Meglitinides

Meglitinides belong to a novel group of insulinotropic agents known as the non-sulfonylurea insulin secreta-gogues (Malaisse 1995). Repaglinide, a benzoic acid derivative, is one of the meglitinide analogues that recently became available. Like sulfonylureas, the insulinotropic effect is mediated through the ATP-regu-lated potassium channels but via different binding sites on the beta-cells (Balfour and Faulds 1998; Fuhlendorff 1998). After oral administration, repaglinide is quickly absorbed from the gastrointestinal tract. The maximum plasma concentrations are reached within 0.8 h and the drug is rapidly eliminated with an approximate half-life of one hour (Novo Nordisk 1997). However, the wide variability of the half-life of re-paglinide elimination kinetics, ranging between 0.5 h and 8 h is a concern.

Its pharmacokinetic profile makes repaglinide a suitable agent for targeting post-prandial hyperglyce-mia (Mooradian and Thurman 1999). It is completely metabolized by the liver and some 90% is excreted by the biliary route with only 8% in the urine (Novo Nordisk 1997). When comparing healthy young individuals with people aged 65 years or over, there was no difference in the pharmacokinetic parameters. However, elderly Type 2 diabetic subjects had a significantly higher mean diurnal plasma concentration and a lower clearance than healthy controls (Hatorp et al 1997). Although AUC (area under curve) and Cmax were significantly increased in subjects with various degrees of renal impairment, a dose adjustment was not necessary. However, the authors recommended a careful and gradual increase in the initial dose (Mar-bury and Hatorp 1998). After a single dose of re-paglinide, patients with moderate to severe liver disease had higher and more prolonged serum concentrations (Hatorp and Haug-Pihale 1998). Although liver disease did not significantly increase the risk of hypoglycemic episodes in the latter study, the safety of repaglinide is still questionable in this subgroup of patients.

One study has compared a fixed dose of 1 mg or 4 mg of repaglinide pre-prandially with placebo over a 6-month period. In previously treated Type 2 diabetics, HbA1c dropped from 8.4% and 8.2% in the 1 mg or 4 mg group respectively, to 8.2% in both groups, while HbA1c rose from 8.4% to 10% in the placebo group (Berger and Strange, 1998). In this study, hypoglycemic episodes occurred in 11%, 27% and 36% in the placebo, 1 mg and 4 mg groups, respectively. The efficacy of repaglinide was compared with glyburide in a multicenter, randomized, double-blind study. Over one year, the reduction in HbA1c was similar in both groups (Marbury and Strange 1998). When added to metformin in suboptimally controlled diabetes (HbA1c = 8.5%), the HbA1c dropped by 1.4% (Moses, Slobodniuk and Donnelly 1997). Combination therapy achieved better control than either drug alone. As with sulfonylurea agents, weight gain and hypoglycemia were the two most frequent adverse effects. However, there is reduced risk of increased hypoglycemic episodes when a meal is omitted and the repaglinide dose is witheld (Tornier et al 1995).

The potential for reduced risk of hypoglycemia is an interesting feature of this new class of agents, especially in older individuals. However, more studies are needed to define the relative value of these agents. Of concern is the wide range of variability in drug elimination kinetics. In addition, a pre-prandial dosing regimen may be an obstacle to achieving long-term compliance in some individuals. Nateglinide is a new meglitinide which is soon to be marketed and has a faster and shorter duration of insulin secretory activity than repaglinide. Thus, nateglinide pharmacokinetics are more favorable in terms of improving post-prandial hyperglycemia (Hirschberg et al 1999; Kalbag et al 1999). Finally, the real advantage of these relatively costly agents over a small dose of short-acting sulfo-nylurea is still not clear (Mooradian 1998).

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