Repaglinide: Characteristics, Mechanism, and Use in Type 2 Diabetes Mellitus

Repaglinide is an oral medication for type 2 diabetes mellitus that improves blood sugar control with diet and exercise. Learn about its dosage, interactions, side effects, and precautions before taking it.

Characteristics of repaglinide and its mechanism of action on insulin secretion

Sixty subjects with glycated hemoglobin (HbA1c) < 10.0% were randomly selected to receive repaglinide or metformin monotherapy for 15 weeks. Blood glucose levels, glycemic variability, β-cell function, and first-phase insulin secretion were compared between these 2 groups at baseline and at 15 weeks. Mouse insulinoma (MIN-6) cells were divided into 3 groups: low glucose, high glucose, and repaglinide 50 nm groups. Cells and cell culture mediums were collected at different timepoints. The expression of pericentrin (PCNT), F-actin, and insulin were tested with immunofluorescence and enzyme-linked immunosorbent assay.All glycemic parameters and variability indexes significantly decreased from baseline to 15 weeks, while no significant difference was found between these 2 groups at baseline or at 15 weeks. Furthermore, there was no significant difference found in fasting insulin and postprandial insulin at baseline and at 15 weeks, while homeostasis model assessment β significantly increased. The first-phase glucose and insulin secretion of the intravenous glucose tolerance test improved in both groups, especially in the repaglinide group. Insulin, PCNT, and F-actin expression in MIN-6 cells decreased after 15 minutes of stimulation with repaglinide, while no difference was observed at 2, 6, and 12 hours. The insulin levels of the cell medium in the repaglinide group remained significantly higher at all timepoints.[1]

Repaglinide, one of the nonsulfonylurea insulin secretagogues, belongs to the meglitinide class, which has a benzoic acid structure. Sulfonylurea receptors (SURs) are a subunit of the ATP-sensitive K+ channel that repaglinide may close, thereby inducing subsequent Ca2+ influx through voltage-gated Ca2+ channels, followed by the exocytosis of Ca2+-dependent insulin granules. The mechanism of repaglinide is similar to sulfonylureas. However, repaglinide exhibits distinct pharmacologic properties in terms of structure, binding profile, duration of action, and mechanisms of excretion. Several studies have demonstrated that Ca2+ elevation activates multiple pathways for the disruption of the cytoskeleton, which may lead to the attenuation of insulin granule mobility. Sulfonylureas (Sus) bind tightly to SURs and exhibit delayed onset and prolonged hypoglycemic effects. Glinides bind to a site at the β-cell membrane that is distinct from the binding site of sulfonylureas. Compared to sulfonylureas, glinides display anti-hyperglycemic activity that is more rapid and shorter. Furthermore, repaglinide has been considered to reduce postprandial glucose levels by enhancing the early phase of insulin secretion and increasing the total amount of insulin secreted.

The most interesting finding was that although repaglinide could increase the 1st-phase insulin secretion, no statistically significant difference could be found between these 2 groups in the end. Deeper MIN-6 cell research revealed that insulin level, PCNT level, and F-actin level decreased at 15 minutes after the intervention, but these did not decrease further after 12 hours, and these did not recover. Furthermore, insulin level, PCNT level and F-actin level exhibited positive relationships in MIN-6 cells.The number of docked insulin granules was decreased after the 1st repaglinide stimulation, despite the later recovery period, suggesting that repaglinide may affect the intracellular motility of insulin granules and their recruitment to the plasma membrane. The investigators assumed that the decrease in PCNT and F-actin induced by repaglinide would affect the exocytotic process, which is probably involved in the regulation of insulin granule motility. This may also explain why repaglinide could not increase insulin secretion without limitations in the later phase. Regulating insulin secretion on demand could effectively prevent hypoglycemia, improve glucose variation, and subsequently protect the vessels.In conclusion, repaglinide does not continue to stimulate the secretion of insulin. This is likely to be one of the important reasons by which repaglinide secretes insulin on-demand. The PCNT-F-actin pathway also plays an important role in the process of the repaglinide regulation effect on insulin secretion.

Use in Type 2 Diabetes Mellitus

Repaglinide, 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.[2]

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.

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.

References

[1]Wang LC, Fang FS, Gong YP, Yang G, Li CL. Characteristics of repaglinide and its mechanism of action on insulin secretion in patients with newly diagnosed type-2 diabetes mellitus. Medicine (Baltimore). 2018 Sep;97(38):e12476. doi: 10.1097/MD.0000000000012476. PMID: 30235745; PMCID: PMC6160250.

[2]Plosker, Greg L, and David P Figgitt. “Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.” PharmacoEconomics vol. 22,6 (2004): 389-411. doi:10.2165/00019053-200422060-00005

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