Oral Antidiabetic Agents - Luzimar Teixeira

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406 Krentz & Bailey Table VII. Cautions in the use of thiazolidinediones Active liver disease This remains a contraindication to the use of thiazolidinediones even though neither rosiglitazone nor pioglitazone have been associated with troglitazone-like hepatotoxicity. In fact, the latter drugs are under investigation as a potential treatment for nonalcoholic steatohepatitis. In 2004, the US FDA recommendation for 2-monthly monitoring of biochemical liver function tests was relaxed. Instead, periodic biochemical monitoring is now left to the supervising clinician’s discretion Heart failure The precise contraindications differ between countries. In Europe, current heart failure or a history of heart failure are contraindications to thiazolidinediones Insulin treatment Although rosiglitazone and pioglitazone are licensed in the US for use in combination with insulin, caution is required. Concerns about higher rates of heart failure underlie this concern. The European Agency for the Evaluation of Medicinal Products considers insulin therapy a contraindication to the use of thiazolidinediones Pregnancy and breast-feeding Thiazolidinediones are classified as pregnancy category C because of growth retardation in mid-to-late gestation in animal models. These drugs should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Polycystic ovary syndrome Thiazolidinediones can cause ovulation to recommence in women with hyperandrogenism and chronic anovulation; risk of pregnancy According to the EU license, rosiglitazone can be given at a dosage of 4 mg/day in combination with a sulphonylurea, increasing to 8 mg/day (either once daily or in divided doses) in combination with metformin. Pioglitazone can be given as a once-daily dosage of 15mg, increasing to 30mg if necessary (maximum 45mg in the US and Europe). The thera- peutic response varies markedly between patients and it can be difficult to predict those most likely to respond. If no effect is observed after 3 months it is appropriate to consider the patient as a nonresponder and to stop the treatment. Rosiglitazone and pioglitazone can be used in the elderly, provided there are no contraindications. Both drugs may be used in patients with mild-to-moderate renal impairment, although the potential for oedema is a concern. In women with anovulatory PCOS the improvement in insulin sensitivity may cause ovulation to resume during thiazolidinedione therapy. A combination heart failure is contraindicated. The choice of which patients to exclude on the basis of cardiac status varies between the product labelling sheets in the US and Europe. Consensus guidelines from the American Heart Association and the American Diabetes Association have recently been published. [62] Patients treated with a combination of insulin plus thiazolidinedione appear to be at highest risk of oedema, although the absolute rate of cardiac failure is low despite the fact the diabetes is a major risk factor for this complication. [62] The guidelines urge a cautious approach and careful clinical monitoring, especially for patients likely to be at higher risk of cardiac failure. The haemogloblin concentration should be checked before starting a thiazolidinedione, bearing in mind that reductions of up to 1 g/ dL in haemoglobin concentration may occur during therapy. No adverse effects on blood pressure have been noted with the thiazolidinediones, even with the increase in plasma volume; on the contrary, there is some evidence for a modest blood pressure-lowering effect. [63] As a precautionary measure, liver function should be assessed by measuring serum ALT before starting therapy and subsequently at 2-monthly intervals (or, in the US, as judged necessary by the prescribing clinician) during the first year of treatment; thereafter, periodic monitoring of liver function is prudent. Pre-existing liver disease, the development of clinical hepatic dysfunction or elevated ALT levels >2.5 times the upper limit for the laboratory serve as contraindications to thiazolidinediones. However, as mentioned earlier, hepatotoxicity has not been a concern with either rosiglitazone or pioglitazone. Isolated cases of nonfatal hepatocellular damage have been reported; however, the issue is clouded by reports suggesting an intrinsically higher risk of liver failure in patients with type 2 diabetes. Nevertheless, precautionary monitoring of liver function remains advisable. When initiating therapy with rosiglitazone or pioglitazone, blood glucose monitoring and titration of drug dosage should be undertaken while bearing in mind that thiazolidinediones exert a slowly generated anti-hyperglycaemic effect that usually requires 2–3 months to reach maximum effect. © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 407 preparation containing rosiglitazone plus metformin subcutaneous depots increase as new small, insulin- (Avandamet ® ; combining rosiglitazone/metformin sensitive adipocytes are formed. There are proviin strengths 1mg/500mg, 2mg/500mg, 4mg/500mg, sional data to suggest that thiazolidinediones exert a 2mg/1000mg, although not all strengths are avail- range of effects on aspects of the metabolic synable in all countries). drome that might reduce the risk of atherosclerotic cardiovascular disease. [63,65] For example, thiazoli- 3.2.4 Efficacy dinediones have been reported to downregulate Addition of rosiglitazone or pioglitazone to the PAI-1 expression. Thiazolidinediones have also treatment schedule of patients whose glycaemic been reported to decrease urinary albumin excretion control with a sulphonylurea or metformin is subop- to a greater extent than expected for the improvetimal has consistently resulted in significant reduc- ment in glycaemic control and to reduce circulating tions in HbA1c. As judged by the available literature, markers of chronic low-grade inflammation. these agents have similar glucose-lowering effects, Preclinical studies suggesting that treatment of glureducing HbA1c by around 0.5–1.5%. [64] However, cose-intolerant animals with a thiazolidinedione the participants in these clinical trials had known preserved β-cell function have yet to be confirmed diabetes of several years’ duration, the effects of in human studies. In insulin-resistant women with a thiazolidinediones being more apparent when β-cell history of gestational diabetes at high risk of type 2 function is less impaired. While earlier use of thia- diabetes troglitazone reduced the incidence of newzolidinediones may be advantageous, the longer- onset diabetes. [66] Whether thiazolidinediones will term picture requires clarification. Estimates of in- prove more effective than conventional antidiabetic sulin sensitivity and β-cell function (based on ana- agents in reducing the decline in β-cell function in lysis of fasting glucose and insulin concentrations) patients with established type 2 diabetes remains to have indicated that both defects can be improved by be determined, although preliminary data in patients the addition of a thiazolidinedione. [64] The effects on who respond to the drugs have been encouraging. [67] plasma lipids and apoproteins have been the subject Also of considerable interest are the clinical impliof debate. Rosiglitazone can cause a small rise in the cations of the aforementioned effects of thiazoliditotal cholesterol concentration, which stabilises nediones on risk factors for cardiovascular disease. within about 3 months. This is accounted for by a These effects, allied to direct anti-atherogenic acrise in both the LDL-cholesterol and the HDL-cho- tions reported in animal studies, are presently being lesterol, leaving the LDL : HDL-cholesterol ratio studied in clinical trials with cardiovascular endand the total : HDL-cholesterol ratio little changed points. [68] or slightly raised. Pioglitazone generally appears to have little effect on total cholesterol, and has been 3.2.5 Adverse Effects shown to reduce triglyceride concentrations in sev- Rosiglitazone and pioglitazone are generally well eral studies. Both thiazolidinediones reduce the pro- tolerated. As noted in section 3.2.3, caution is adportion of the smaller, more dense (more atherogen- vised in heart disease; in the UK this includes a ic) LDL particles. [64] To date, no prospective com- history of cardiac failure, oedema, anaemia and liver parative studies of the two drugs have been reported function requiring intermittent monitoring in accorand the clinical implications of these changes are dance with the package labelling. If contraindicauncertain. [63] tions arise during treatment, monitoring should be Weight gain, similar in magnitude to sulphonylu- intensified and, if necessary, treatment discontinrea therapy (typically 1–4kg) and stabilising over ued. Hypoglycaemia may occur several weeks after 6–12 months, has been observed during thiazo- adding a thiazolidinedione to a sulphonylurea; selflidinedione therapy. There is some evidence that the monitoring of blood glucose can be helpful in identidistribution of body fat is altered such that visceral fying the point at which the dosage of the sulphonyadipose depots are little changed or reduced, while lurea should be reduced. Since PPARγ is expressed © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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