Oral Antidiabetic Agents - Luzimar Teixeira

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392 Krentz & Bailey Table III. Pharmacokinetic properties of sulphonylureas [19] Sulphonylureas Daily dosage (mg) Duration of action a Activity of metabolites Main route of elimination First generation Chlorpropamide b 100–500 Long Active Urine >90% Tolbutamide c 500–2000 Short Inactive Urine ≈100% Second generation Glibenclamide (glyburide) 2.5–15 Intermediate to long Active Bile ≈50% Glimepiride 1–6 Intermediate Active Urine ≈80% Glipizide 2.5–20 Short to intermediate Inactive Urine ≈70% Gliquidone 15–180 Short to intermediate Inactive Bile ≈95% Gliclazide 40–320 d Intermediate Inactive Urine ≈65% a b c d Long >24h; intermediate 12–24h; short
Oral Antidiabetic Agents 393 be monitored by periodic measurement of HbA1c (or nylurea therapy generally has modest effects on fructosamine if HbA1c is not available). blood lipid profiles, although some studies have noted a small decrease in plasma triglyceride levels 1.1.4 Efficacy – possibly linked to improved glycaemic control – The blood glucose-lowering efficacy of sulpho- and minor increments in high-density lipoprotein nylureas has been evaluated in many retrospective (HDL)-cholesterol. When a sulphonylurea is used in and prospective studies, and from decades of collec- combination with another antidiabetic agent, the tive worldwide clinical experience. When used as glucose-lowering efficacy of the sulphonylurea is monotherapy in patients inadequately controlled by approximately additive to the effect of the other nonpharmacological measures, sulphonylureas can agent. Once again, response is crucially dependent be expected to reduce fasting plasma glucose by an on the presence of adequate β-cell function. Early average of 2–4 mmol/L accompanied by a decrease use of such combination therapy is indicated when in HbA1c of 1–2%. [4,19,21] However, individual re- optimal titration of a single agent does not achieve sponses are variable. Since the hypoglycaemic ef- adequate glycaemic control. fect of sulphonylureas is attributable to increased The combination of two different types of agents insulin secretion, the effectiveness of these drugs is is more likely to achieve glycaemic targets, albeit dependent on adequate β-cell function. The afore- for a variable period of time. If combination therapy mentioned progressive β-cell failure that determines is started at a stage when hyperglycaemia is already the natural history of type 2 diabetes may require an marked (after ‘failure’ of monotherapy), then β-cell increased dosage of sulphonylureas if glycaemic depletion is likely to be advanced. Under these control deteriorates. Rapid and uncontrollable dete- circumstances, oral combination therapy is likely to rioration of glycaemic control during sulphonylurea offer limited benefit and the need for an early move therapy is sometimes termed ‘secondary sulphony- to insulin treatment is usually clear. Since there are lurea failure’. This phenomenon, which is some- occasional exceptions to this rule, a limited trial of thing of a misnomer, occurs in approximately combination oral therapy may be worthwhile. How- 5–10% of patients per annum with suggestions of ever, the temptation to procrastinate unduly on differences in ‘failure’ rates between some com- transferring the patient to insulin treatment should pounds. [21,22] The inability to maintain acceptable be firmly resisted, not least since some patients glycaemic control is common to all sulphonylureas derive rapid symptomatic benefit from insulin therand is held to reflect an advanced stage of β-cell apy. Impending metabolic decompensation, with or failure, that is, it is a reflection of disease progres- without ketosis, mandates immediate insulin treatsion rather than a true failure of therapy. Individuals ment; more severe degrees of decompensation, for who have greater degrees of β-cell reserve usually example obtundation, dehydration, ketosis-assorespond well to sulphonylureas; early use of sulpho- ciated vomiting, necessitates emergency hospitalisanylureas as first-line monotherapy in these patients tion for treatment with intravenous insulin, fluids will produce better blood glucose lowering than late and electrolytes. intervention in patients with severely compromised β-cell function. 1.1.5 Adverse Events The plasma insulin concentrations achieved Hypoglycaemia, usually subclinical or minor but during sulphonylurea therapy do not usually extend occasionally life threatening, is the most common beyond the range observed in the general non-diabe- and potentially most serious adverse effect of sultic population (including those with impaired glu- phonylurea therapy. [23] Patients receiving sulphocose tolerance), and suggestions that sulphonylurea- nylureas should receive instruction on the recogniinduced hyperinsulinaemia might increase the risk tion and prevention of hypoglycaemia and the of detrimental insulin-induced effects on the cardio- prompt actions they must take should warning vascular system remain unsubstantiated. [12] Sulpho- symptoms develop. Severe protracted hypogly- © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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