Oral Antidiabetic Agents - Luzimar Teixeira

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396 Krentz & Bailey cell proinsulin synthesis and act via signalling path- daily dosages is a potential disincentive. Repagliways distinct from the KATP channel (figure 2). The nide should ideally be taken about 15–30 minutes short half-life of repaglinide results in enhancement before a meal. Starting with a low dose, for example of the first-phase and early second-phase of insulin 0.5mg before each main meal, the effect on glysecretion that is less sustained than that observed caemic control is monitored and the dosage titrated with sulphonylureas. [27-29] Theoretical benefits on up every 2 weeks to a maximum of 4mg before each cardiovascular outcomes from preferentially target- main meal; if a meal is not consumed the correing the postprandial period remain to be con- sponding dose of repaglinide should be omitted. If firmed. [28,29] It is unclear whether postprandial glycaemic targets are not met, consider early introhyperglycaemia per se is detrimental to the vascular duction of combination therapy (e.g. with metforendothelium or whether closely associated metabol- min). Unlike some sulphonylureas and metformin, ic disturbances, for example dyslipidaemia, are re- repaglinide is suitable for patients with moderate sponsible. Thus, the mechanism of the association renal impairment, although careful upward dose between post-challenge hyperglycaemia and mor- titration and close monitoring is still recommended. tality observed in the multicentre DECODE (Diabe- In contrast with the US, the UK license for nateglites Epidemiology: Collaborative analysis Of Diag- nide currently restricts use to combination therapy nostic criteria in Europe) study is uncertain. [30] Ran- with metformin in patients who do not achieve glydomised trials that are currently in progress should caemic targets with the latter drug as monotherhelp clarify this issue. apy. [29] In the US, nateglinide may also be used as monotherapy or combined with a thiazolidinedione. 1.2.2 Pharmacokinetics Nateglinide should be used with caution in patients Repaglinide is rapidly and almost completely with hepatic disease. absorbed after oral administration, with peak plasma concentrations achieved in about 1 hour. [27] The 1.2.4 Efficacy drug is rapidly metabolised in the liver to inactive Repaglinide (0.5–4mg taken about 15–30 minmetabolites, which are mainly excreted in bile. utes before meals) results in dose-dependent in- When taken about 15 minutes before a meal, repagcreases in insulin secretion with reduced postprandilinide produces a prompt insulin-releasing effect, al hyperglycaemia; a lesser reduction in fasting which is limited to a period of about 3 hours, roughhyperglycaemia is also observed. Overall reductions ly coinciding with the duration of meal digestion. in HbA1c are similar in magnitude to those observed Nateglinide has a slightly faster onset and shorter with sulphonylureas, that is 1–2%. Combined with duration of action, its binding to target receptors metformin, nateglinide reduces HbA 1c by up to lasting only seconds. A 60mg dose of nateglinide 1.5%. taken 20 minutes before an intravenous glucose [28,29] tolerance test restored first-phase insulin release and 1.2.5 Adverse Events lowered glucose concentrations. [28,29] The overall incidence of hypoglycaemic episodes 1.2.3 Indications and Contraindications is lower with repaglinide than with sulphonyureas. Repaglinide may be used as monotherapy in pa- Sensitivity reactions, usually transient, can occur. tients inadequately controlled by nonpharmacologi- Increased plasma levels of repaglinide have been cal measures. Suitable candidates for rapid-acting reported when co-administered with gemfibrozil. A insulin releasers include individuals with irregular small increase in bodyweight can be expected in lifestyles wherein meals are unpredictable or patients starting repaglinide as initial monotherapy, missed. The lower risk of hypoglycaemia associated but there may be little change in weight among with its use makes repaglinide an attractive option patients switched from a sulphonylurea. Nateglinide for some elderly patients, particularly if other agents appears to have little effect on bodyweight when are contraindicated. However, the need for multiple combined with metformin. [29] © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 397 Intestinal lumen Brush border α-Amylase Starch Maltose maltotriose dextrins Sucrose α-Glucosidase inhibitor (acarbose, miglitol, voglibose) Enterocyte Microvillus α-Glucosidase enzymes Villus Fig. 3. α-Glucosidase inhibitors (e.g. acarbose) competitively inhibit the activity of α-glucosidase enzymes in the brush border of small intestinal enterocytes (reproduced from Krentz and Bailey, [4] with permission from the Royal Society of Medicine Press). 2. α-Glucosidase Inhibitors carbohydrate digestion until further along the intestinal tract, in turn causing glucose absorption to be Inhibitors of intestinal α-glucosidase enzymes delayed. The α-glucosidase inhibitors should be takretard the rate of carbohydrate digestion, thereby en with meals containing digestible carbohydrates, providing an alternative means to reduce postprannot monosaccharides; these drugs generally do not dial hyperglycaemia. [31] Acarbose, the first α- significantly affect the absorption of glucose. Since glucosidase inhibitor to be marketed, was introα-glucosidase inhibitors move glucose absorption duced in the early 1990s. Recently, two additional more distally along the intestinal tract they alter agents, miglitol and voglibose, have been introglucose-dependent release of intestinal hormones duced in some countries. [4] The α-glucosidase inhibthat enhance nutrient-induced insulin secretion. Reitors do not cause weight gain, can reduce postpranlease of gastric inhibitory polypeptide, which occurs dial hyperinsulinaemia and have lowered plasma triglyceride concentrations in some studies. [31] Their mainly from the jejunal mucosa, may be reduced by good safety record is a further advantage, but limited α-glucosidase inhibitors, whereas glucagon-like gastrointestinal tolerability has substantially limited peptide-1 (7–36 amide) secretion (mostly from the their use. The relatively high cost of α-glucosidase ileal mucosa) is increased. Overall, α-glucosidase inhibitors is another consideration that has influthrough the attenuated rise in postprandial glucose inhibitors reduce postprandial insulin concentrations enced prescribing. In the UK, acarbose use remains low. levels. [31] 2.1 Mode of Action The α-glucosidase inhibitors competitively inhibit the activity of α-glucosidase enzymes in the brush border of enterocytes lining the intestinal villi (figure 3). High affinity binding prevents these enzymes from cleaving their normal disaccharide and oligosaccharide substrates into monosaccharides prior to absorption. This defers the completion of 2.2 Pharmacokinetics Acarbose is absorbed only to a trivial degree (
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