, Volume 22, Issue 6, pp 389-411
Date: 22 Sep 2012

Repaglinide

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Summary

Abstract

Repaglinide (Prandin®, NovoNorm®, GlucoNorm®), an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA1c) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules.

Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA1c level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<$US1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters.

Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (≤3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups.

In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation.

Epidemiology and Cost of Type 2 Diabetes Mellitus

The prevalence of diabetes mellitus is projected to increase to over 3% of the of Type 2 Diabetes world’s population (≈220 million people) by the year 2010. Globally, 97% of Mellitus patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed.

Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at $US91.8 billion (70% of total costs) and indirect costs at $US39.8 billion (30%), for a total of $US132 billion. Data from more than 7000 patients in eight European countries indicate that the mean cost per patient with diabetes was $US2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications.

Clinical Profile of Repaglinide

Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5–4mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks’ duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75–15 mg/day and better glycaemic control than glipizide 5–15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy.

Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3–6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60–120mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year.

Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting.

The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2–2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy.

Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible.

Pharmacoeconomic Analyses of Repaglinide

Two US cost analyses have been conducted with repaglinide in patients with type Analyses of Repaglinide 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin ($US8924) than for patients who received metformin only ($US9448), metformin plus glibenclamide ($US9576) or repaglinide only ($US11 910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA1c level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from $US6106 with glipizide gastrointestinal therapeutic system (GITS) to $US9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy.

Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. Two US analyses, conducted from the perspective of Medicare, showed that combination therapy including repaglinide was a dominant treatment strategy over comparator regimens. One analysis compared repaglinide plus rosiglitazone versus rosiglitazone, the other compared repaglinide plus metformin versus nateglinide plus metformin. Both used a similar model that projected lifetime costs and clinical outcomes (e.g. QALYs attained) discounted at an annual rate of 3%. Long-term complications were projected using data on HbA1c level changes from short-term clinical trials. The third analysis, conducted in Canada from a third-party payer perspective, showed a favourable incremental cost-effectiveness ratio of <$US1000 per QALY gained (2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. This study also used a lifetime time horizon but a higher discount rate of 5% annually. Long-term complications were projected from short-term clinical trial data on changes in PPBG levels. All three cost-effectiveness analyses attributed the favourable results with repaglinide-containing regimens primarily to projected reductions in cardiovascular complications.

A degree of caution must be used when interpreting results of economic analyses with repaglinide. Since the cost-effectiveness analyses have not yet been fully published, many aspects of the study methodology are not readily available. Moreover, with respect to modelled cost-effectiveness analyses in general, there is always a degree of uncertainty when projecting long-term costs and clinical outcomes from short-term clinical trial data. In addition, all analyses have been conducted in the US or Canada, and it is unclear whether the favourable results with repaglinide-containing regimens observed in North American analyses also apply to Europe and other areas. Nevertheless, economic analyses of repaglinide appeared to use well accepted study methods. For example, in the absence of longterm prospective comparative data on the development of cardiovascular and other diabetic complications with repaglinide and other antidiabetic agents, standard modelling techniques were used in most studies.