72.1 ± 11.2 and 48.8 ± 7.7 mU/L at the respective times) and 120mg four times daily (73.5 ± 12.5, 70.2 ± 11.0 and 49.4 ± 7.6 mU/L at the respective times) dosages were significantly (p < 0.05) more effective than the 30mg (62.9 ± 12.1, 58.9 ± 11.3 and 41.5 ± 7.9 mU/L at the respective times) and 60mg (63.1 ± 9.8, 61.7 ± 10.6 and 43.3 ± 7.7 mU/L at the respective times) dosage regimens, but not significantly different from each other. Average plasma glucose decreased significantly (p < 0.05) relative to placebo during all intervals at all doses (except 30mg during 0–4 hours), but the effect achieved with 60mg (average plasma glucose of 224 ± 18.2, 204 ± 16.9 and 193 ± 14.7 mg/dL at 0–4, 0–11 and 0–24 hours, respectively) did not change significantly at the 120mg three times daily (231 ± 17.7, 207 ± 16.8 and 194 ± 15.2 mg/dL at the respective times) or the 120mg four times daily (238 ± 21.2, 207 ± 18.5 and 185 ± 16.7 mg/dL at the respective times) dosages. In two additional shortterm dose-ranging studies in patients with type 2 diabetes, doses of nateglinide from 30mg to 240mg © 2004 Adis Data Information BV. All rights reserved.

McLeod

three times daily before meals produced proportional increases in postprandial insulin levels, but these translated into proportional decreases in post-meal glucose excursions only up to the 120mg dose.[47] In a study in which the pharmacodynamics and pharmacokinetics of increasing intravenous doses (15–120mg) of nateglinide were studied in healthy volunteers, exposure to plasma insulin (6–28 mU • h/L) and decreases in plasma glucose exposure (by 27–74 mg • h/dL) were dose-related, as was plasma nateglinide Cmax (2–16 mg/L).[36] Early nateglinide plasma concentrations and exposure correlated significantly (r = 0.39–0.51; p < 0.01–0.05) with early plasma insulin concentrations. Nateglinide concentration at 10 minutes after an oral dose of 120mg was strongly correlated with (r = 0.97–0.99), and was the best predictor of, the plasma insulin concentrations from 10 to 30 minutes postdose. Insulin levels returned to baseline by 90 minutes postdose, and glucose levels essentially did so by 3.5 hours. The results of this study indicate a rapid onset and short duration of action of nateglinide and suggest that these should minimise insulin exposure and the potential for hypoglycaemia. The relationships between plasma nateglinide concentrations and plasma insulin and glucose will be discussed more thoroughly in section 5. 3.2 Synergy of Nateglinide and Meal Ingestion on Insulin Secretion

In light of the effect of food on the pharmacokinetics of nateglinide, meal ingestion and its timing might also be expected to affect the pharmacodynamics of nateglinide. In healthy subjects, the maximum secretion of plasma insulin in response to nateglinide 60mg was markedly enhanced when the drug was taken either 10 minutes prior to meal ingestion (by approximately 80 mU/L over basal) or immediately after meal ingestion (by approximately 60 mU/L over basal), as compared with during a continuous fast (by approximately 15 mU/L over basal).[29] Fasting plasma glucose decreased in response to the 60mg dose, and a meal-related increase Clin Pharmacokinet 2004; 43 (2)

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Placebo 30mg three times daily 60mg three times daily 120mg three times daily 120mg four times daily

a 140

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Plasma insulin (mU/L)

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80

60

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20 Breakfast

Lunch

Dinner

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265

235

205

175

145

115 8

12

16

20

24

Time after morning dose (h)

Fig. 2. Mean plasma insulin concentrations (a) and mean plasma glucose concentrations (b) in patients with type 2 diabetes after administration of nateglinide or placebo 10 minutes before breakfast, lunch and dinner (three times daily), and evening snack (four times daily). Values are means ± SEM for n = 10 (reproduced from Walter et al.,[56] with permission).

in plasma glucose was prevented when nateglinide 60mg was taken 10 minutes prior to meal ingestion, but not when it was taken just after the meal was ingested (an increase in plasma glucose of approximately 20 mg/dL was still seen).[29] Similar results

© 2004 Adis Data Information BV. All rights reserved.

have been obtained in an additional study in healthy subjects.[28] In patients with type 2 diabetes, doses of nateglinide from 120 to 240mg given 10 minutes before meal ingestion produced significantly (p < 0.05) greater stimulation of insulin secretion than when

Clin Pharmacokinet 2004; 43 (2)

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given during a continuous fast, by nearly 10-fold for peak insulin stimulation (increased by approximately 30–50 mU/L versus 4–5 mU/L fasting) and 5-fold for insulin exposure during 0–4 hours (increased by approximately 80–120 mU • h/L versus 2–8 mU • h/ L fasting; figure 3).[57] Thus, nateglinide administration is synergistic with meal ingestion in increasing insulin secretion. Another issue related to drug administration relative to meals for oral antidiabetic medications is the risk of hypoglycaemia that can result from aggressive pharmacological control of plasma glucose. Hypoglycaemia is a well-documented and potentially severe adverse effect of sulfonylurea therapy.[59,60] Long-acting sulfonylureas, which stimulate prolonged insulin secretion, can cause severe hypoglycaemia, especially in the elderly[61] and in the event of a missed meal.[62] In clinical pharmacology and clinical efficacy and safety studies with nateglinide, in which approximately 2400 patients with type 2 diabetes were treated (approximately 1200 for 6 months or longer), only 2.4% of them

experienced hypoglycaemia and only 0.3% discontinued the studies because of hypoglycaemia.[25] In addition, the risk of hypoglycaemia after a missed meal has been investigated in a crossover study of 13 patients with type 2 diabetes on a nateglinide treatment regimen (120mg three times daily 10 minutes before meals for 6 weeks).[58] When the lunchtime dose of nateglinide or placebo and the meal were withheld, the average glucose concentration after nateglinide did not differ from placebo over hours 0–4 (hour 0 being the time lunch would have been consumed). Only one case of hypoglycaemic symptoms occurred with nateglinide treatment, at hour 3 on the day of the missed lunchtime meal. Hence, the potential for nateglinide to induce hypoglycaemia in the event of a missed meal is comparable with that of placebo, provided that the nateglinide dose is not administered when the meal is missed. The US prescribing information advises that patients who skip meals should also skip their scheduled dose of nateglinide in order to reduce the risk of hypoglycaemia.

140

*

120 AUE-R4 for plasma insulin (mU•h/L)

Placebo 60mg 120mg 180mg 240mg

*

100

*

80

60

40

20

*

0 Fed, no nateglinide Day –1

Fed, plus nateglinide Day 1

Fasting, plus nateglinide Day 4

Fig. 3. Mean integrated plasma insulin response from before treatment to after breakfast (AUE-R4) on day –1 (baseline), after nateglinide administration 10 minutes before breakfast on day 1, and after nateglinide administration during fasting on day 4. Mean placebo data for all treatment groups are displayed. Values are means ± SEM. * indicates p < 0.05 for the comparison of each dose versus placebo in the same treatment period (reproduced from Keilson et al.,[57] with permission).

© 2004 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2004; 43 (2)

Nateglinide

3.3 Stimulation of Early Phase of Insulin Secretion

Two distinct phases of insulin secretion can be demonstrated in persons with normal glucose tolerance in response to intravenous glucose.[63,64] The early rapid-phase insulin response of patients with type 2 diabetes to glucose is essentially absent, and this loss is believed to be an important factor in the deterioration of glucose tolerance in these patients.[65] Nateglinide at a dose of 60mg orally 20 minutes prior to intravenous glucose challenge[66] or 120mg orally 15 minutes prior to challenge[65] has been shown to enhance the initial phase of insulin secretion in response to intravenous glucose in patients with type 2 diabetes. Figure 4 shows the insulin response to an intravenous bolus of glucose given 15 minutes after nateglinide 120mg. The integrated plasma insulin concentration was significantly increased (by 131 ± 30 mU • min/L) when compared with placebo (by 33 ± 7 mU • min/L; p < 0.001) during the initial phase (up to 10 minutes) of glucose-stimulated insulin secretion. Glucose tolerance, as indicated by the glucose disappearance rate constant up to 1 hour postinjection, was significantly improved by nateglinide (0.87 ± 0.04%/min) over placebo (0.76 ± 0.03%/ min). These results suggest that the rapid stimulation of early phase insulin release by nateglinide does acutely improve glucose tolerance in patients with type 2 diabetes. It remains to be determined whether long-term treatment with nateglinide will prevent deterioration of glucose tolerance over the course of the disease in these patients. 3.4 Glucose Dependence of Insulinotropic Effect of Nateglinide

In an in vitro study, the sensitivity of isolated rat pancreatic cells to nateglinide stimulation of insulin secretion was inversely related to the ambient glucose concentration.[67] At 3 mmol/L ambient glucose, the half-maximal effective concentration of nateglinide (EC50) was 14 μmol/L, whereas at 16 © 2004 Adis Data Information BV. All rights reserved.

107

mmol/L ambient glucose the nateglinide EC50 was 0.9 μmol/L. Conversely, the sensitivity of β-cells to glucose stimulation of insulin secretion was increased in the presence of nateglinide. At 5 μmol/L nateglinide, the EC50 for glucose was 8 μmol/L, whereas it was 9.7 μmol/L in the absence of nateglinide. The authors suggested that this phenomenon could help to explain the low incidence of hypoglycaemic adverse events seen in patients treated with nateglinide. The stimulatory effect of nateglinide on insulin secretion has been found in 12 healthy subjects to be dependent on the ambient glucose concentration (unpublished data). In a study in which plasma glucose levels were maintained constant at either euglycaemic (5.5 mmol/L), hypoglycaemic (3.7 mmol/L) or hyperglycaemic (7.5 mmol/L) conditions from 1 hour prior to nateglinide administration until 4 hours afterwards, insulin secretion was absent under hypoglycaemic conditions, but increased proportionally under euglycaemic and hyperglycaemic conditions. These observations may explain in part why hypoglycaemia is infrequently seen as an adverse effect in patients with type 2 diabetes treated with nateglinide. Nateglinide stimulation of insulin secretion may be self-limiting, because the drug becomes virtually ineffective once ambient glucose reaches hypoglycaemic levels. 3.5 Inhibition of Hepatic Glucose Production

Fasting hyperglycaemia in type 2 diabetes is believed to be primarily due to inappropriate endogenous glucose production, a considerable portion of which comes from the liver.[68-70] Postprandial hyperglycaemia in type 2 diabetes has been attributed to impaired suppression of hepatic glucose production.[71,72] The potential for nateglinide to inhibit hepatic glucose production was studied in 13 patients with type 2 diabetes who were treated for 6 weeks with nateglinide 120mg three times daily or placebo before meals.[39] The basal rates of hepatic glucose production were not affected by treatment, but postprandial glucose production was significantly suppressed to 54 ± 10% of basal with nategliClin Pharmacokinet 2004; 43 (2)

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McLeod

90

Placebo Nateglinide Glibenclamide

* *

60

80

*

* *

*

50

*

*

*

* 70 40

*

* Insulin (mU/L)

60

50

* * * ** * *

30

20 −30

0

5

10

15

* 40

*

* 30

20

10 0

60

120

180

240

300

Time after bolus (min) Fig. 4. Plasma insulin concentrations before and after intravenous injection of glucose together with nateglinide, glibenclamide (glyburide) or placebo in 21 subjects with type 2 diabetes. Single oral doses of nateglinide, glibenclamide and placebo were administered in random order 15 minutes before glucose. Values are means ± SEM. * indicates p < 0.01 for nateglinide versus glibenclamide (reproduced from Kahn et al.,[65] with permission).

nide compared with 91± 8% with placebo. Suppression of hepatic glucose production of >50% was maintained for 2.1 ± 0.2 hours with nateglinide versus 1.6 ± 0.2 hours with placebo. The suppression of hepatic glucose production may contribute to nateglinide control of postprandial glucose excursions. 3.6 Nateglinide in Combination with Other Antidiabetic Agents 3.6.1 Metformin

The mechanism of action of metformin differs from that of nateglinide, and metformin has been successfully combined with many antidiabetic agents. The hypoglycaemic effects of metformin are primarily attributed to suppression of hepatic glucose production, particularly hepatic gluconeogenesis, and enhancement of peripheral tissue insu© 2004 Adis Data Information BV. All rights reserved.

lin sensitivity.[12] Despite evaluation for more than 40 years, the primary molecular mechanism of the hypoglycaemic effects of metformin remains unclear. Two studies (a clinical pharmacology study[46] and an efficacy and tolerability study[73]) have shown beneficial pharmacodynamic interactions between metformin and nateglinide in patients with type 2 diabetes. In a randomised crossover doubleblind study, 12 patients received metformin 500mg three times daily 10 minutes prior to meal ingestion for 3 weeks, then additionally received either nateglinide 120mg or placebo three times daily 10 minutes prior to meal ingestion for 1 day.[46] After a 6-day washout period during which metformin treatment was continued, the patients were crossed over to the alternative additional 1-day treatment. The final period of the study comprised a 7-day washout with no hypoglycaemic medications followed by Clin Pharmacokinet 2004; 43 (2)

Nateglinide

Change from baseline

FPG (mmol/L)

Glucose AUC (mmol • h/L)

**

HbA1c (%) 1.0 0.5 0 −0.5 −1.0 −1.5 −2.0 −2.5

*

***

*** ***

*

© 2004 Adis Data Information BV. All rights reserved.

Placebo Nateglinide Metformin Nateglinide + metformin

***

A double-blind placebo-controlled parallel group study assessed the effects of nateglinide alone (120mg three times daily 10 minutes before meals; n = 179), metformin alone (500mg three times daily 10 minutes before meals; n = 178), the combination of the two drugs (n = 172), and placebo (n = 172) given for 24 weeks on fasting plasma glucose, HbA1c and on glucose excursions after liquid glucose challenge.[73] Both drugs significantly reduced HbA1c and fasting plasma glucose (by 0.5% and 0.7 mmol/L with nateglinide and by 0.8% and 1.6 mmol/L with metformin versus increases of 0.5% and 0.4 mmol/L with placebo; p < 0.0001). The effect of combination of drugs was additive (decrease of 1.4% in HbA1c and 2.4 mmol/L in

fasting plasma glucose; p < 0.01 versus monotherapy; figure 5). After the glucose challenge, nateglinide was significantly (p < 0.0001) more effective than metformin or placebo in inhibiting plasma glucose excursions (AUC0–130min –2.1, –1.1 and –0.6 mmol • h/L, respectively ), and the combination of drugs was significantly (p < 0.0001) more effective (–2.5 mmol • h/L) than metformin alone or than placebo. All regimens were well tolerated, but the incidence of events suggestive of hypoglycaemia was also additive for the combination therapy (26.2% versus 12.8% with nateglinide alone and 10.1% with metformin alone). The investigators concluded that: (i) nateglinide controls plasma glucose primarily by inhibiting mealtime excursions, whereas metformin decreases fasting plasma glucose; and (ii) the combination has additive effects on HbA1c and maintains an excellent safety and tolerability profile.

***

1 day of nateglinide treatment alone (open-label). Predose baseline fasting plasma glucose levels were comparable among all the treatment groups (metformin plus placebo, 12.9 ± 2.3 mmol/L; metformin plus nateglinide, 13.5 ± 3.2 mmol/L; nateglinide alone, 14.8 ± 3.9 mmol/L). After the morning meal (0–4 hours), plasma glucose excursions were significantly (p < 0.005) less in the group receiving metformin plus nateglinide (increased by 1.1 ± 1.7 mmol/L) than metformin plus placebo (increased by 3.1 ± 1.2 mmol/L). Over the whole interval of glucose measurement (0–15 hours), there was a mean decrease in plasma glucose with combination nateglinide plus metformin treatment (by 1.4 ± 2.2 mmol/L) that was significantly different from the mean increase seen with metformin plus placebo (by 1.1 ± 1.7 mmol/L; p < 0.001). Nateglinide alone was significantly more effective than metformin plus placebo in decreasing glucose excursions during hours 0–4 after the morning meal (increased by 1.9 ± 2.4 mmol/L versus 3.1 ± 1.2 mmol/L, respectively; p < 0.05). The mean decrease in plasma glucose over 0–15 hours with metformin plus nateglinide (by 1.4 ± 2.2 mmol/L) differed significantly from the increase seen with nateglinide alone (by 0.9 ± 2.4 mmol/L; p<0.001). These results were not related to any pharmacokinetic interaction between the drugs, as none was found.

109

NS

Fig. 5. Adjusted mean change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and integrated glucose concentration (AUC) after challenge with oral liquid glucose (intent-to-treat population). All parameters were significantly reduced from baseline (p < 0.0001) in the active treatment groups. All values were significantly reduced compared with placebo except for glucose AUC with metformin monotherapy (not significant [NS]). * indicates p < 0.01, ** indicates p < 0.001, *** indicates p < 0.0001 (reproduced from Horton et al.,[73] with permission).

Clin Pharmacokinet 2004; 43 (2)

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A similar trial in 467 patients in which nateglinide was given as add-on therapy in patients whose plasma glucose was inadequately controlled by metformin alone gave similar results for both nateglinide 60mg and 120mg plus metformin 1g twice daily. The combination of metformin plus nateglinide (60 or 120mg) was significantly (p < 0.01–0.05) more effective in reducing HbA1c (by 0.4% and 0.6% compared with 0% with metformin plus placebo) and fasting plasma glucose (by 0 mmol/L and 0.2 mmol/L compared with an increase of 0.5 mmol/L with metformin plus placebo).[74] Nateglinide has been approved as monotherapy in the US[25] and in combination with metformin in the US[25] and Europe[5] when metformin alone does not sufficiently control plasma glucose. 3.6.2 Troglitazone

Trials similar to those conducted for nateglinide in combination with metformin were also conducted for nateglinide plus troglitazone. Although troglitazone has now been withdrawn from the market, the results of these trials are of interest, since the mechanism of action of troglitazone differs from that of nateglinide. Troglitazone interacts with the liver and peripheral sites to increase insulin sensitivity, whereas nateglinide stimulates insulin secretion. To test the interaction between these drugs, 12 patients with type 2 diabetes were treated with troglitazone 600 mg/day for 3 weeks, then given 1 day of treatment with nateglinide 120mg or placebo (in a crossover fashion) plus troglitazone, followed by a 7-day washout period and a final single treatment day with nateglinide alone. The maximum postprandial plasma glucose excursions were blunted significantly (p < 0.001) more by the combination of drugs (peak increase in glucose 47.5 ± 11.2 mg/dL) compared with troglitazone plus placebo (103 ± 8.6 mg/dL) or nateglinide alone (58.3 ± 8.7 mg/dL);[39] nateglinide alone was significantly more effective than troglitazone plus placebo (p < 0.001). Results were similar when average glucose concentration over 0–4, 0–11 and 0–24 hours were compared. The maximum stimulation of plasma insulin was to 42.5 ± 4.3 mU/ © 2004 Adis Data Information BV. All rights reserved.

L for the combination, 28.6 ± 3.9 mU/L for troglitazone plus placebo, and 62.0 ± 9.4 mU/L for nateglinide alone (p < 0.05 for combination versus either drug alone and for nateglinide vs troglitazone). All treatments were equally well tolerated. The potentiated pharmacodynamic effects were not related to any pharmacokinetic interaction between the drugs. A 16-week double-blind efficacy and tolerability trial was also performed with the combination of troglitazone and nateglinide (similar to the trials with metformin), and the combination was significantly more effective (p < 0.001) in decreasing fasting plasma glucose (by 3.9 mmol/L) and HbA1c (by 2.2%) relative to placebo, compared with either drug alone (by 2.7 mmol/L and 1.2% for troglitazone and by 1.2 mmol/L and 1.0% for nateglinide).[75] It remains to be determined whether nateglinide has any pharmacodynamic interaction with any of the other thiazolidinedione antidiabetic agents. 3.6.3 Glibenclamide (Glyburide)

In a double-blind crossover study in 13 patients with type 2 diabetes, glibenclamide 10mg once daily was given alone for 3 weeks, then either nateglinide 120mg three times daily 10 minutes before meals or placebo was given in combination with glibenclamide. After a 7- to 14-day washout (of nateglinide or placebo), the alternative treatment was given in combination with glibenclamide, followed by a 5- to 7-day washout of all drugs. Finally, nateglinide was given alone for 1 day. No significant differences were observed between glibenclamide plus nateglinide versus glibenclamide plus placebo in average glucose concentrations over 4 or 11 hours after breakfast or over the 24-hour observation period.[47] In another 12-week trial in patients with type 2 diabetes whose plasma glucose was inadequately controlled on glibenclamide alone (10mg once daily), the addition of nateglinide 60 or 120mg three times daily before meals produced only small additional beneficial effects on fasting plasma glucose and HbA1c.[25] Clin Pharmacokinet 2004; 43 (2)

Nateglinide

It appears from these studies that there is no pharmacokinetic (see section 2.4) or pharmacodynamic interaction of clinical significance between these two drugs.

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4. Comparison of Nateglinide with Other Antidiabetic Agents: Pharmacokinetics and Pharmacodynamics

4.1 Repaglinide 3.7 Pharmacodynamic Effects in Special Populations

The effects of nateglinide in special populations have not yet been extensively s udied. In eight patients with type 2 diabetes with impaired renal function, there was no relationship (r = 0.09) between renal clearance and the effects of nateglinide 90mg three times daily before meals on postprandial plasma insulin after 1 day of treatment. After 6 days of treatment, fasting insulin levels (4.4 ± 1.2 mU/L) were not different from pretreatment (4.2 ± 1.4 mU/ L on day 1 and 4.8 ± 1.6 mU/L on day 2). This preliminary study suggests that nateglinide is effective in patients with type 2 diabetes with renal impairment,[48] but further studies using the recommended 120mg three times daily dosage are needed to confirm this conclusion. Pooled data from completed core studies showed no apparent increases in the incidence of hypoglycaemia in patients with renal impairment.[39] The effects of nateglinide in elderly patients have also been analysed retrospectively, pooling the efficacy data (change from baseline in HbA1c) from two similarly designed blinded placebo-controlled trials in patients with type 2 diabetes. The mean decrease from baseline in HbA1c was similar in nateglinidetreated patients aged 65 years or older (by 0.54%; n = 99) and in those under 65 years of age (by 0.42%; n = 239).[76] Similarly, pooled data from completed core studies showed no apparent increases in the incidence of hypoglycaemia in elderly patients.[39] © 2004 Adis Data Information BV. All rights reserved.

The pharmacology and pharmacokinetics of repaglinide are in many ways similar to those of nateglinide. Both nateglinide and repaglinide are rapidly absorbed, reaching Cmax within 1 hour; their bioavailabilities are 73% and 56%, respectively. With the exception of volume of distribution, which is 31L for repaglinide but only 10L for nateglinide, their pharmacokinetic parameters (e.g. elimination half-life and fraction excreted unchanged in urine) are not remarkably different (table I).[23] Both drugs are extensively bound to serum proteins (≥98%). Their metabolism by CYP differs in that, whereas nateglinide is metabolised primarily by CYP2C9 (~70%) and less so by CYP3A4 (~30%), repaglinide is metabolised by CYP3A4 only.[23] Both drugs are recommended to be taken within 30 minutes prior to meal ingestion, as both the rate and extent of absorption of both drugs are decreased if they are taken after a meal is consumed.[22] In contrast to nateglinide, however, the absorption of repaglinide is not accelerated if it is taken just prior to meals.[22] Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas via inhibition of ATP-sensitive K+ channels in pancreatic β-cells,[30] as does nateglinide, both agents sensitising the β-cells to glucose stimulation of insulin release.[67] The molecular kinetics of the actions of nateglinide and repaglinide on these channels, however, differ considerably. The onset of inhibition by nateglinide is three times more rapid (t1/2(on) 4.1 ± 0.3 min) and the duration of inhibition by nateglinide is five times shorter (t1/2(off) 35 ± 3.8 min) than those for repaglinide (t1/2(on) 12 ± 2.4 min and t1/2(off) 175 ± 1.0 min) in rat pancreatic β-cells.[77] Moreover, although the US product labelling for repaglinide indicates that its effect on glucose stimulation of insulin release diminishes at low glucose concentraClin Pharmacokinet 2004; 43 (2)

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tions, a direct comparison of nateglinide and repaglinide in isolated rat islet cells showed that the potency of nateglinide in stimulating insulin release was directly related to ambient glucose concentrations, (see section 3.4) but that of repaglinide was not affected by ambient glucose concentrations.[67] These observations may help to explain some differences observed between the two drugs in early clinical comparisons. In a study conducted in 15 healthy subjects, single pre-meal doses of nateglinide 120mg, repaglinide 0.5 or 2mg and placebo were administered in a crossover fashion with 48 hours between doses.[78] Plasma insulin concentrations at 10 and 15 minutes postdose were significantly (p < 0.05) higher with nateglinide than with either dose of repaglinide or placebo, and peaked at 45 minutes postdose with nateglinide (94.1 ± 17.1 mU/L) as compared with 60 minutes for both repaglinide 0.5mg (78.7 ± 17.1 mU/L) and 2mg (105.4 ± 19.6 mU/L). Insulin levels decreased rapidly thereafter to levels similar to placebo within 2 hours postdose with nateglinide, whereas with repaglinide insulin levels remained significantly (p < 0.05) higher than placebo from 2 to 8 hours postdose. The average insulin response over 0–8 hours postdose was 25% lower with nateglinide (28 ± 3 mU/L) than with repaglinide 2mg (37 ± 6 mU/L; p < 0.05). Peak postprandial glucose concentrations were significantly (p < 0.01) lower with nateglinide than with the lower dose of repaglinide or placebo and were marginally lower than with the higher repaglinide dose (p < 0.07). Mean plasma glucose reached a similar nadir of ~70 mg/dL in all treatment groups by 1.5 hours postdose, but returned to pre-meal levels with nateglinide within 4 hours. Repaglinide, in contrast, produced a sustained hypoglycaemia up to 6 hours postdose. The potential of nateglinide for delayed hypoglycaemia was compared with that of repaglinide in a double-blind study in eight patients with type 2 diabetes given single doses of nateglinide 120mg, repaglinide 2mg or placebo at the start of a 2-hour hyperglycaemic clamp in a crossover design.[79] Sig© 2004 Adis Data Information BV. All rights reserved.

McLeod

nificantly less insulin (by approximately 20%) was secreted from 2 to 6 hours after nateglinide administration than after repaglinide. Plasma insulin levels remained significantly elevated with repaglinide relative to placebo for at least 30 minutes longer than with nateglinide, and the glucose nadir was significantly lower after repaglinide (by approximately 20%) than after nateglinide. It appears that nateglinide has a faster onset and shorter duration of action than repaglinide, which may confer to nateglinide less potential for delayed hypoglycaemia than repaglinide. 4.2 Glibenclamide

Glibenclamide, also known as glyburide, is a second-generation sulfonylurea oral hypoglycaemic agent that also lowers blood glucose via stimulation of insulin release.[31] Its long-term mechanism of action has not been clearly established, as the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug.[31] There are numerous brands of nonmicronised glibenclamide tablets, and there is also the micronised formulation, which may account in part for the wide variation in pharmacokinetic parameters reported for glibenclamide (table I).[23] The tmax with the micronised formulation is 1.8 hours, and this formulation is 100% bioavailable. Glibenclamide binding to plasma proteins is high (99%), as with nateglinide and repaglinide. Glibenclamide is metabolised in the liver by CYP2C9, and no unchanged drug is excreted in the urine. Unlike repaglinide and nateglinide, there is no effect of food whatsoever on glibenclamide absorption. Glibenclamide inhibits ATP-sensitive K+ channels in pancreatic β-cells, as do nateglinide and repaglinide, the order of potency being repaglinide > glibenclamide > nateglinide.[77] The onset of action on these channels is similar for nateglinide and glibenclamide (t1/2(on) 4.1 ± 0.3 min and 4.2 ± 0.4 min, respectively), but the time for reversal of inhibition with nateglinide is twice as fast (t1/2(off) 35 ± 3.8 min) as with glibenclamide (68 ± 4.0 Clin Pharmacokinet 2004; 43 (2)

Nateglinide

© 2004 Adis Data Information BV. All rights reserved.

Glucose (mmol/L)

1.0 0.5 0.0 −0.5 −1.0 −1.5 −2.0 −2.5

0

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78

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72

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300 250 200 150 100 50 0 −50 0 60

IRI (pmol/L)

b

∇

A double-blind comparison of the effects of nateglinide and glibenclamide on post-meal glucose excursions and insulin secretion has been made in 152 patients with type 2 diabetes previously treated by diet only.[80] Patients received either nateglinide 120mg three times daily before meals (n = 51), glibenclamide 10mg once daily (first titrated from 5 to 10mg after 2 weeks; n = 50), or placebo (n = 51) for 8 weeks. Glibenclamide reduced fasting plasma glucose (by 2.9 ± 0.3 mmol/L) significantly more than did nateglinide (by 1.0 ± 0.3 mmol/L; p < 0.001) relative to placebo. After challenge with a liquid meal, nateglinide reduced the glucose spike (0–4 hours) relative to placebo to approximately twice the extent of that by glibenclamide (4.94 ± 0.74 vs 2.71 ± 0.71 mmol • h/L; p < 0.03), whereas glibenclamide stimulated twice the insulin secretion (as indicated by AUC for C-peptide: 1.83 ± 0.24 vs 0.95 ± 0.23 nmol • h/L). After challenge with a solid meal, nateglinide and glibenclamide elicited similar overall glucose control (figure 6a), but nateglinide stimulated the rapid phase of insulin secretion more than glibenclamide, whereas glibenclamide stimulated more prolonged insulin secretion (figure 6b), resulting in significantly (p = 0.01) greater insulin

Nateglinide Glibenclamide Placebo

a

∇

min).[77] Glibenclamide does not sensitise the β-cells to glucose stimulation of insulin release, as do nateglinide and repaglinide; on the contrary, it desensitises them.[67] At 100 nmol/L glibenclamide, the EC50 for glucose stimulation of insulin release is 15.1 mmol/L, compared with 11.7 mmol/L in the absence of glibenclamide. Moreover, while nateglinide potency in stimulating insulin release is directly related to ambient glucose concentrations (see section 3.4), glibenclamide potency is inversely related – at lower glucose concentrations, nateglinide is less potent but glibenclamide is more potent (glibenclamide EC50 32 nmol/L at 3 mmol/L ambient glucose versus 640 nmol/L at 16 mmol/L ambient glucose).[67] Some of these experimental preclinical observations may relate to differences seen between nateglinide and glibenclamide in clinical studies.

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Time (min) Fig. 6. Change from baseline (pretreatment) in (a) fasting-plasmaglucose-adjusted 12-hour glucose profiles and (b) 12-hour immunoreactive insulin (IRI) profiles during solid-meal challenges performed before and after 7 weeks of treatment with nateglinide (120mg three times daily, before meals), glibenclamide (glyburide) [10mg once daily] or placebo. All values are means ± SEM (reproduced from Hollander et al.,[80] with permission).

exposure during 0–12 hours (as indicated by insulin AUC: 1702 ± 228 versus 866 ± 217 pmol • h/L). Similar results were observed when insulin responses to intravenous glucose were studied in type 2 diabetes patients after treatment with nateglinide, glibenclamide or placebo (see section 3.3 and figure 4),[65] and were associated with a significantly lower (68.7 ± 2.7 mg/dL) and later (270 ± 15 minutes) glucose nadir with glibenclamide as compared with nateglinide (89.5 ± 3.3 mg/dL at 230 ± 15 minutes). The results of a glucose clamp study in healthy subjects (see section 3.4) also support the conclusion that nateglinide stimulates the first phase of insulin secretion, (unpublished data) whereas glibenclamide stimulates the later phase of insulin secretion. The initial phase of insulin secretion stimulated by nateglinide rapidly reverses when ambient glucose is low, but is sustained in the presence of hyperglycaemia. Glibenclamide-stimulated insulin secretion is slower to manifest and more prolonged, regardless of ambient glucose. Clin Pharmacokinet 2004; 43 (2)

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Glibenclamide and nateglinide have also been compared in a missed-meal situation to assess potential for hypoglycaemia under these conditions. Since glibenclamide is given in clinical practice only once daily, if a later meal (e.g. lunch) is missed, patients can run the risk of hypoglycaemia. With nateglinide, in contrast, the dose of medication can simply be skipped when a meal is missed. When nateglinide 120mg three times daily or glibenclamide 10mg once daily were administered to 13 patients with type 2 diabetes in a crossover design study,[58] and the lunchtime meal and dose of medication (placebo or nateglinide) were withheld, the subsequent glucose nadir was significantly (p < 0.01) lower with glibenclamide than with nateglinide (by approximately 40%) or placebo (by approximately 45%), and the incidence of hypoglycaemia (<3 mmol/L) was greater with glibenclamide (four confirmed cases) than with nateglinide (one unconfirmed case). These results suggest that the potential for hypoglycaemia after a missed meal is greater with glibenclamide than nateglinide treatment. Despite current recommendations advocating treatment of type 2 diabetes to a target HbA1c of less than 7%, the adverse effects of treatment with oral hypoglycaemic agents is often perceived as outweighing the benefits in patients whose HbA1c approaches this target level.[81] Since the risk of hypoglycaemia is likely to be highest as normal glycaemia is approached, a retrospective pooled analysis was performed of confirmed hypoglycaemia (<60 mg/dL) in patients whose baseline HbA1c was 8% or less in placebo-controlled clinical studies.[81] The rate of hypoglycaemia in the nateglinide-treated group was 3.6%, compared with 0.9% with metformin and 26% with glibenclamide. These results indicate that target HbA1c levels can be achieved with nateglinide treatment in the great majority of patients while maintaining a good riskbenefit ratio, and that the risk of hypoglycaemia is higher with glibenclamide than with nateglinide. © 2004 Adis Data Information BV. All rights reserved.

McLeod

5. Pharmacokinetic-Pharmacodynamic Relationships of Nateglinide Population pharmacokinetic-pharmacodynamic relationships have been assessed using the results of two published studies (one efficacy and safety study[51] and one dose-ranging study[56]) and two unpublished studies (one dose-ranging study and one study combining nateglinide with glibenclamide background treatment);[39] in patients with type 2 diabetes. The dose-ranging studies assessed nateglinide dosages of 30–240mg three times daily. One of the efficacy studies was a dose-comparison of four doses of nateglinide (30–180mg three times daily) versus placebo, and the other compared two doses of nateglinide plus glibenclamide to placebo. In both efficacy studies, a liquid meal challenge was used to study postprandial glucose regulation by study drugs. 5.1 Plasma Nateglinide Concentrations and Plasma Insulin, Glucose and Glycated Haemoglobin

At the study endpoint, there were significant correlations between nateglinide dose, Cmax and AUC0–4 with stimulation of insulin secretion, albeit the correlation was weaker in the trial assessing combination treatment with glibenclamide. These correlations were maintained even after removing the effect of dose (table II). Nateglinide AUC0–4 was significantly correlated with the average decrease in glucose concentration over the same interval in the dose-comparison study, but not in the combination treatment study. 5.2 PharmacokineticPharmacodynamic Model

As previously mentioned, the results of preclinical in vitro studies and a clinical study in healthy volunteers suggest that nateglinide increases pancreatic β-cell sensitivity to glucose, i.e. it produces a leftward shift in the glucose-insulin dose-response curve. To determine if nateglinide has any effect on Clin Pharmacokinet 2004; 43 (2)

Nateglinide

115

Table II. Correlation analysis of nateglinide maximum concentrations and exposure with dose-adjusted pharmacodynamic responses Dose comparison studya (n = 177)

Glibenclamide (glyburide) combination studyb (n = 86)

AUC0–4

Cmax

AUC0–4

Spearmanc

–0.390

–0.367

0.047

0.013

p-valued

0.0001

0.0001

0.670

0.909

Spearman

–0.156

–0.131

0.173

0.214

p-value

0.038

0.084

0.114

0.050

Spearman

0.152

0.135

0.147

0.313

p-value

0.045

0.074

0.152

0.004

Spearman

0.234

0.242

0.128

0.275

p-value

0.002

0.001

0.244

0.011

Pharmacodynamic response and measure of correlation

Cmax

Average % change in plasma glucose

Maximum % change in plasma glucose

Average % change in plasma insulin

Maximum % change in plasma insulin

a

This study was a double-blind comparison of four doses of nateglinide (30, 60, 120 and 180mg three times daily) versus placebo.[56]

b

This double-blind study compared two doses of nateglinide plus glibenclamide with placebo.[51]

c

Spearman partial correlation coefficients, after accounting for dose.

d

Probability > |r|

AUC0–4 = area under the concentration-time curve from 0 to 4 hours; Cmax = peak plasma concentration.

the glucose-insulin dose-response curve in patients with type 2 diabetes, data from two dose-ranging studies (one published and one unpublished) were used to construct four possible pharmacokineticpharmacodynamic models: 1. nateglinide has no effect on the glucose sensitivity of insulin secretion; 2. nateglinide increases the maximum insulin secretion stimulated by glucose; 3. nateglinide increases the glucose sensitivity of insulin secretion; 4. nateglinide increases both the maximum stimulated insulin secretion and its sensitivity to glucose. The third model best fit the data from the two dose-ranging studies, significantly relating the logtransformed percentage change in insulin to the percentage change in glucose according to a sigmoidmaximum response model (figure 7). According to the model, the relative change in glucose required to achieve a given change in insulin decreases with increasing nateglinide concentrations. When the model was subsequently tested using the data from the two efficacy studies, similar results were ob© 2004 Adis Data Information BV. All rights reserved.

served, but the effect of nateglinide was greater in the study comparing nateglinide doses of 30–180mg with placebo (shown in figure 7) than in the trial combining nateglinide with glibenclamide. This observation is not unexpected, as the patients were already stabilised on glibenclamide treatment in the latter trial, whereas they were not receiving background treatment in the former. 5.3 Pharmacokinetics and the Incidence of Hypoglycaemia

The two efficacy studies were assessed for relationship of hypoglycaemia rates (per week) to dose of nateglinide, total exposure to nateglinide and nateglinide Cmax. In the study that compared nateglinide doses of 30–180mg with placebo, all three parameters were significantly correlated (p < 0.001; r = 0.25 for pharmacokinetic predictors and 0.19 for dose) with hypoglycaemia rate. In the study in which nateglinide was combined with glibenclamide, none of these three parameters was significantly correlated with hypoglycaemia. Hence, it appears that the incidence of hypoglycaemia with Clin Pharmacokinet 2004; 43 (2)

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McLeod

Nateglinide (mg/L) 0 2 5 10

Insulin change (%)

400 300 200 100

0 −50

0

50

100

Glucose change (%) Fig. 7. A model was constructed to describe the enhancement by nateglinide of the insulin response to glucose from two dose-ranging studies and then was applied to two safety and efficacy studies. The modelling was based on the principle that the dominant stimulus for insulin secretion is glucose. Nateglinide was modelled as a modifier of the change in insulin versus change in glucose relationship. The best model supports nateglinide exertion of its effects by increasing glucose sensitivity of insulin secretion rather than by increasing maximal insulin secretion. This figure illustrates the leftshifting effect with increasing nateglinide plasma concentrations (within its therapeutic range).

nateglinide is low[25] and is related to dose, Cmax and total exposure when nateglinide is administered as monotherapy. 6. Therapeutic Use of Nateglinide in Clinical Practice Unless otherwise cited, the information provided in this section comes from the US product labelling for nateglinide. Nateglinide is approved for treatment of type 2 diabetes in Europe and the US, and has been launched in the Japan, US, Europe and many other countries. It is approved in the US as monotherapy to lower blood glucose in patients whose hyperglycaemia is not adequately controlled by diet and exercise alone and who have not been chronically treated with other antidiabetic agents. It is also indicated for treatment in combination with metformin of patients whose hyperglycaemia is not adequately © 2004 Adis Data Information BV. All rights reserved.

controlled with metformin alone (in the US and Europe). Nateglinide should not be substituted for metformin, glibenclamide or any other insulin secretagogue, nor should it be added to any antidiabetic drug with a primary mode of action of stimulating insulin secretion. Nateglinide cannot be used in patients with type 1 diabetes or in patients with diabetic ketoacidosis, because these conditions should be treated with insulin. Coadministration of nateglinide with metformin or any other glucose-lowering agent can lead to increased risk of hypoglycaemia. Geriatric patients, malnourished patients, and those with adrenal insufficiency are more susceptible to the glucose-lowering effects of antidiabetic medications. Intense physical activity or alcohol ingestion can also predispose to hypoglycaemia. Nateglinide is metabolised extensively by the liver and should be used with caution in patients with moderately to severely impaired liver function. The recommended starting and maintenance dosage of nateglinide, whether given alone or in combination with metformin, is 120mg three times daily to be taken 1–30 minutes before meals. If a patient misses a meal, the scheduled dose of medication should be skipped in order to reduce the likelihood of hypoglycaemia. If a patient has near normoglycaemia, a starting and maintenance dosage of 60mg three times daily before meals can be used. These dosage regimens allow flexibility of treatment that is desirable and necessary in younger patients whose type 2 diabetes has been diagnosed at an early stage when hyperglycaemia may not yet be so severe as to mandate more aggressive treatment. This flexibility is also advantageous in elderly patients in whom non-flexibility of treatments like long-lasting sulfonylureas and NPH insulin coupled with the inability or unforeseen unwillingness of the patient to comply with diet and drug treatment plans can lead to dangerous metabolic consequences.[21] On the other hand, flexible treatment schedules might not be accepted by some patients because of insufficient instruction, or they may not be feasible Clin Pharmacokinet 2004; 43 (2)

Nateglinide

because of noncompliance or cognitive impairment.[21] Careful patient counselling should address all these possibilities. Patients should be instructed carefully concerning their nateglinide dosage regimen, including to skip their medication if they miss a meal, and should be educated as to the risks and signs of hypoglycaemia and its management.[23] Fasting blood glucose and HbA1c levels should be monitored regularly and discussed with patients. Periodic home blood glucose monitoring, including after meals, should be encouraged in patients receiving nateglinide.[23] 7. Conclusions The pharmacokinetic profile of nateglinide is characterised by rapid and virtually complete absorption and rapid elimination from plasma, and its bioavailability after oral administration is 73%. Nateglinide is extensively metabolised by the mixed-function oxidase system (primarily CYP2C9, and less so CYP3A4) and eliminated largely by the kidney. Unchanged nateglinide is the primary circulating component in plasma. No significant circadian effect has been observed and no significant accumulation noted upon repeated administration. There are no apparent differences in nateglinide pharmacokinetics in patients with type 2 diabetes and healthy subjects, with linear pharmacokinetics observed over the dose range 60–240mg. When given prior to a meal, nateglinide is absorbed more rapidly and Cmax is greater than when it is given during a continued fast. When nateglinide is given after a meal, its absorption is delayed and Cmax is decreased. Therefore, it is highly preferable to administer nateglinide prior to starting a meal, and its pharmacokinetics are similar when it is administered anytime from 1 to 30 minutes prior. No significant alteration in the pharmacokinetic parameters of nateglinide has been found in patients with impaired renal function, so no dosage adjustment is considered necessary for these patients. The number of patients studied with type 2 diabetes and © 2004 Adis Data Information BV. All rights reserved.

117

renal insufficiency, however, is limited; therefore, more information on these patients would be very valuable. No dosage adjustment is advised in mild hepatic insufficiency; however, in moderate to severe hepatic dysfunction, caution is advised, as no information is available yet in such patients. Nateglinide is extensively bound to serum proteins, but in vitro displacement studies have shown no influence by a number of highly protein bound drugs on serum protein binding of nateglinide, and vice versa. In clinical studies, no relevant drug-drug interactions have been observed with digoxin, warfarin (substrate for CYP3A4 and 2C9), diclofenac (substrate for CYP2C9), or with the oral hypoglycaemic agents troglitazone (CYP3A4 inducer), glibenclamide or metformin. Nateglinide administered prior to meals stimulates rapid and short-lived insulin secretion in a dose-dependent manner, thereby decreasing mealtime plasma glucose concentrations. Effects on mealtime plasma insulin translate into efficacy in the treatment of patients with type 2 diabetes, as assessed by decreases in fasting plasma glucose and in fasting HbA1c. Synergism has been noted between the insulinotropic effects of nateglinide and meal administration, with only a limited insulin response to nateglinide occurring in fasting patients. Nateglinide stimulates the early phase of insulin secretion and suppresses hepatic glucose production, both of which are known to be abnormal in type 2 diabetes. Nateglinide effects on insulin and glucose control are dose-related up to 120mg three times daily. A model has been proposed wherein the pharmacodynamic action of nateglinide appears to be related to increasing the sensitivity of pancreatic β-cells to the insulin-stimulating effects of plasma glucose. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips their dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low. The low potential of Clin Pharmacokinet 2004; 43 (2)

118

nateglinide for inducing hypoglycaemia may be related to the inverse relationship between its stimulation of insulin secretion and plasma glucose levels. The potential for nateglinide to produce hypoglycaemia is lower than that of repaglinide and glibenclamide. Elderly patients appear to respond similarly to younger patients in terms of nateglinide efficacy and safety, as is so for renally impaired patients. Nateglinide is more rapid than repaglinide and is more rapid and more effective than glibenclamide in stimulating postprandial insulin secretion. Nateglinide blunts mealtime glucose excursions more effectively than either repaglinide or glibenclamide, without producing prolonged insulin exposure or sustained hypoglycaemia as occurs with repaglinide and glibenclamide. The safety of nateglinide in the long-term treatment of type 2 diabetes remains to be demonstrated, as data are not available yet for treatment of duration longer than 1 year.[39] It also remains to be further explored whether nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic microvascular and macrovascular complications[23] and/or preserve pancreatic β-cell function. A very large and comprehensive clinical trial (NAVIGATOR) has been started to assess the effects of nateglinide and valsartan (an angiotensin II blocker), alone or in combination, on the progression to diabetes in patients with a cardiovascular disease (aged 50 years or older) or a cardiovascular risk factor (aged 55 years or older). The trial and its extensions are expected to involve over 7000 subjects recruited from 600–800 centres in 40 countries, and to last over 5 years until at least 1000 subjects have had a cardiovascular event. The primary goal of the trial is to elucidate whether restoration of early phase insulin secretion and improvements in insulin sensitivity can prevent type 2 diabetes and associated cardiovascular disease in high-risk patients. The results of this trial should provide valuable information elucidating the pathophysiology of type 2 diabetes. © 2004 Adis Data Information BV. All rights reserved.

McLeod

Acknowledgements Sincerest thanks are extended to Cynthia Lategan, Pratapa Prasad and Monica Ligueros-Saylan for their contributions to the preparation and review of the manuscript. The author has provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

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Correspondence and offprints: Dr James F. McLeod, Novartis Pharmaceuticals, One Health Plaza, East Hanover, NJ 07936, USA. E-mail: [email protected]

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