Oral Antidiabetic Agents - Luzimar Teixeira

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398 Krentz & Bailey 2.3 Indications and Contraindications breast-feeding are traditionally regarded to be contraindications for all oral antidiabetic drugs, mainly An α-glucosidase inhibitor may be used as because of a lack of safety data rather than evidence monotherapy for patients with type 2 diabetes that is of detrimental effects. inadequately controlled by nonpharmacological measures. Because α-glucosidase inhibitors target 2.4 Efficacy postprandial hyperglycaemia, they can be a useful An α-glucosidase inhibitor can reduce peak confirst-line treatment in patients who have a combinacentrations of blood glucose and reduce interprandition of only slightly raised basal glucose concentraal troughs. Used as monotherapy to patients who tions and more marked postprandial hyperglycomply appropriately with dietary advice, an α- caemia. A recent multicentre clinical trial (STOPglucosidase inhibitor will typically reduce postpran- NIDDM [Study TO Prevent NonInsulin-Dependent dial glucose concentrations by 1–4 mmol/L. The Diabetes Mellitus]) confirmed the utility of acarbose incremental area under the postprandial plasma gluin preventing the transition from impaired glucose cose curve can be more than halved in some individtolerance to diabetes [32] (see section 2.4). Acarbose uals. There seems to be a ‘carry-over’ effect that can be used in combination with other antidiabetic may produce a reduction in basal glycaemia up to agents. When starting therapy with an α-glucosidase 1 mmol/L. The decrease in HbA1c is usually about inhibitor it is said to be important to ensure that the 0.5–1.0%, provided that a high dose of the drug is patient is taking a diet rich in complex carbohytolerated and dietary compliance is maintained. drates, as opposed to simple sugars. Acarbose [33] There may be a trivial alteration in the gastrointestishould be taken with meals, starting with a low dose, nal absorption of other oral antidiabetic agents when for example 50 mg/day, and slowly titrating up over used in combination therapy. In general, the extra several weeks. Monitoring of glycaemic control, benefit to glycaemic control achieved by addition of particularly postprandially, may be helpful. The an α-glucosidase inhibitor to another antidiabetic postprandial action of these agents would not be agent is additive. In the recently published multicenexpected to induce hypoglycaemia, at least when tre STOP-NIDDM trial acarbose reduced the risk of they are used as monotherapy. The maximum dosprogression from impaired glucose tolerance to type age of α-glucosidase inhibitors may be limited by 2 diabetes (relative hazard 0.75; 95% CI 0.63, 0.90; gastrointestinal symptoms; this is certainly our exp = 0.0015). [32] This study randomised 1429 patients perience with acarbose (see section 2.5). Intuitively, with impaired glucose tolerance to acarbose 100mg patients experiencing gastrointestinal adverse efthree times daily or placebo, of whom data were fects with metformin may not be the best candidates available for a modified intention-to-treat analysis in whom to add an α-glucosidase inhibitor. A hisin 1368 patients. Glucose tolerance was determined tory of chronic intestinal disease serves as a – largeusing a 75g oral glucose tolerance test. Intriguingly, ly theoretical – contraindication to acarbose and new cases of hypertension and major cardiac events, other agents in this class. High dosages of acarbose including overt and clinically silent myocardial incan occasionally increase liver enzyme concentrafarction, were also reduced by acarbose therapy. tions, and it is recommended that transaminase con- [34] The latter were not primary endpoints of the study, a centrations are measured at intervals in patients relimitation acknowledged by the investigators. ceiving the maximum dosage (200mg three times [34] The results of ongoing trials using acarbose and daily in the UK, a dosage rarely attained in practice other agents in this class are awaited. for the aforementioned reasons). If liver enzymes [35] are raised, the dosage of acarbose should be reduced to a level at which normal enzyme concentrations 2.5 Adverse Effects are re-established. Alternative causes of hepatic dys- The most common problems with α-glucosidase function should be considered. Pregnancy and inhibitors are gastrointestinal adverse effects. In the © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 399 guanidine derivatives in the 1920s. These early antidiabetic agents were all but forgotten as insulin became widely available and it was not until the late 1950s that three antidiabetic biguanides were reported: metformin, phenformin and buformin. Phen- formin was withdrawn in many countries in the 1970s because of a high incidence of lactic acidosis; buformin received limited use in a few countries, leaving metformin as the main biguanide on a global basis. Metformin is the only biguanide available in the UK and, since 1995, the US. [23,40] Extensive clinical experience with metformin has been com- plemented by favourable results from the UKPDS. Metformin also enjoys the accolade of being among the least expensive of the oral antidiabetic agents. STOP-NIDDM trial 31% of acarbose-treated patients compared with 19% on placebo discontinued treatment early. [32] If the dosage is too high (relative to the amount of complex carbohydrate in the meal), undigested oligosaccharides pass into the large bowel. [23] Carbohydrates fermented by the flora of the large bowel cause flatulence, abdominal discomfort and sometimes diarrhoea. This is most likely to occur during the initial titration of the drug and can sometimes be minimised by slow titration and by ensuring dietary compliance with meals rich in complex carbohydrate. In some patients the gastrointestinal symptoms may gradually subside with time, suggesting an adaptive response within the gastrointestinal tract. Hypoglycaemia is only likely to be encountered when an α-glucosidase inhibitor is used in combination with a sulphonylurea or insulin. [23] No clinically significant drug interations have been reported. However, agents affecting gut motility can potentially influence the efficacy and gastrointestinal effects of acarbose; cholestyramine may increase the glucose-lowering effect of acarbose. 3. Insulin Sensitisers Insulin resistance is a prominent metabolic defect in most patients with type 2 diabetes. [36,37] Defective insulin action is not confined to glucose metabolism, subtle defects also being demonstrable in the regulation of other aspects of intermediary metabolism (e.g. lipolysis), using appropriate investigative techniques. Many cross-sectional and prospective studies have implicated insulin resistance in the pathogenesis of type 2 diabetes and the related metabolic syndrome of cardiovascular risk. [38] Therefore, defective insulin action at target tissue level is an attractive therapeutic target in type 2 diabetes. [39] The biguanides and, in particular, the thiazolidinediones act directly against insulin resistance, and so are regarded as insulin sensitising drugs. 3.1 Biguanides The finding that Galega officinalis (goat’s rue or French lilac), historically used as a traditional treatment for diabetes in Europe, was rich in guanidine led to the introduction of several glucose-lowering 3.1.1 Mode of Action Metformin has a variety of metabolic effects, some of which may confer clinical benefits that extend beyond glucose lowering (table V). However, the molecular mechanisms of metformin have yet to be fully identified. At the cellular level, metformin improves insulin sensitivity to some extent, an action mediated via post-receptor signalling pathways for insulin. [41,42] Recent data have suggested that adenosine 5′-monophosphate-activated protein Table V. Metabolic and vascular effects of metformin Anti-hyperglycaemic action suppresses hepatic glucose output increases insulin-mediated glucose utilisation decreases fatty acid oxidation increases splanchnic glucose turnover Weight stabilisation or reduction Improves lipid profile reduces hypertriglyceridaemia lowers plasma fatty acids and LDL-cholesterol; raises HDLcholesterol in some patients No risk of serious hypoglycaemia Counters insulin resistance decreases endogenous or exogenous insulin requirements reduces basal plasma insulin concentrations Vascular effects increased fibrinolysis decreases PAI-1 levels improved endothelial function HDL = high-density lipoprotein; LDL = low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1. © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Page 1 and 2: Drugs 2005; 65 (3): 385-411 REVIEW
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