Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 48, Num. 3, 2002, pp. 246-248

Journal of Postgraduate Medicine, Vol. 48, Issue 3, 2002 pp. 246-248

Drug Review

Repaglinide: A Short Acting Insulin Secretagogue for Postprandial Hyperglycaemia

Ambavane V, Patil R, Ainapure SS

Department of Pharmacology, LTM Medical College and General Hospital, Sion, Mumbai - 400022, India.

Code Number: jp02086

Type 2 diabetes mellitus is a complex and heterogeneous disorder. The pathogenesis involves multiple mechanisms which contribute to hyperglycaemia, most notably impaired insulin secretion by pancreatic b-cells, reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin resistance) and increased hepatic glucose production. Although basal insulin secretion may remain within the normal range, the meal-time insulin response is blunted or delayed in patients with type 2 diabetes mellitus, which causes post­prandial hypoglycaemia.¹

In some patients with type 2 diabetes mellitus, blood glucose control may initially be achieved with appropriate bodyweight reduction, diet and exercise. But, most patients eventually require drug therapy to maintain adequate glycaemic control. Various oral hypoglycaemic agents have been developed over the past 40 years. These include sulphonylureas, biguanides, a -glucosidase inhibitors and thiazolidinediones. These drugs act through different mechanisms of action and can be used as monotherapy or in various combinations.²

Repaglinide, a carbamoylmethyl benzoic acid derivative and nateglinide, a d­phenylalanine derivative, belong to a new class of oral hypoglycaemic agents known as the meglitinide analogues. This class was developed to specifically control meal-related (prandial) glucose fluctuations in patients with type 2 diabetes mellitus.³ Like the sulphonylureas, they reduce blood glucose by stimulating insulin secretion. These agents decrease the risk of hypoglycaemia associated with the use of some oral hypoglycaemic agents and to decrease the likelihood of secondary failure related to pancreatic b-cell exhaustion.⁴ Repaglinide was approved by FDA in 1997. This article reviews the pharmacology of repaglinide and its role in the treatment of type 2 diabetes mellitus.

Mechanism of Action

Like the sulphonylureas, repaglinide acts by stimulating release of insulin from the b-cells of the islets of pancreas inhibiting ATP-sensitive K⁺ channels, thereby activating the Ca⁺⁺ channels with increase in intracellular calcium to release insulin.⁵ However, repaglinide acts on a different binding site than the sulphonylureas.^6,7 Repaglinide is not effective in the absence of functioning beta-cells.

Repaglinide increases the amount of insulin released in a natural and physiological pulsatile pattern.⁸

The activity of repaglinide is dose-dependent. Mean insulin levels begin to rise approximately 1.5 hours after the preprandial dose of repaglinide and declines towards baseline levels between meal-time.^9,10

The rapid onset of action and the short duration of hypoglycaemic effect of repaglinide makes this agent suitable for preprandial administration. The main advantage of preprandial administration is that patients can miss or postpone a meal (and the corresponding repaglinide dose) without increasing the risk of hypoglycaemia or compromising glycaemic control.³

Pharmacokinetics

Repaglinide is rapidly absorbed after oral administration. Peak concentration occurs within 1 hr. of a single oral dose of 2mg. The mean oral bioavailability of repaglinide ranges from 56 to 63%.³

Repaglinide is highly bound to plasma proteins (>98%).^11,12 Repaglinide is rapidly cleared from the blood-stream with a terminal elimination half-life (t^l/₂) of <1 hour.^11,12 Plasma concentrations of repaglinide fall rapidly, reaching predose concentrations within 4 or 5 hours after oral administration of 2 mg Repaglinide.⁹ Repaglinide is metabolised in the liver to inactive metabolites through the CYP3A4 enzyme system.¹¹ Repaglinide and its metabolites are eliminated via the biliary-faecal route.

Mild to moderate renal impairment (creatinine clearance > 30 ml/min) and advanced age has little influence on the pharmacokinetics of repaglinide.^11,13 However, individuals with severe renal impairment (creatinine clearance < 30 ml/min) or chronic liver disease, have higher and more prolonged serum levels of repaglinide than those in healthy individuals.¹³

Drug Interactions

The pharmacokinetic properties of digoxin, theophylline and warfarin are not affected by co-administration of repaglinide.^11,12,14 In addition, repaglinide pharmacokinetics in healthy individuals are not affected to a clinically relevant extent by concurrent administration of cimetidine, rifampicin, ketoconazole, simvastatin or ethinyl estradiol or nifedipine which are agents known to affect CYP-mediated drug metabolism.^14,15

The risk of hypoglycaemia may be increased when repaglinide is used along with salicylates, sulfonamindes, chloramphinecol, coumarins, probenecid, mono-amine oxidase (MAO) inhibitors, and B-adrenergic blockers.³

Dosage

There is no fixed dosage regimen for repaglinide. Dosages should be titrated within the recommended dosage range (< 16mg/day) to achieve optimal glycaemic control.

The repaglinide starting dosage is 0.5mg. preprandially. However, if patients are transferred from another oral hypoglycaemic drug or if HbA1c >8%, the starting dose should be higher (1-2mg.).^3,11,12 Repaglinide can be given 15min. before a meal. If the patient misses a meal or adds a meal, he should omit or add the accompanying repaglinide dose.³ The recommended maximum single dose is 4mg. And the maximum daily dosage is 16mg./day.³

When repaglinide is given in place of another oral hypoglycaemic, the first repaglinide dose may be taken the day after the final dose of the previous drug and patients should be closely monitored for hypoglycaemia, in case the glucose lowering effects of the two drugs overlap. If the previous drug was a sulphonylurea with a long t1/2, the patients may require observation for a week or longer.¹¹ When given in combination with metformin, the starting dose and dose adjustments for repaglinide are the same as for repaglinide monotherapy.

Contraindications and Precautions

Repaglinide is contraindicated in patients with a known hypersensitivity to repaglinide, in patients with type 1 diabetes mellitus (since repaglinide is not effective in the absence of functioning beta-cells) and in diabetic ketoacidosis as it requires treatment with insulin. The safety of this drug in pregnancy has not been proved. Repaglinide should be used cautiously in patients with impaired hepatic function.¹¹

Adverse Drug Reactions

Adverse events occurring in repaglinide recipients are usually mild to moderate in intensity and similar to those occurring with sulphonylureas; the incidence of hypoglycaemia and URTIs tends to be higher than in placebo recipients^11,16,17,18 but lower than in sulphonylureas.

However, in contrast to sulphonylureas, the risk of hypoglycaemia does not increase if patients on repaglinide therapy miss a meal and also omit the corresponding dose.^19,20 The risk of hypoglycaemia increases when repaglinide is combined with metformin,²¹ troglitazone²² or bedtime NPH.²³ Thus, proper patient selection, dosage and instructions are important to avoid hypoglycaemic attacks.

The other adverse effects reported are sinusitis, rhinitis, bronchitis, headache,³ nausea, diarrhea, constipation, vomiting and dyspepsia. Musculoskeletal disorders including arthralgia and backpain may occur in some patients.¹¹

Role of Repaglinide in Treatment of Type 2 Diabetes Mellitus, Especially Postprandial Hyperglycaemia

Type 2 diabetes mellitus patients initially achieve adequate glycaemic control with the dietary restriction and exercise alone, but most of them eventually require drug treatment.^24,25 Various oral hypoglycaemic agents are available, all of which have different mechanisms of action. Biguanides and thiazolidinediones reduce insulin resistance, whereas sulphonylureas, repaglinide and nateglinide are beneficial as insulin secretagogues.²

Along with FBG control, postprandial glucose regulation is becoming an important target for these patients. This is because, studies have shown that postprandial hyper-glycaemia is an important factor associated with development of macrovascular and micravascular complications, especially coronary heart disease associated with type 2 diabetes mellitus.²⁶ Some agents which target postprandial hyper-glycaemia have been developed. For example; fast acting insulin analogues (insulin lispro and insulin aspart) mimic physiological insulin response to meals and oral a-glucosidase inhibitors (miglitol, acarbose) reduce post-prandial bloos glucose by modifying carbohydrate absorption from the gut. But, repaglinide is the first insulin secretagogue, developed to target postprandial hyperglycaemia. Its rapid onset of action and short-lived hypoglycaemic effect, makes repaglinide an ideal agent for controlling postprandial hyperglycaemia. It is very effective both, as monotherapy ^16,17 as well as, in combination with other oral hypoglycaemics.

Despite the increasing number of oral hupoglycaemic agents available for patients with type 2 diabetes mellitus, these agents have a limited capacity to provide stable long term glycaemic control ²⁴ because of a progressive loss in R-cell function.²⁴ Therefore, most patients receiving oral antidiabetic agents require combination therapy at some time to achieve or maintain glycaemic control.

Repaglinide has shown better results when combined with other therapies like metformin, troglitazone, rosiglitazone and pioglitazone^21,22,27 In patients whose diabetes is poorly controlled with metformin alone, the addition of repaglinide provided a greater overall improvement in glycaemic control than either therapy alone.²¹

Conclusion

Repaglinide is a very useful addition to the currently available oral hypoglycaemic agents. When given preprandially, repaglinide is equal in efficacy to various sulphonylureas, but is associated with a reduced risk of serious hypoglycaemia. In addition, patients on repaglinide therapy can miss or postpone a meal without increasing risk of hypoglycaemia or compromising glycaemic control. Repaglinide when combined with metformin, has shown better glycaemic control in patients with type 2 diabetes mellitus.

Thus, repaglinide is a promising new drug in the treatment of type 2 diabetes mellitus, as monotherapy in patients whose blood glucose cannot be controlled by diet or exercise alone, or in combination with metformin in patients whose blood glucose cannot be controlled adequately on metformin alone.

Ambavane V, Patil R, Ainapure SS

Department of Pharmacology, LTM Medical College and General Hospital, Sion, Mumbai - 400022, India.

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