Use
Glitazones lower blood glucose and haemoglobin A1c (HbA1c)
in type 2 diabetes mellitus patients who are inadequately con-
trolled on diet alone or diet and other oral hypoglycaemic drugs.
An effect on mortality or diabetic complications has yet to be
established, but they have rapidly become very widely used.
Mechanism of action
Glitazones bind to the peroxisome-proliferating activator
receptor γ (PPARγ), a nuclear receptor found mainly in
adipocytes and also in hepatocytes and myocytes. It works
slowly, increasing the sensitivity to insulinpossibly via effects
of circulating fatty acids on glucose metabolism.
Adverse effects
The first two glitazones caused severe hepatotoxicity and are not
used. Hepatotoxicity has not proved problematic with rosiglita-
zoneorpioglitazone, although they are contraindicated in
patients with hepatic impairment and liver function should be
monitored during their use. The most common adverse effects
are weight gain (possibly partly directly related to their effect on
adipocytes) and fluid retention due to an effect of PPARγrecep-
tors on renal tubular sodium ion absorption. They can also exac-
erbate cardiac dysfunction and are therefore contraindicated in
heart failure. Recently, an association with increased bone frac-
tures and osteoporosis has been noted. They are contraindicated
during pregnancy. A possible increase in myocardial infarction
withrosiglitazonehas been noted, but the data are controversial.
Pharmacokinetics
Bothrosiglitazoneandpioglitazoneare well absorbed, highly
protein bound and subject to hepatic metabolism.
Drug interactions
Glitazones are additive with other oral hypoglycaemic drugs.
They potentiate insulin, but this combination is contraindi-
cated in Europe because of concerns that it might increase the
risk of heart failure, although the combination is widely used
in the USA. Pioglitazoneis an inducer of CYP3A and may
cause treatment failure with concomitantly administered
drugs which are CYP3A substrates (e.g. reproductive steroids).
ACARBOSE
Acarboseis used in type 2 diabetes mellitus in patients who
are inadequately controlled on diet alone or diet and other
oral hypoglycaemic agents. Acarboseis a reversible competi-
tive inhibitor of intestinal α-glucoside hydrolases and delays
the absorption of starch and sucrose, but does not affect the
absorption of ingested glucose. The postprandial glycaemic
rise after a meal containing complex carbohydrates is reduced
and its peak is delayed. Fermentation of unabsorbed carbohy-
drate in the intestine leads to increased gas formation which
results in flatulence, abdominal distension and occasionally
diarrhoea. As with any change in a diabetic patient’s medica-
tion, diet or activities, the blood glucose must be monitored.
290 DIABETES MELLITUS
Key points
Type 2 diabetes mellitus and oral hypoglycaemic agents- Type 2 (non-insulin-dependent) diabetes mellitus is
caused by relative deficiency of insulin in the face of
impaired insulin sensitivity. Such patients are usually
obese. - About one-third of such patients finally require insulin
treatment. This is especially important when they are
losing muscle mass. - The dietary goal is to achieve ideal body weight by
consuming an energy-restricted healthy diet low in
saturated fat (Chapter 27). - Oral hypoglycaemic drugs are useful in some patients as
an adjunct to diet. - Metformin, a biguanide, lowers blood glucose levels
and encourages weight loss by causing anorexia.
Diarrhoea is a common adverse effect. It is
contraindicated in patients with renal impairment,
heart failure, obstructive pulmonary disease or
congenital mitochondrial myopathies because of
the risk of lactic acidosis, a rare but life-threatening
complication. - Acarbose, an α-glucosidase inhibitor, delays the
absorption of starch and sucrose. It flattens the rise in
plasma glucose following a meal and may improve
control when added to diet with or without other
drugs. However, it can cause bloating, flatulence and
diarrhoea associated with carbohydrate malabsorption. - Sulphonylureas (e.g. tolbutamide) and related drugs
(e.g. nateglinide) release insulin from β-cells by closing
ATP-sensitive Kchannels, thereby depolarizing the cell
membrane. They are well tolerated and improve blood
glucose at least initially, but stimulate appetite,
promoting weight gain. They differ from one another
in their kinetics, the longer-acting drugs being
particularly likely to cause hypoglycaemia which can be
severe, especially in the elderly and should not be used
in these patients. - Thiazolidinediones (e.g. pioglitazone, rosiglitazone)
activate PPARγreceptors and increase insulin sensitivity.
They lower blood sugar but cause weight gain and fluid
retention. They are contraindicated in heart failure.
Effects on longevity or complications are unknown.
Case history
A 56-year-old woman with a positive family history of dia-
betes presents with polyuria, polydipsia, blurred vision and
recurrent attacks of vaginal thrush. She is overweight at
92 kg, her fasting blood sugar is 12 mmol/L and haemoglobin
A1C is elevated at 10.6%. She is treated with glibenclamide
once daily in addition to topical antifungal treatment for the
thrush. Initially, her symptoms improve considerably and she
feels generally much better, but after nine months the
polyuria and polydipsia recur and her weight has increased
to 102 kg.
Comment
Treatment with a sulphonylurea without attention to diet
is doomed to failure. This patient needs to be motivated to
take dietary advice, restricting her energy intake and
reducing her risk of atherosclerosis. If hyperglycaemia is still
not improved, metformin (which reduces appetite) would
be appropriate.