Oral Antidiabetic Agents - Luzimar Teixeira

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402 Krentz & Bailey Princeton, NJ, USA) 1 and elsewhere (although not secretion. Indeed, the reduction of basal insulin conin the UK). A combined rosiglitazone/metformin centrations, notably in hyperinsulinaemic patients, (Avandamet ® , GlaxoSmithKline, Philadelphia, PA, should itself improve insulin sensitivity by relieving USA) [see section 3.2] preparation is also available the insulin-induced downregulation of insulin recepin some parts of the world. tor number and suppression of post-receptor insulin During long-term treatment with metformin it is pathways. [35] Bodyweight tends to stabilise or deadvisable to check (e.g. annually) for the developprovements crease slightly during metformin therapy. Small imment of contraindications, particularly an elevated in the blood lipid profile may be observ- serum creatinine concentration (yearly measurement ed in hyperlipidaemic patients; plasma concentra- of creatinine clearance posing practical difficulties). tions of triglycerides, fatty acids and low-density Metformin can reduce gastrointestinal absorption of lipoprotein (LDL)-cholesterol tend to fall, whereas cyanocobalamin (vitamin B12). While anaemia is cardioprotective HDL-cholesterol tends to rise. very rare, an annual haemoglobin measurement is These effects appear to be independent of the antiprudent in patients at risk of nutritional deficiencies. hyperglycaemic effect, although a lowering of trig- It is advised to stop metformin treatment temporariinsulin lyceride and free fatty acids is likely to help improve ly during use of intravenous radiographic contrast sensitivity and benefit the glucose-fatty acid media, surgery and any other intercurrent situation cycle. in which the exclusion criteria could be invoked. [46] In the UKPDS, overweight patients who started Substitution with insulin may be appropriate at such oral antidiabetic therapy with metformin showed a times. Metformin alone is unlikely to cause serious statistically significant 39% reduced risk of myocarhypoglycaemia, but hypoglycaemia becomes an is- dial infarction compared with conventional treatsue when metformin is used in combination with an ment (p = 0.01). [47] No clear relationship is evident insulin-releasing agent or insulin. between metformin dosage and decreased coronary artery events. This suggests that patients who can 3.1.4 Efficacy only tolerate a low dosage of metformin may benefit The long-term blood glucose-lowering efficacy from continuing the drug, even when other agents of metformin is broadly similar to sulphonylureas. have to be added to optimise glycaemic control. The As monotherapy in patients who are not adequately decrease in myocardial infarction observed with controlled on nonpharmacological therapy, optimal- metformin therapy in the UKPDS was not attributaly titrated metformin therapy typically reduces fast- ble to more effective lowering of HbA1c or major ing plasma glucose by 2–4 mmol/L, corresponding effects on classic cardiovascular risk factors such as to a decrease in HbA 1c by approximately 1–2%. [40] plasma lipids. Consequently, other potentially The effect is dependent upon the presence of some vasoprotective effects of metformin have been inendogenous β-cell function, and is largely indepen- voked. Reported benefits of metformin on non-clasdent of bodyweight, age and duration of diabetes. sic cardiovascular risk factors (table V) include in- However, given the progressive nature of type 2 creased fibrinolysis and a reduced concentration of diabetes, re-assessment of dosage and consideration the anti-thrombolytic factor plasminogen activator of additional therapy are required to maintain gly- inhibitor-1 (PAI-1). [41,46] The mechanism of the caemic control in the long term. [4,21] Metformin has cardioprotective effects of metformin remains unseveral features that mark it out as a good choice for certain. Detracting somewhat from this generally first-line monotherapy. The anti-hyperglycaemic ac- favourable view was evidence of an initially greater tion of metformin means that it is unlikely to cause mortality when metformin was added to a sulphonysevere hypoglycaemia. This may be explained in lurea in a UKPDS substudy, [47] but longer-term folpart because metformin does not stimulate insulin low-up has shown the benefits of metformin to be 1 The use of trade names is for product identification purposes only and does not imply endorsement. © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 403 sustained. [48] The explanation may have been, at least in part, a spuriously low mortality rate in the comparator sulphonylurea monotherapy group. [47,49] The small number of events in this substudy adds to the uncertainty. Sulphonylurea plus metformin is a commonly used combination and it would be reassuring to have definitive safety data. Since each class as monotherapy appears safe from the cardiovascular perspec- tive, alternative explanations have been postulated to explain similar findings seen in observational studies. [49] One plausible confounder might be greater cardiovascular risk attributable to more severe metabolic derangements in patients treated with the combination. Results from US trials and various large databases of follow-up with sulphonylurea plus metformin combination therapy have been reassuring. [21,49,50] Additional well designed compara- tive studies of appropriate statistical power would be required to quantify the risk to benefit equation for combination treatment with sulphonylurea plus metformin. However, recent results from the 5-year follow-up of UKPDS – with no further attempt to continue in randomised groups – show that the adverse impact of sulphonylurea plus metformin combination seen initially is no longer evident. [48] At this point, the aforementioned benefits observed on mortality and cardiovascular disease in overweight patients initially randomised to metformin monotherapy, while diminished, remained significant. Consistent with the action of metformin on insulin sensitivity, addition of metformin to patients receiving insulin therapy may necessitate a reduction of insulin dosage. Some patients also show an improvement in glycaemic control, although this is not always impressive. Metformin reduces the weight gain associated with insulin therapy and, by decreasing the insulin dosage, there may be a decrease in hypoglycaemic episodes. The regimen has usually involved once-daily bedtime long-acting (lente) insulin or twice-daily insulin suspension isophane with metformin at mealtimes. In the US Diabetes Prevention Program, metformin reduced the incidence of new cases of diabetes in overweight and obese patients with impaired glucose tolerance by 33% overall. This compares with an intensive regimen of diet and exercise, which reduced the risk by 58%. [51] Younger, more obese individuals showed the most response to the preventive effects of metformin. 3.1.5 Adverse Effects Abdominal discomfort and other gastrointestinal adverse effects, including diarrhoea, are encountered fairly commonly during the introduction of metformin. Symptoms may remit if the dose is reduced and re-titrated slowly, but about 10% of patients cannot tolerate the drug at any dose. The most serious feared adverse event associated with metformin is lactic acidosis; the occurrence is rare (about 0.03 cases per 1000 patient-years), but the mortality rate is high. [14,38] Since the background incidence of lactic acidosis amongst type 2 diabetic patients has not been established, it is possible that a proportion of cases that have been attributed to the drug were caused by other factors; this remains an area of controversy. Most cases of lactic acidosis in patients receiving metformin are due to inappropriate pre- scription of the drug. [23,40,46,52] The leading contraindication is renal insufficiency. [52] Metformin increases glycolysis to lactate, particularly in the splanchnic bed. The situation will be aggravated by any hypoxic condition or impaired liver function. [53] Hyperlactataemia occurs in cardiogenic shock and other illnesses that decrease tissue perfusion, and metformin is often only an incidental factor in these cases. [54] In the absence of reliable data to the con- trary, metformin treatment should be stopped immediately in all cases of suspected or proven lactic acidosis, regardless of cause. Lactic acidosis is typically characterised by a raised blood lactate concentration (e.g. >5 mmol/L), decreased arterial pH and/ or bicarbonate concentration with an increased ani- on gap ([Na + ] – [Cl – + HCO3 – ] >15 mmol/L). Presenting symptoms are often nonspecific, but fre- quently include hyperventilation, malaise and abdominal discomfort. Treatment should be commenced immediately without waiting to determine whether metformin is a cause; bicarbonate remains the therapy of choice but evidence of its efficacy is scanty. The value of haemodialysis in removing accumulat- © 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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Page 27: Oral Antidiabetic Agents 411 46. Ho

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