Antidiabetics + ACE inhibitors

The concurrent use of ACE inhibitors and antidiabetics normally appears to be

uneventful but hypoglycaemia, marked in some instances, has occurred in a
small number of diabetics taking insulin or sulphonylureas with captopril,
enalapril, lisinopril or perindopril. This has been attributed, but not proved, to be
due to an interaction. The United Kingdom Prospective Diabetes Study Group
(UKPDS) found no differencein the incidence of hypoglycaemia between patients
taking atenolol and those taking captopril. No pharmacokinetic interaction has
been found to occur between spirapril and glibenclamide. Subcutaneous
exenatide has no important effect on the pharmacokinetics of lisinopril, and does
not alter its efficacy.
Clinical evidence
Numerous case reports, small case-control studies, and a pharmacological study
in healthy subjects suggest that ACE inhibitors increase the risk of
hypoglycaemia in patients receiving insulin or oral antidiabetics, and these are
summarised in Table 13.2, (p.472). Conversely several larger casecontrol
studies and two randomised controlled studies have not found a significantly
increased risk of hypoglycaemia with ACE inhibitors, and these are also
summarised in Table 13.2. It is worth highlighting that one of these, the United
Kingdom Prospective Diabetes Study Group (UKPDS), found that the number of
patients experiencing hypoglycaemic attacks did not differ between patients
receiving atenolol 50 to 100 mg daily or captopril25 to 50 mg twice daily for
hypertension.
A brief report states that spiraprildoes not have a pharmacokinetic interaction
with glibenclamide. The manufacturer of exenatide notes that, in a study in
hypertensive patients exenatide 10 micrograms twice daily did not alter the
steady-state AUC or maximum level of lisinopril 5 to 20 mg daily, but it did delay
the time to maximum level by 2 hours. However, exenatide did not alter the
blood-pressure lowering effect of lisinopril.
Mechanism
Not understood. An increase in glucose utilisation and increased insulin
sensitivity have been suggested. Other possibilities (e.g. altered renal function)
are discussed in a series of letters in The Lancet.
There is also an isolated report of persistent severe hypoglycaemia in a nondiabetic patient associated with both captopriland ramipriltherapy. Conversely,
high natural ACE activity has been associated with a higher risk of severe
hypoglycaemia.
Importance and management
This interaction is not well established nor understood, and it remains the subject
of considerable study and debate. However, some cases of severe
hypoglycaemia have undoubtedly occurred due to the use of ACE inhibitors by
diabetic patients. Nevertheless, some authors consider the risk of severe
hypoglycaemia in diabetic patients treated with ACE inhibitors to be very low and
negligible compared with the benefits of this class of drugs in diabetes.

Moreover, some recent guidelines on the treatment of hypertension in diabetes

recommend that all patients with diabetes and hypertension should be treated
with an ACE inhibitor. To be on the safe side, it would be prudent to warn all
patients receiving insulin or oral antidiabetics who are just starting any ACE
inhibitors (although only captopril, enalapril, lisinopril and perindopril have been
implicated) that excessive hypoglycaemia has been seen very rarely and
unpredictably.
The problem has been resolved in some patients by reducing the sulphonylurea
dosage by a half to three-quarters. Subcutaneous exenatide has no important
pharmacokinetic interaction with lisinopril, and would therefore not be expected
to have a pharmacokinetic interaction with any other ACE inhibitor, although this
needs confirmation. A false positive urine ketone test canalso occur with
captopril when using the alkaline-nitroprusside test (Ketodiastix), which may
affect the monitoring of diabetic control.

Antidiabetics + Antimalarials
Hydroxychloroquine. The effect of hydroxychloroquine on diabetic control with
insulinor glibenclamide(glyburide) was investigated in a randomised, doubleblind, placebo-controlled study in 38 patients with poorly controlled type 2
diabetes. The addition of hydroxychloroquine 200 mg three times daily to
insulincaused a significant improvement in the glycaemic profile and the daily
insulindose had to be reduced by about 25%. Patients taking glibenclamidewith
hydroxychloroquine also had a significant improvement in their plasma glucose
levels. One patient receiving insulinand hydroxychloroquine had severe
hypoglycaemia after 2 months of treatment, and it was necessary to drastically
reduce the daily dose of insulin. The authors suggested that hydroxychloroquine
might inhibit insulin degradation or increase glucose utilisation in peripheral
tissues.
Antidiabetics + Azoles; Fluconazole
Fluconazole appears not to affect the diabetic control of most patients taking
sulphonylureas, but isolated reports describe hypoglycaemic coma in one patient
taking glipizide and hypoglycaemia and aggressive behaviour in a patient taking
gliclazide. There is some evidence that the blood glucose-lowering effects of both
glipizide and glibenclamide (glyburide) may be modestly increased. Fluconazole
may cause increases in plasma levels of glimepiride (marked) and nateglinide
(modest).
Clinical evidence
(a) Chlorpropamide
After taking fluconazole 100 mg daily for 7 days, the AUC of single 250-mg doses
of chlorpropamide was increased by 28% in 18 healthy subjects but the

maximum plasma levels and blood glucose levels were unchanged. There was no
evidence of hypoglycaemia.

(b) Glibenclamide (Glyburide)

After taking fluconazole 100 mg daily for 7 days, the AUC of a single 5-mg dose
of glibenclamide was increased by 44% and maximum plasma levels rose by
19% in 20 healthy subjects. The change in blood glucose levels was not
statistically significant but the number of subjects who had symptoms of
hypoglycaemia increased. In another study, a group of 14 postmenopausal
diabetic women with vulvovaginal candidiasis taking either gliclazide or
glibenclamide were given fluconazole 50 mg daily for 14 days. In contrast, none
of the patients in this study developed symptoms of hypoglycaemia and their
glycosylated haemoglobin and fructosamine concentrations were unchanged. No
pharmacokinetic data were reported.
(c) Gliclazide
A group of 14 postmenopausal diabetic women with vulvovaginal candidiasis
taking either gliclazide or glibenclamide were given fluconazole 50 mg daily for
14 days. None of the patients developed symptoms of hypoglycaemia and their
glycosylated haemoglobin and fructosamine concentrations were unchanged. No
pharmacokinetic data were reported. However, a 56-year-old HIV-positive patient
(antiretroviral treatment refused) and type 2 diabetes who had been taking
gliclazide for 2 years was given fluconazole 50 mg daily for 2 weeks for oral
candidiasis, and prophylactic co-trimoxazole (sulfamethoxazole 400 mg and
trimethoprim 80 mg daily). One week after the re-introduction of fluconazole at a
higher dose of 200 mg daily he was hospitalised because of weakness and
aggressive behaviour. His blood glucose level was 2.2 mmol/L and gliclazide was
stopped. He experienced brief loss of consciousness 2 days later while driving his
car, but his condition then improved and neurological symptoms did not recur
during 3 months follow-up without gliclazide treatment. For the possible
contribution of sulfamethoxazole to this interaction, see Mechanism, below.
(d) Glimepiride
A double-blind study in 12 healthy subjects found that fluconazole 400 mg on
day one then 200 mg daily for a further 3 days increased the AUC and peak
plasma level of a single 0.5-mg dose of glimepiride by about 2.5-fold and 1.5fold, respectively. Fluconazole increased the mean elimination half-life of
glimepiride from 2 to 3.3 hours.
(e) Glipizide
After taking fluconazole 100 mg daily for 7 days, the AUC of a single 2.5-mg dose
of glipizide was increased by 49% and their maximum serum levels rose by 17%
in 13 healthy subjects. Although blood glucose levels were lowered the change
was not statistically significant. However, the number of subjects who had
symptoms suggestive of hypoglycaemia increased. A diabetic patient taking
glipizide 2.5 mg three times daily went into a hypoglycaemic coma within 4 days

of starting to take fluconazole 200 mg daily. Her blood glucose levels had fallen
to less than about 0.05 mmol/L. She rapidly recovered when given glucose.
(f) Nateglinide
In a randomised, double-blind, crossover study, 10 healthy subjects were given a
single 30-mg dose of nateglinide on day 4 of a course of fluconazole (given as
400 mg on day one, then 200 mg daily). Fluconazole raised the AUC of
nateglinide by 48% (range 20 to 73%) and increased the nateglinide half-life
from 1.6 to 1.9 hours. Despite these pharmacokinetic changes fluconazole did
not potentiate the blood glucose lowering effects of nateglinide.
It was predicted that thisinteraction may occur with miconazole(which inhibits
the same isoenzymes as fluconazole), but this needs confirmation.
(g) Tolbutamide
After taking a single 150-mg dose and a further 6 doses of fluconazole 100 mg
daily, the AUC of a single 500-mg dose of tolbutamide was increased by about
50%, and the peak plasma levels were raised in 13 healthy subjects. The half-life
of the tolbutamide was increased about 40%. Blood glucose levels remained
unaltered and none of the subjects showed any evidence of hypoglycaemia.
However, the authors caution against extrapolating this finding to diabetic
patients taking tolbutamide regularly
Mechanism
Fluconazole is an inhibitor of the cytochrome P450 isoenzyme CYP2C9, by which
many of the sulphonylureas are metabolised. Inhibition of this isoenzyme leads
to an accumulation of the sulphonylurea and therefore an increase in its effects.
The hypoglycaemia in the patient taking gliclazide and fluconazole may have
been enhanced by sulfamethoxazole, which also inhibits CYP2C9 (see also
sulfonamides (p.506)). The moderate pharmacokinetic changes seen when
fluconazole is given with nateglinide are also thought to be mediated by CYP2C9.
Importance and management
The almost total absence of adverse reports implies that fluconazole does not
usually markedly disturb the control of diabetes in those taking sulphonylureas.
For fluconazole the increased plasma levels of glipizide and glimepiride, and the
single case of severe hypoglycaemia, as well as the hypoglycaemic symptoms
shown by those taking glibenclamide (glyburide) or gliclazide suggest that
patients taking these sulphonylureas in particular should be warned to be alert
for any evidence of hypoglycaemia. However, there seems to be no reason for
avoiding concurrent use. Note that in the study of fluconazole with nateglinide a
sub-therapeutic dose was given to healthy subjects, so in clinical practice a
greater blood glucose-lowering effect may possibly occur.
Antidiabetics + Azoles; Itraconazole or Ketoconazole
(b) Ketoconazole
After an overnight fast and breakfast the next morning, 7 healthy subjects were
given a single 500-mg dose of tolbutamidebefore and after taking ketoconazole
200 mg daily for a week. Ketoconazole increased the elimination half-life of

tolbutamidemore than threefold (from 3.7 to 12.3 hours) and increased its AUC
by 77%. Ketoconazole increased the blood glucose-lowering effects of
tolbutamideby about 10 to 15%, and 5 of the subjects experienced mild
hypoglycaemic symptoms (weakness, sweating and a reeling sensation) at about
2 hours after the dose.
Ketoconazole 200 mg for 5 days increased the AUC and maximum plasma levels
of a single 2-mg dose of repaglinideby 15 and 8%, respectively, in healthy
subjects. Ketoconazole 200 mg twice daily for 5 days increased the AUC of a
single 8-mg dose of rosiglitazoneby 47% in 10 healthy Korean subjects. The US
manufacturer refers to a 7-day study in which ketoconazole 200 mg twice daily
modestly increased the AUC of pioglitazone.

Mechanism
The modest changes in repaglinide pharmacokinetics with ketoconazole and
itraconazole may be because repaglinide is metabolised by both CYP2C8 and
CYP3A4, and one pathway may have the capacity to compensate if the other is
inhibited. Similarly, itraconazole modestly affects nateglinide metabolism via
CYP3A4. Although it has been suggested that ketoconazole may inhibit the
metabolism of rosiglitazone via CYP2C8 and CYP2C9, ketoconazole is normally
only considered to be a significant inhibitor of CYP3A4.
Antidiabetics + Azoles; Miscellaneous
Hypoglycaemia has been seen infew diabetics taking tolbutamide, glibenclamide
or gliclazidewhen they were given miconazole. Posaconazole slightly enhanced
the blood glucose-lowering effects of glipizide in healthy subjects, but did not
affect the metabolism of a single dose of tolbutamide. Voriconazole is predicted
to increase the levels of the sulphonylureas. Clotrimazole used intravaginally
appears not to interactwith gliclazide or glibenclamide.
Clinical evidence
(a) Clotrimazole
A group of 15 postmenopausal diabetic women with vulvovaginal candidiasis
taking either gliclazideor glibenclamide(glyburide) were treated with intravaginal
clotrimazole 100 mg daily for 14 days. None of the patients developed symptoms
of hypoglycaemia and their glycosylated haemoglobin and fructosamine
concentrations were unchanged. No pharmacokinetic data were reported.
(b) Miconazole
A diabetic patient taking tolbutamidewas hospitalised with severe
hypoglycaemia about 10 days after starting to take miconazole. In 1983 the
French Commission Nationale de Pharmacovigilance reported 6 cases of
hypoglycaemia in diabetics taking sulphonylureas (5 with gliclazideand one with
glibenclamide(glyburide)), which occurred within 2 to 6 days of miconazole being

started. The same organisation reported a further 8 cases in the 1985 to 1990
period but individual sulphonylureas were not named.
Three other cases of hypoglycaemia (two with gliclazideand one with
glibenclamide) are reported elsewhere, in patients given miconazole up to 750
mg daily. Miconazole has been predicted to interact with nateglinide, see
fluconazole, (p.479)
(c) Posaconazole
A study in 12 healthy subjects found that posaconazole 400 mg twice daily for 10
days had no significant effects on the steady-state pharmacokinetics of
glipizide10 mg daily, but there was a small significant decrease in blood glucose
levels following concurrent use. Glipizidedid not affect the pharmacokinetics of
posaconazole. In a study using tolbutamideas a probe drug for CYP2C9,
posaconazole 200 mg once daily for 10 days had no effect on tolbutamide
metabolism.
Mechanism
Miconazole and voriconazole are inhibitors of the cytochrome P450 isoenzyme
CYP2C9, by which many of the sulphonylureas are metabolised. Inhibition of this
isoenzyme would therefore be expected to lead to an accumulation of the
sulphonylurea and therefore an increase in its efAntidiabetics + Azoles;
Miscellaneous fects, as seen with miconazole. Clotrimazole is probably not
absorbed in sufficient quantities to cause an interaction.
Importance and management
The interaction between miconazole and the sulphonylureas is established and
clinically important, but of uncertain incidence. Concurrent use need not be
avoided but it should be monitored and the dosage of the sulphonylurea reduced
if necessary. Patients should be warned. Information about other sulphonylureas
not cited is lacking but it seems possible that they may interact similarly with
miconazole. Posaconazole slightly enhanced the blood glucose-lowering effects
of glipizide in healthy subjects, but the clinical relevance of this is not known.
Posaconazole does not appear to affect tolbutamide metabolism. The
manufacturers of voriconazole advise increased blood-glucose monitoring in
patients taking sulphonylureas, and until more is known this seems prudent.
Information about intravaginal clotrimazole is very sparse, but it appears not to
interact with gliclazide or glibenclamide, and probably not with any of the other
oral antidiabetics, not least because its absorption from the vagina is very small.
Antidiabetics + Disopyramide
Disopyramide occasionally causes hypoglycaemia, which may be severe. Isolated
reports describesevere hypoglycaemia when disopyramide was given to diabetic
patients taking gliclazide, or metformin and/or insulin.
Clinical evidence, mechanism, importance and management
Disopyramide occasionally and unpredictably causes hypoglycaemia, which may
be severe.1-7 The reasons are not fully understood, but in vitro studies suggest

that disopyramide and its main metabolite may enhance insulin release from the
pancreas.
There is a report of severe hypoglycaemia in an 82-year-old woman with diabetes
who was taking gliclazide, which occurred 6 months after she started
disopyramide 300 mg daily. A further case of hypoglycaemia associated with
disopyramide occurred in a 70-year-old woman who had been taking
metformin500 mg twice daily and insulin62 units daily. Within 3 months of
starting disopyramide 250 mg twice daily her insulindose was reduced to 24
units daily, she stopped taking metforminand was eating substantial snacks to
avoid hypoglycaemia.
The insulin requirements of another patient with type 2 diabetes were markedly
reduced when disopyramide was started. The manufacturers note that patients
at particular risk for hypoglycaemia are the elderly, the malnourished, and
diabetics, and that impaired renal function and impaired cardiac function may be
predisposing factors. They advise close monitoring of blood glucose levels and
withdrawal of disopyramide if problems arise.
This is not simply a problem for diabetics, but certainly within the context of
diabetes the blood glucose-lowering effects of disopyramide may possibly cause
particular difficulties. Although not strictly an interaction,the concurrent use of
disopyramide and antidiabetics should be well monitored because of the
potential for severe hypoglycaemia, as the cases show.
Antidiabetics + Diuretics;Thiazide and related
By raising blood sugar levels, the thiazide and related diuretics can reduce the
effects of the antidiabetics and impair the control of diabetes. However, this
effect appears to be dose related, and is less frequent at the low doses now more
commonly used for hypertension. Hyponatraemia has rarely been reported when
chlorpropamide was given with a thiazide and potassium-sparing diuretic. An
isolated report describes severe hypoglycaemia in a patient taking glibenclamide
(glyburide) shortly after metolazone was started. Voglibose had no important
effect on the pharmacokinetics of hydrochlorothiazide.