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Item #10 

Glitazones and Insulin: A Combination with Known Risks

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, 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.  

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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.

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