Oral Antidiabetic Agents - Luzimar Teixeira

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 bigua-
nide (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)