More type 2 diabetes patients will get a "glitazone" along with insulin, now that Avandia (rosiglitazone) and Actos (pioglitazone) are both APPROVED for use with insulin.
Until now, Actos was the only
glitazone approved for use with insulin. Adding a glitazone to insulin lowers
blood glucose and allows many patients to reduce their insulin dose.
The drawback is that using a
glitazone with insulin might increase the risk of heart failure. Glitazones can
cause edema and lead to or worsen heart failure, especially when used with
insulin.
There has been some discussion about a possible increased risk of congestive
heart failure in patients taking Avandia, especially in combination with
insulin. In February 2001, after reviewing a supplemental New Drug Application
seeking an indication for combination use of rosiglitazone and insulin, the FDA
decided to add new heart failure warnings to Avandia's package insert.
The indication for use with insulin was not approved at this time.1
Now two years later, the FDA has approved the use of Avandia in
combination with insulin based on additional safety data.
Treatment with Avandia has been associated with an increased incidence of
edema and congestive heart failure (CHF). All glitazones can cause fluid
retention, which can exacerbate or lead to CHF. Some suggest that glitazone-induced
peripheral edema and fluid retention is related to increased endothelial cell
permeability.3
The glitazone-induced edema is often unresponsive to diuretic therapy, but
resolves with discontinuation of the drug. The incidence of edema seems to be
similar with Avandia and Actos (4.8% and 5%, respectively).
The incidence of edema is greater when
either drug is used with insulin, and the use of insulin itself has been
associated with CHF. The risk of edema appears to be dose-related
Past clinical studies have shown an
increased incidence of heart failure and other cardiovascular adverse events in
patients on Avandia plus insulin compared to insulin alone.2
In addition, in the fixed dose trials three of ten patients who developed heart
failure on Avandia plus insulin had no known prior evidence of CHF, or
pre-existing cardiac condition.1,2,9
The patients who developed adverse cardiovascular events were generally older
and had diabetes for a longer period of time.
A more recent study
assessing the safety of Avandia plus insulin compared to insulin alone
shows no evidence of an increased risk of cardiovascular adverse events. This
double-blind study was conducted in 220 patients with type 2 diabetes and
chronic renal failure. The patients received either 4 mg or 8 mg of Avandia
plus insulin (n=112) or insulin only (n=108).
Actos was originally thought to be safer than Avandia when used in combination with insulin. Until recently, Actos was the only glitazone to be approved for use with insulin. But in January 2002, the Actos labeling was also revised to include a warning concerning its use with insulin. Also added at this time were clinical data showing a potential increased risk of heart failure when Actos is used in combination with insulin.
Both
Actos and Avandia are now indicated for monotherapy, or in
combination with metformin, a sulfonylurea, or insulin. The original CHF
warnings added to the Avandia labeling in 2001 remain. The revised
package insert also contains additional information from the most recent
Avandia plus insulin trials. The recommended Avandia dose, when used
in combination with insulin, is 4 mg daily.2
Doses above 4 mg daily are not advised.
There is also a precaution that the insulin dose might need to be reduced by 10%
to 25% if hypoglycemia occurs or if FPG concentrations fall below 100 mg/dL. It
is still recommended that Avandia be used with caution in patients at
risk for heart failure. Patients with NYHA Class III and IV heart failure were
excluded from clinical trials of both Avandia and Actos.
Therefore, neither of these drugs should be used in patients with more severe
heart failure.
While oral agents are
effective for treatment of type 2 diabetes, many patients will eventually
progress to insulin therapy at some point. Clinical trials looking at the
effects of rosiglitazone plus insulin have shown that the combination can
produce significant reductions in HbA1c values.10
However, certain patients are not candidates for therapy with the currently
available glitazones. Avandia and Actos should be avoided in
patients with severe heart failure, and those at risk of CHF should be closely
monitored. Advise patients to watch for signs and symptoms of heart failure,
such as shortness of breath, weight gain, edema, fatigue, etc.
Alert patients on Avandia
or Actos to report any sign of heart failure, shortness of breath, edema,
rapid weight gain. Don't give Avandia or Actos to patients with
severe heart failure. Recommend that patients take no more than 4 mg/day of
Avandia if it's being used with insulin.
Advise them to reduce their
insulin dose by 10% to 25% if they develop hypoglycemia.
Anon. Avandia/insulin safety warnings cited in FDA ad letters to GSK.
FDC Reports-"The Pink Sheet." August 6, 2001. pg.3-4. Niemeyer NV, Janney
LM. Thiazolidinedione-induced edema.
Pharmacotherapy
2002;22:924-9. Thomas ML, Lloyd SJ. Pulmonary edema associated with
rosiglitazone and troglitazone.
Ann Pharmacother
2001;35:123-4. Wang CH, Weisel RD, Liu PP, et al. Glitazones and
heart failure. Critical appraisal for the clinician.
Circulation
2003;107:1350-4.
Nichols GA, Hillier TA, Erbey JR, et al. Congestive heart failure in type 2
diabetes.
Diabetes Care
2001;24:1614-19. Raskin P, Rendell M, Riddle MC, et al. A
randomized trial of rosiglitazone therapy in patients with inadequately
controlled insulin-treated type 2 diabetes.
Diabetes Care
2001;24:1226-32.
Source: Diabetes In Control Dot Com.
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