Oka5648 nps radar august 07
Pioglitazone (Actos) for type 2 diabetes mellitus
The TGA advise that long-term use of pioglitazone may increase the risk of bladder cancer.
See the August 2011 In Brief.
Pioglitazone improves glycaemic control but it is unclear whether it improves diabetes-relatedclinical complications and mortality. Prescribers should consider this — along with recentlyemerging safety information — when assessing the ratio of potential harms and benefitsfor each patient.
Consider pioglitazone after other oral antidiabetic agents have been tried.
It can be considered when:
either metformin or a sulfonylurea is contraindicated or not tolerated.
combination therapy with metformin and a sulfonylurea fails to provide adequateglycaemic control.
Insulin should also be considered instead of pioglitazone in these scenarios.
Pioglitazone is currently approved as combination therapy in patients with type 2 diabetesthat is inadequately controlled with insulin.
Pioglitazone is associated with weight gain, oedema and fluid retention and should not beused in patients with moderate to severe heart failure.
An analysis of data in a clinical trial database has found an increased rate of fractures of thearm, hand and lower leg among women using pioglitazone.
Doses should not be increased until after 8 weeks of treatment, as the full effect of the drugmay not be seen before this time. In clinical trials of glitazone treatment, 25% to 30% ofpatients had no improvement in glycaemic control.
• as triple oral therapy with maximally tolerated doses
of metformin and
Authority required (streamlined)
Pioglitazone is not
listed on the Pharmaceutical Benefits
Pioglitazone can be used in patients with type 2 diabetes
whose blood glucose concentrations are inadequatelycontrolled (HbA1c > 7%) either:
Reason for PBS listing
• as dual oral therapy with metformin or
Pioglitazone was recommended for listing by
when combination therapy with metformin and a
the Pharmaceutical Benefits Advisory Committee
sulfonylurea is contraindicated or not tolerated; or
(PBAC) on a cost-minimisation basis compared with
• as dual therapy with insulin in patients with
rosiglitazone.1 The indication was extended to include
type 2 diabetes when HbA1c is > 7% despite
triple oral therapy on a cost-minimisation basis compared
concomitant use of insulin plus metformin or
a sulfonylurea, or insulin alone where metforminis contraindicated.
Place in therapy
Pioglitazone’s effect on morbidity
and mortality is unclear
Pioglitazone is a thiazolidinedione (‘glitazone’)antidiabetic drug that should be considered
Most clinical trials of pioglitazone have measured
a third-line choice. Metformin (or, when this is
surrogate outcomes such as effects on lipids or insulin
contraindicated, a sulfonylurea) is usually the drug
sensitivity over a period of 26 weeks or less. They did
of first choice for type 2 diabetes. When combination
not attempt to investigate whether pioglitazone alters
therapy is required, metformin and a sulfonylurea
the natural progression of diabetes.
is the combination of first choice. Pioglitazone can
Only one study (the PROspective pioglitAzone Clinical
Trial In macroVascular Events [PROactive] study) has
• monotherapy (with metformin or a sulfonylurea) no
investigated the effect of pioglitazone (in combination
longer controls blood glucose but adding metformin
with existing therapies) on diabetes-related morbidity
or a sulfonylurea is contraindicated or not tolerated.3
and mortality.10 This study randomised 5238 patients withtype 2 diabetes and a history of cardiovascular disease
• the combination of metformin and a sulfonylurea
(except those with heart failure of New York Heart
no longer adequately controls blood glucose levels.
Association [NYHA] Class II or above) to pioglitazone
Insulin should also be considered instead of pioglitazone
or placebo. It reported a significant improvement in a
secondary endpoint of all-cause mortality, myocardial
Pioglitazone (15–45 mg/day) decreased HbA
infarction and stroke. However, as the primary endpoint*
a further 0.6% to 1.7% when added to treatment
did not reach significance, and the secondary endpoint
with metformin, a sulfonylurea, or insulin compared
was not defined in the original protocol, this could be
with continuing monotherapy with these antidiabetic
a chance finding and should be treated cautiously.
agents.4–7 Patients were enrolled in these trials because
A recent meta-analysis pooled individual patient data
they were inadequately controlled on initial monotherapy
from 19 trials of pioglitazone and found a significant
and often had HbA1c approaching 9% and beyond.
increase in the risk of serious heart failure and a
Greater reductions in HbA1c are seen in patients who
significant reduction in the composite endpoint of
have poorer glycaemic control (HbA1c ≥ 9% before
all-cause mortality, myocardial infarction and stroke.11
treatment) than patients with better control
The meta-analysis is limited by the fact that many of the
included trials were not designed to assess cardiovascular
In an unpublished study of patients (n = 299)
risk, and that 80% of the events included in the meta-
inadequately controlled on metformin and a
analysis came from the PROactive study. Furthermore,
sulfonylurea, adding pioglitazone to metformin and
there was no significant reduction in the composite
the sulfonylurea (i.e. triple therapy) decreased HbA
with an active comparator rather than placebo.
Dyslipidaemia is a problem in type 2 diabetesand contributes to the metabolic syndrome.
* The primary endpoint was all-cause mortality, non-fatal myocardial infarction
Pioglitazone increases HDL–cholesterol concentration
(including silent myocardial infarction), stroke, acute coronary syndrome, coronary
and decreases triglyceride concentration.8
or leg revascularisation, or leg amputation.
Lifestyle changes remain important
Pioglitazone is approved for use with insulin
Dietary changes, regular exercise, weight loss
Pioglitazone is approved as combination therapy
and smoking cessation reduce cardiovascular risk
in patients with type 2 diabetes who require insulin.†
factors and improve glycaemic control for people
Pioglitazone (15–30 mg/day) reduced HbA1c by a
with diabetes. If glycaemic control has declined,
further 1% to 1.3% over 16 weeks in patients
assess the patient’s adherence to lifestyle changes
inadequately controlled with insulin.7 Oedema and
as part of your overall review and reinforce their
hypoglycaemia occur more frequently when glitazones
are combined with insulin (see Safety issues).
Metformin with a sulfonylurea is the
Consider initiating insulin rather
combination of first choice
In patients with type 2 diabetes, drug therapy often
The addition of insulin or pioglitazone results in similar
needs to increase over time to maintain glycaemic
improvements in blood glucose levels when this is no
control; 3 years after diagnosis, 50% of patients will
longer adequately controlled by the combination of
require more than one antidiabetic drug, increasing
metformin and a sulfonylurea. In a single head-to-head
trial of pioglitazone and bedtime NPH insulin among
Metformin improves glycaemic control and reduces
people who had failed dual therapy, pioglitazone reduced
the incidence of macrovascular complications and death
HbA1c levels by 1.9% ± 1.5% at 4 months while insulin
among patients with type 2 diabetes.13 The sulfonylureas
reduced HbA1c levels by 2.3% ± 1.5%.16 Follow-up in
improve glycaemic control and reduce the incidence of
this trial was only 4 months, so it is uncertain whether
microvascular complications in diabetes.14
the response to treatment or the safety profile remains
Metformin and a sulfonylurea is the preferred
similar in both groups in the long term.
combination because of evidence that it reduces diabetic
Consider using insulin instead of pioglitazone because:
complications, because it is probably more cost-effective
• insulin reduces the risk of diabetes complications14,
and because clinicians have many years of experience
whereas the effect of pioglitazone (alone or in
combination with other oral antidiabetics) on
What constitutes ‘intolerance’ of metformin
diabetes–related morbidity and mortality is still
Metformin is contraindicated in people with severe
• the long-term safety profile of insulin is better
renal impairment or other risk factors for lactic acidosis.
defined. Many pioglitazone trials are of short duration
It may also cause gastrointestinal adverse effects such
(≤ 1 year). The only completed long-term trial of
as diarrhoea, nausea and abdominal bloating, but these
pioglitazone (in combination with existing therapies)
are often transient and it is not usually necessary to stop
in patients with type 2 diabetes (n = 5238; median
treatment duration 2.8 years) reported significantlyhigher rates of heart failure, oedema and weight gain
Hypoglycaemia is the most common adverse effect
among the pioglitazone group than among those
with sulfonylureas but can be minimised by splitting
or reducing the daily dose. The elderly are at greaterrisk of hypoglycaemia, so shorter-acting agents such
For information on initiating insulin see NPS News 56:
as gliclazide or glipizide are preferred.
Managing hyperglycaemia in type 2 diabetes
Both pioglitazone and the sulfonylureas are associated
Other third-line choices include acarbose, repaglinide
with weight gain so patients should not be switched
(not currently PBS listed), or rosiglitazone.
to pioglitazone because of this adverse effect.
† The alternative glitazone, rosiglitazone should not be initiated in patients already using
insulin because of increased risk of an ischaemic or congestive heart failure event.
Consult the Australian Medicines Handbook
or refer to this review atwww.npsradar.org.au for additional information about contraindicationsand intolerance to metformin.
glitazones may be used cautiously but should be initiatedat the lowest dose.18 Particular care is advised in patients
Pioglitazone should not be used in patients with
who may be predisposed to developing heart failure,
moderate to severe heart failure limiting physical
such as the elderly or those receiving insulin.20
Pioglitazone more than doubles the risk of oedema,
Hypoglycaemia is uncommon with pioglitazone alone
compared with placebo or active comparator.17
but may occur when it is combined with a sulfonylurea
In the PROactive study significantly more patients
or insulin. Adjust the dose of sulfonylurea or insulin to
using pioglitazone developed heart failure, compared
reduce the risk of hypoglycaemia (see Dosing issues).
with those receiving placebo (11% vs 8%, p < 0.0001).10
Report suspected adverse reactions to the Adverse
A consensus statement from the American Heart
Drug Reactions Advisory Committee (ADRAC) online
Association and the American Diabetes Association18
(www.tgasime.health.gov.au) or by using the 'Blue Card'
notes that oedema is more common when glitazones are
distributed with Australian Prescriber. For information
used in combination therapy (around 7% of patients in
about adverse drug reaction reporting, see the
pioglitazone trials) and most likely when glitazones are
used with insulin (12% to 18% when pioglitazone is
The Therapeutic Goods Administration is monitoring
Assess risk factors for heart failure before prescribing
the safety information related to the glitazones and is
glitazones — both medical (e.g. history of heart failure,
currently liaising with sponsors to effect changes in the
myocardial infarction or coronary heart disease; hyper-
product information following recommendations by its
tension; left ventricular hypertrophy; age > 70 years;
expert advisory committees — the Australian Drug
diabetes for > 10 years) and pharmacological
Evaluation Committee (ADEC) and ADRAC.
(e.g. use of NSAIDs or calcium-channel blockers).
Fluid retention, peripheral oedema and the
Prescribers and patients should be alert for symptoms
risk of heart failure
of developing heart failure. Checking weight dailycan provide an early warning of fluid accumulation.
Diabetes is a risk factor for heart disease and congestiveheart failure.18 Glitazones are associated with fluid
Weight gain is a problem
retention and oedema, which could exacerbate existingheart failure or cause it to develop in patients at risk.
Weight gain is associated with all glitazones and is dose
Regulatory agencies recently strengthened warnings
dependent.8 Average weight gains of up to 4 kg were
about heart failure among patients taking pioglitazone.19
seen in clinical trials.4–7,10 Weight gain is more likely whenpioglitazone is combined with sulfonylureas4 or insulin.7
Glitazones should not be used
in patients with
moderate to severe heart failure. In patients who are
Weight continued to increase for as long as data were
asymptomatic or have only mild cardiac insufficiency,
recorded in trials (up to 84 weeks) so studies of longerduration are required to determine whether weight gaineventually plateaus in patients taking a glitazone.8
Refer to this review at www.npsradar.org.au to see the New York Heart
Reinforce lifestyle measures for limiting weight gain
Association grading of heart failure.
Pioglitazone appears to increase the risk
within 1 month.26 If a patient presents with symptoms
of peripheral fractures among women
suggestive of liver disease, this should be seriouslyconsidered and investigated.
An analysis of patient data contained within themanufacturer's clinical trial database found a higher
risk of fracture among women taking pioglitazone
Pioglitazone is metabolised by CYP2C8 and CYP3A4.
than in those taking a placebo or active comparator
While no significant drug interactions have been
(1.9 fractures vs 1.1 fractures per 100 patient–years).
reported to date, no formal pharmacokinetic interaction
Most of these fractures were in the distal upper limb
studies have been conducted.9 Caution is advised if
(forearm, hand, wrist) or lower leg (foot, ankle, fibula
combining pioglitazone with drugs metabolised by
and tibia). No increase in risk of fracture was found
these enzymes. Interactions reported between another
antidiabetic drug, repaglinide, and gemfibrozil27 and
One observational study suggested that the glitazones
trimethoprim28 are mediated via CYP2C8 and could
could cause bone loss among elderly women but not
potentially occur if pioglitazone is used concurrently
Glitazones may cause or
Agents affecting CYP3A4 include erythromycin,
worsen macular oedema
ketoconazole, itraconazole, some ‘statins’(e.g. atorvastatin, simvastatin), calcium-channel
A small number of postmarketing reports have
blockers (e.g. diltiazem, verapamil), St John’s
suggested that there may be an association between
the glitazones and the development or worsening ofdiabetic macular oedema resulting in a decrease in
There is an increased risk of hypoglycaemia when
visual acuity.9,23 Any changes in vision reported by
pioglitazone is combined with sulfonylureas or insulin.
patients taking pioglitazone should be investigated.
Because they induce fluid retention, combining
Remain vigilant for signs of liver toxicity
pioglitazone with NSAIDs carries a theoreticalincreased risk of oedema and heart failure.24
The first available glitazone, troglitazone, was
Consult the Australian Medicines Handbook
withdrawn from the market after reports of liver
product information for more detailed information
toxicity. The risk of liver toxicity appears to be
significantly lower with pioglitazone, but several casereports exist for both pioglitazone and rosiglitazone,including elevated liver enzymes concentrations,
hepatocellular damage, hepatitis and liver failure.8,24,25
The recommended dose of pioglitazone is 15–45 mg/day.
Patients with liver disease (including transaminase
Patients should start at the lower dose of 15 mg/day,
concentrations increased by more than 2.5 times
particularly those at risk of hypoglycaemia.
the upper limit of normal) should not be started
A proportion of patients does not respond to glitazone
therapy with a decrease in fasting plasma glucose
Glitazone-induced liver toxicity is unpredictable.
concentration and/or HbA1c (primary treatment failure).
Liver function tests are recommended before starting
The non-responder rate observed in clinical trials of
a glitazone and every 2 months thereafter. However,
glitazones was 25% to 30%.8 One trial of pioglitazone
monitoring liver function should not be viewed as
30 mg/day specifically divided patients into two groups
always predicting the problem effectively: in some
based on their responsiveness: in those patients who did
cases of troglitazone liver toxicity, normal enzyme
not respond (30 out of 70), the mean HbA1c decreased
concentrations progressed to irreversible liver failure
by only 0.1% after 3 months’ therapy.29
Allow time for response before
Information for patients
Pioglitazone doses should not be increased until
• monitor for weight gain or ankle oedema
8 weeks after initiation of treatment; it has takenbetween 8 and 16 weeks for the full glycaemic
• report any signs indicative of heart failure
response to be seen in most of the glitazone trials
(such as breathlessness during daily activities)
at any given dose. As HbA1c testing is recommended
• report signs of liver toxicity (abdominal pain,
3-monthly in patients whose therapy has changed or
who are not meeting glycaemic goals, this seems an
For more detailed information about pioglitazone,
appropriate point to scrutinise the patient’s response
suggest or provide the Actos consumer medicine
and consider if any modifications to therapy are
necessary. If patients continue to show no effect afterincreasing the dose, pioglitazone should be stopped.
1. Pharmaceutical Benefits Pricing Authority. Therapeutic
7. Rosenstock J, et al. Int J Clin Pract 2002;56:251–7.
20. Delea TE, et al. Diabetes Care 2003;26:2983–9.
relativity sheets. Canberra: Australian Government
8. Diamant M, Heine RJ. Drugs 2003;63:1373–405.
21. FDA Medwatch. Actos (pioglitazone) Tablets. Rockville,
Department of Health and Ageing, 2007.
9. Eli Lilly Australia Pty Ltd. Actos product information
Maryland: Food and Drug Administration, 2007.
10. Dormandy JA, et al. Lancet 2005;366:1279–89.
/Actosmar0807.pdf (accessed 28 August 2007).
11. Lincoff AM, et al. JAMA 2007;298:1180–8.
22. Schwartz AV, et al. J Clin Endocrinol Metab
2. Pharmaceutical Benefits Advisory Committee. November
2007 PBAC outcomes — positive recommendations.
12. Turner RC, et al. JAMA 1999;281:2005–12.
23. European Medicines Agency. Press release: European
Canberra: Australian Government Department of Health
13. UKPDS Group. Lancet 1998;352:854–65.
Medicines Agency: Committee for Medicinal Products
and Ageing, 2007. http://www.healthconnect.gov.au
14. UKPDS Group. Lancet 1998;352:837–53.
for Human Use 11–14 December 2005.
15. DeFronzo RA. Ann Intern Med 1999;131:281–303.
16. Aljabri K, et al. Am J Med 2004;116:230–5.
3. National Institute for Clinical Excellence. Guidance on
17. Richter B, et al. Cochrane Database Syst Rev
/pr/42148405en.pdf (accessed 31 October 2007).
the use of glitazones for the treatment of type 2
24. Anonymous. Prescrire International 2002;11:170–6.
diabetes: Technology Appraisal 63. London:
18. Nesto RW, et al. Circulation 2003;108:2941–8.
National Institute for Clinical Excellence, 2003.
19. FDA Medwatch. Information for Healthcare
_Review_Guidance.pdf (accessed 2 August 2007).
Professionals – Pioglitazone HCl (marketed as Actos,
26. Tolman KG, Chandramouli J. Clin Liver Dis
Actoplus Met, and Duetact). Rockville, Maryland: Food
4. Kipnes MS, et al. Am J Med 2001;111:10–7.
and Drug Administration, 2007. http://www.fda.gov
27. Niemi M, et al. Diabetologia 2003;46:347–51.
5. Einhorn D, et al. Clin Ther 2000;22:1395–409.
28. Niemi M, et al. Br J Clin Pharmacol 2004;57:441–7.
6. Miyazaki Y, et al. Diabetes Care 2001;24:710–9.
29. Satoh N, et al. Diabetes Care 2003;26:2493–9.
Updated March 2008: addition of information on triple therapy.
Updated October 2007: fracture, macular oedema, information about PROactive.
The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence.
Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.
Il Corso, rivolto ad un massimo di 40 partecipanti,è destinato a Medico Chirurgo (Discipline di riferi-mento: endocrinologia, medicina interna, geriatria,malattie metaboliche e diabetologia,nefrologia)collana dei QUADERNI Sede NH Marina Hotel, Molo Ponte Calvi 5, Genova Iscrizione Iscrizione on line sul sito www.etagamma.it La partecipazione, libera e gratuita, sarà garanti
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