Oral Antidiabetic Agents - Luzimar Teixeira

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400 Krentz & Bailey Metformin Intestine Fat ↑ Anaerobic glucose metabolism ↑ Glucose uptake and oxidation ↑ Lactate ↓ Fatty acids ↓ Glyconeogenesis ↓ Glycogenesis ↓ Oxidation of FA ↑ Glucose uptake and oxidation ↑ Glycogenesis ↓ Oxidation of FA Liver Muscle ↓ Hepatic glucose production ↑ Insulin-mediated glucose disposal ↓ Blood glucose concentration Fig. 4. Actions of metformin. Inhibition of hepatic glucose production is regarded as the principal mechanism through which metformin lowers blood glucose (reproduced from Krentz and Bailey, [4] with permission from the Royal Society of Medicine Press). FA = fatty acids; ↑ indicates increase; ↓ indicates decrease. nant glucose-lowering mechanism of action of metformin is to reduce excessive rates of hepatic glucose production. Metformin reduces gluconeogene- sis by increasing hepatic sensitivity to insulin (figure 4) and decreasing the hepatic extraction of certain gluconeogenic substrates (e.g. lactate). Hepatic glycogenolysis is also decreased by metformin. In- sulin-stimulated glucose uptake in skeletal muscle is enhanced by metformin. This involves an increase in the movement of insulin-sensitive glucose trans- porter molecules to the cell membrane; an increase in the activity of the enzyme glycogen synthase promotes synthesis of glycogen. Metformin also kinase (AMPK) is a possible intracellular target of metformin. [43] Through phosphorylation of key proteins, AMPK acts as a regulator of glucose and lipid metabolism and cellular energy regulation. [44] Since metformin lowers blood glucose concentrations without causing overt hypoglycaemia it is most appropriately classed as an anti-hyperglycaemic – as distinct from hypoglycaemic – agent. The clinical efficacy of metformin in patients with type 2 diabetes requires the presence of insulin. The drug does not stimulate insulin release and a small decrease in fasting insulin concentrations is typically observed in patients with hyperinsulinaemia. [21] The predomi- © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 401 acts in an insulin-independent manner to suppress other class of oral antidiabetic agent or with insulin. oxidation of fatty acids and to reduce triglyceride The drug is contraindicated in patients with imlevels in patients with hypertriglyceridaemia. [19] paired renal function (i.e. serum creatinine This reduces the energy supply for hepatic gluco- >120–130 µmol/L, depending on lean body mass), neogenesis and has favourable effects on the glu- as a precaution against drug accumulation. Cardiac cose-fatty acid (Randle) cycle (in which fatty acids or respiratory insufficiency, or any other condition are held to compete with glucose as a cellular energy predisposing to hypoxia or reduced perfusion (e.g. source). [37] Glucose metabolism in the splanchnic hypotension, septicaemia) are further contraindicabed is increased by metformin through insulin-indetions, as well as liver disease, alcohol abuse and a pendent mechanisms. This may contribute to the blood glucose-lowering effect of the drug, and in history of metabolic acidosis. Metformin can be turn may help to prevent gains in bodyweight. Coland other exclusions are not present. A difficulty in used in the elderly, provided that renal insufficiency lectively, the cellular effects of metformin serve to counter insulin resistance and to reduce the putative practice is that significant renal dysfunction may be toxic metabolic effects of hyperglycaemia (glucose present without the aforementioned elevation of se- toxicity) and fatty acids (lipotoxicity) in type 2 rum creatinine. diabetes. The improvement in insulin sensitivity can cause ovulation to resume in cases of anovulatory polycys- 3.1.2 Pharmacokinetics tic ovary syndrome (PCOS) [an unlicensed applica- Metformin is a stable hydrophilic biguanide that tion of the drug in the absence of diabetes]. [45] is quickly absorbed and eliminated unchanged in the Metformin should be taken with meals or immedurine. It is imperative that metformin is only preiately before meals to minimise possible gastrointesscribed to patients with renal function that is suffitinal adverse effects. Treatment should be started cient to avoid accumulation of the drug. Renal clearwith 500 or 850mg once daily, or 500mg twice daily ance of metformin is achieved more by tubular secretion than glomerular filtration, the only signif- (one tablet with the morning and evening meals). icant drug interaction being competition with cime- The dosage is increased slowly – one tablet at a time tidine, which can increase plasma metformin conof – at intervals of about 2 weeks until the target level centrations. There is little binding of metformin to glycaemic control is attained. If the target is not plasma proteins. Metformin is not metabolised, and attained and an additional dose produces no greater so does not interfere with the metabolism of co- effect, return to the previous dose and, in the case of administered drugs. Metformin is widely distribut- monotherapy, consider combination therapy by aded, high concentrations being retained in the walls of ding in another agent (e.g. a sulphonylurea, prandial the gastrointestinal tract; this provides a reservoir insulin releaser or thiazolidinedione). The maximal from which plasma concentrations are maintained. effective dosage appears to be about 2000 mg/day, Nevertheless, peak plasma metformin concentragiven in divided doses with meals, the absolute tions are short-lived: in patients with normal renal maximum being 2550 or 3000 mg/day in different function the plasma half-life (t 1 /2) for metformin is countries. Several single tablet combinations of a 2–5 hours, and almost 90% of an absorbed dosage is eliminated within 12 hours. [40] sulphonylurea (usually glibenclamide) with a biguanide (metformin or phenformin) have been available 3.1.3 Indications and Contraindications in some European countries and elsewhere for more Metformin is the therapy of choice for overformin than a decade. A slow-release formulation of metweight and obese patients with type 2 diabetes. [42] It and a fixed-dose combination of metformin can be equally effective in normal weight patients. with glibenclamide is available in the US Metformin can also be used in combination with any (Glucovance ® , Bristol-Myers Squibb Company, © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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