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Repaglinide

A Review of its Therapeutic Use in Type 2 Diabetes Mellitus

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Summary

Abstract

Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic β-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion.

In clinical trials of up to 1-year’s duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) ≤15 mg/day and greater control than patients receiving glipizide ≤15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in 1 short term study (n = 192).

Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day.

Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime.

In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial.

In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone.

Pharmacodynamic Properties

Repaglinide is a carbamoylmethyl benzoic acid derivative. Like the sulphonylureas, repaglinide acts by stimulating release of insulin from the β-cells of the pancreas.

There are some notable differences between repaglinide and the sulphonylureas: repaglinide acts on a unique receptor site on the β-cell membrane and inhibition of ATP-sensitive potassium channels appears to be the sole mechanism through which repaglinide stimulates insulin secretion. Furthermore, in vitro experimentation has indicated that, unlike sulphonylureas, repaglinide does not stimulate insulin secretion in the absence of glucose, does not inhibit glucose-stimulated proinsulin biosynthesis in isolated rat β-cells and is able to overcome the metabolic stress induced by 2,4-dinitrophenol.

In in vitro and in vivo studies, repaglinide displayed greater insulinotropic and hypoglycaemic potency than glibenclamide (glyburide) and glimepiride, and had a faster onset of action.

In patients with type 2 diabetes mellitus, preprandial repaglinide causes a dose-related increase in insulin levels and a corresponding decrease in postprandial glucose levels. In 1 study (n = 143), blood glucose levels were significantly reduced in patients receiving preprandial repaglinide (3 times daily) versus those receiving placebo over 4 weeks of treatment.

In a dose-regimen study, 3-times-daily preprandial administration of repaglinide was shown to be more effective at lowering blood glucose than the same total dosage given twice daily.

In 2 further studies, patients with type 2 diabetes mellitus receiving repaglinide were able to miss a meal or add an extra meal (and the corresponding repaglinide dose) without significantly affecting blood glucose levels.

Pharmacokinetic Properties

Repaglinide is rapidly and completely absorbed, with maximum plasma concentrations (Cmax) occurring ≈1 hour after oral administration.

Absolute oral bioavailability of repaglinide ranged from 56 to 63% and the volume of distribution was between 24 and 3 1L in healthy volunteers; repaglinide is >98% bound to human serum albumin.

Repaglinide Cmax and area under the plasma concentration-time curve increased in a dose-dependent fashion in patients with type 2 diabetes mellitus receiving total daily doses ranging from 0.125 to 16mg; no accumulation of repaglinide was noted over 4 weeks of treatment.

Repaglinide is rapidly cleared from the bloodstream with a terminal elimination half-life of ≤1 hour and is extensively metabolised in the liver by cytochrome P450 (CYP) to inactive metabolites. The primary route of elimination of repaglinide and its metabolites is via biliary-faecal excretion. In a study of radiolabelled repaglinide, 90% of a single 2mg oral dose of 14C-repaglinide was recovered in the faeces (<2% was excreted unchanged) with 8% excreted in urine within 96 hours after administration.

Mild to moderate renal impairment (creatinine clearance ≥30 ml/min) and advanced age had little influence on the pharmacokinetics of repaglinide in patients with type 2 diabetes mellitus or otherwise healthy volunteers. However, individuals with severe renal impairment (creatinine clearance <30 ml/min) [including some individuals who were on haemodialysis] or chronic liver disease (Child Pugh grade B or C) had significantly higher and more prolonged serum levels of repaglinide than those in healthy individuals.

Drug interaction studies in healthy volunteers showed that the pharmacokinetic properties of digoxin, theophylline and warfarin were not affected by coadministration of repaglinide. Likewise, repaglinide pharmacokinetics were not affected to a clinically relevant extent by concurrent administration of cimetidine, ketoconazole, rifampicin, ethinylestradiol, simvastatin or nifedipine (agents known to affect CYP-mediated drug metabolism).

Clinical Efficacy

Repaglinide has been evaluated in a number of well designed studies in patients with type 2 diabetes mellitus, both as monotherapy and in combination with other oral antidiabetic agents (metformin, troglitazone, pioglitazone and rosiglitazone) or insulin. Most clinical trials used a preprandial administration regimen (repaglinide administered before each meal); however, the use of twice-daily repaglinide has also been investigated. The antidiabetic efficacy of preprandial repaglinide (0.5 to 4mg before each meal) has been evaluated in patients with type 2 diabetes mellitus receiving a fixed diet of 3 meals a day as well as in patients who were free to vary their number of daily meals.

Preprandial Administration in Fixed Meal Schedules. Although repaglinide has shown glucose-lowering efficacy when given twice daily, this agent was more effective when given on a 3-times-daily basis compared with the same dose given twice daily in a double-blind, randomised study in 18 pharmacotherapy-naíve patients with type 2 diabetes mellitus. Consequently, subsequent trials have adopted a preprandial administration regimen.

In clinical trials of up to 1-year duration, preprandial repaglinide consistently improved or maintained glycaemic control in patients with type 2 diabetes mellitus.

In 3 placebo-controlled studies (n = 74 to 352), glycaemic control [as measured by changes in glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (PPBG) levels] was significantly improved compared with that in placebo recipients over 18 to 24 weeks of therapy with repaglinide 0.25 to 8mg preprandially 3 times daily.

Preprandial repaglinide 0.5 to 4mg 3 times daily provided equivalent glycaemic control to glibenclamide ≤15 mg/day in 1 short term (n = 192) and 2 1-year (n = 425 and 544) double-blind, randomised, parallel-group studies. In all studies, no significant differences between treatment groups were observed for mean change from baseline HbA1c, FBG or PPBG.

Most of the patients included in these studies (87 to 100%) had already achieved some degree of glycaemic control with previous oral hypoglycaemic treatment. This control was generally maintained over the study duration in both treatment groups: a slight improvement in glycaemic control was observed in the short term study whereas a slight deterioration was observed in the 1-year trials after an initial improvement during the first 3 months or so.

Preprandial repaglinide 1 to 4mg 3 times daily was at least as effective as glipizide in a 1-year double-blind, randomised comparative trial (n = 256). Significant improvements in favour of repaglinide were observed for mean change in FBG and HbA1c levels (p < 0.05 for both).

In all trials, pharmacotherapy-naíve patients responded particularly well to repaglinide therapy, with these patients achieving sustained and prolonged reductions in HbA1c and FBG.

Combined with Other Oral Antidiabetic Agents or Insulin. Repaglinide 0.5 to 4mg 3 times daily has been investigated in combination with metformin 1 to 3 g/day, troglitazone 200 to 600 mg/day, rosiglitazone 2 to 4mg twice daily, pioglitazone 30mg once daily and intermediate-acting insulin (NPH) administered at bedtime in patients with type 2 diabetes mellitus whose symptoms were inadequately controlled with previous medications.

In all of these studies, HbA1c and FBG were significantly improved during combination therapy compared with treatment with either study drug as mono-therapy. The efficacy of repaglinide monotherapy was similar to that of metformin monotherapy and significantly better than that of troglitazone.

It should be noted, however, that troglitazone is no longer available for treatment in patients with type 2 diabetes mellitus and repaglinide is not currently indicated for use in combination with any thiazolidinediones or insulin.

Preprandial Administration in Flexible Meal Schedules. The efficacy of repaglinide (0.5 to 4mg preprandially) in patients following a flexible meal time table has been examined in the clinical setting in 2 large studies.

In a 16-week, double-blind, placebo-controlled study involving 394 pharmacotherapy-naíve patients with type 2 diabetes mellitus, significant improvements in glycaemic control versus placebo and baseline were shown in all patients receiving repaglinide, regardless of whether they ate 2, 3 or 4 meals a day.

The use of preprandial repaglinide in a flexible meal-related dosage schedule was further evaluated in a large, noncomparative (uncontrolled), prospective investigation surveying 5985 patients with type 2 diabetes mellitus. Overall, significant improvements in HbA1c, FBG and PPBG were observed after a mean of 46 days of treatment. Patients lost bodyweight and reduced snacking and nearly 80% reported a ‘sense of relief’ at the prospect of being able to miss meals, with 50% of patients varying their meal times on a daily basis.

Tolerability

In studies conducted to date, repaglinide (0.5 to 4mg preprandially 2 to 4 times daily during fixed or flexible meal schedules) was well tolerated in patients with type 2 diabetes mellitus. Overall, adverse events occurring in repaglinide recipients were usually mild to moderate in intensity and similar to those occurring with sulphonylureas; hypoglycaemia was higher and upper respiratory tract infection was slightly higher in repaglinide recipients compared with placebo recipients. In a trial comparing repaglinide with metformin, repaglinide was associated with less frequent diarrhoea but a higher rate of hypoglycaemia. Repaglinide also appears to be well tolerated in elderly patients with type 2 diabetes mellitus.

In comparative trials of 1-year’s duration, the most commonly occurring adverse events in patients receiving repaglinide (n = 1228) were hypoglycaemia (16%), upper respiratory tract infection (10%), headache (9%), rhinitis (7%) and bronchitis (6%). These adverse events occurred with a similar incidence in patients treated with sulphonylureas. In these trials, the incidence of hypoglycaemia was 18% in sulphonylurea (including glibenclamide, glipizide and gliclazide) recipients (n = 597). However, the incidence of serious hypoglycaemia (FBG levels <2.5 mmol/L) tended to be higher in the sulphonylurea treatment group (0.6 vs 1%).

In another meta-analysis of these studies, the absolute rate of major hypoglycaemic events associated with blood glucose <2.5 mmol/L was 2.5 times higher in patients treated with sulphonylureas than those treated with repaglinide (3.3 vs 1.3%; p < 0.05). Furthermore, the risk of hypoglycaemia was not increased in patients receiving repaglinide who missed or postponed a meal in 1 comparative study (n = 42), in contrast with patients receiving glibenclamide.

The incidence of cardiovascular events (which are common in patients with type 2 diabetes) was similar between patients receiving repaglinide and sulphonylurea therapy in 1-year comparative clinical trials; the incidence of cardiovascular mortality was also similar between patients receiving repaglinide or sulphonylureas (≈0.5%).

In patients receiving repaglinide in combination with metformin, troglitazone or bedtime NPH, the incidence of hypoglycaemia was increased compared with patients receiving monotherapy; however, the incidence of serious hypoglycaemia was low. No tolerability data are available in patients receiving repaglinide in combination with rosiglitazone or pioglitazone.

Dosage and Administration

Repaglinide is indicated for use in patients with type 2 diabetes mellitus whose blood glucose cannot be adequately controlled by diet or exercise alone, and in combination with metformin in patients whose glucose levels are inadequately controlled with metformin or repaglinide monotherapy. In all cases, repaglinide is an adjunct to diet and exercise, which remain the primary form of treatment for these patients.

There is no fixed dosage regimen for repaglinide in patients with type 2 diabetes. Within the recommended limits (≤16 mg/day), individual repaglinide dosages should be determined by the physician and titrated to achieve optimal glycaemic control.

Repaglinide is given in a preprandial dosage schedule (1 meal, 1 dose). Doses are usually given within 15 minutes of a meal, but this may vary from immediately before to up to 30 minutes prior to the meal. If the patient misses or adds a meal, they should omit or add the accompanying repaglinide dose.

The recommended starting dosage of repaglinide is 0.5mg preprandially; however, in patients who are transferring from another oral hypoglycaemic agent, the recommended starting dose is slightly higher (1mg in Europe; 1 to 2mg in the US). The maximum recommended single dose is 4mg taken with the main meal.

When repaglinide therapy is being instigated in place of therapy with other oral blood glucose-lowering agents, the first repaglinide dose may be taken the day after the final dose of the previous drug. However, patients should be monitored closely for hypoglycaemia.

Repaglinide can be given in combination with metformin when blood glucose is inadequately controlled with metformin or repaglinide alone. In these cases, the starting dose and dosage adjustments for repaglinide are the same as for repaglinide monotherapy.

Contraindications to repaglinide include type 1 diabetes mellitus, diabetic ketoacidosis and known hypersensitivity to the drug or its active ingredients. The safety of repaglinide has not been established in paediatric patients, pregnancy or breastfeeding and the use of repaglinide in these patients is contraindicated in Europe.

Patients with impaired renal function, including those with severe dysfunction or those requiring haemodialysis, do not require initial dosage adjustment of repaglinide; however, subsequent increases should be made carefully.

Patients in the US with impaired liver function are advised to use repaglinide cautiously; repaglinide treatment is contraindicated in patients with severe liver dysfunction in Europe.

There are no restrictions in the US on the use of repaglinide in elderly patients, although greater sensitivity of some older individuals to repaglinide therapy cannot be ruled out. In Europe, treatment of individuals >75 years is not recommended because of a lack of clinical data in these patients.

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Authors and Affiliations

  1. Adis International limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 10, New Zealand

    Christine R. Culy & Blair Jarvis

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  1. Christine R. Culy
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  2. Blair Jarvis
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Correspondence to Christine R. Culy.

Additional information

Various sections of the manuscript reviewed by: R.B. Goldberg, Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida, USA; G.D. Johnston, Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, Belfast, Northern Ireland; R. Landgraf, Diabetes Center, Department of Internal Medicine, University of Munich, Germany; W.J. Malaisse, Laboratory of Experimental Medicine, Brussels Free University, Brussels, Belgium; T.C. Marbury, Orlando Clinical Research Center, Orlando, Florida, USA; A.D. Mooradian, Department of Internal Medicine, St Louis University Medical School, St Louis, Missouri, USA; R. Moses, Department of Biomedical Science, University of Wollongong, Wollongong, New South Wales, Australia.

Data Selection

Sources: Medical literature published in any language since 1966 on repaglinide, identified using AdisBase (a proprietary database of Adis International), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘repaglinide’ or ‘NN 623’. Medline search terms were ‘repaglinide’ or ‘NN 623’. EMBASE search terms were ‘repaglinide’ or ‘NN 623’. Searches were last updated 16 August, 2001.

Selection: Studies in patients with type 2 diabetes mellitus who received repaglinide. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Type 2 diabetes mellitus, noninsulin-dependent, repaglinide, pharmacodynamics, pharmacokinetics, therapeutic use, hypoglycaemia.

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Culy, C.R., Jarvis, B. Repaglinide. Drugs 61, 1625–1660 (2001). https://doi.org/10.2165/00003495-200161110-00008

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