Breay W. Paty, MD, FRCPC (biography and disclosures)
Update September 23, 2010:
The FDA has announced severe restrictions on the access to Avandia in the United States. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so. However, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class.
Furthermore, on the same date as the FDA announcement (September 23, 2010), the European Medicines Agency recommended that Avandia be withdrawn from the European market.
In addition, the US agency halted the TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) trial — the head-to-head cardiovascular safety trial of rosiglitazone versus pioglitazone. It was felt that, given the current state of evidence, the study’s outcome would not realistically yield a significant benefit to public health.
Although the evidence of CV risk of Avandia is still not considered conclusive, this action will have the practical effect of severely curtailing the prescribing of Avandia in the United States. These restrictions do not apply to Canada, but given that practice patterns are similar between the two countries, it will likely also have a chilling effect on Avandia prescriptions in Canada.
What I Did Before
Thiazoladinediones, such as rosiglitazone (Avandia®) and pioglitazone (Actos®), have been prescribed commonly in the past decade for the treatment of type 2 diabetes. These agents improve peripheral insulin sensitivity and delay the onset of diabetes in patients at risk. Since their introduction, certain contraindications and side effects have been well known, including worsening heart failure, edema (including macular edema) and weight gain. In the past, I avoided TZDs in anyone with NYHA Class III or IV heart failure, or peripheral or macular edema. Also, if a patient gained more than 10% of their pre-treatment body weight after starting a TZD, I would discontinue the drug. I still adhere to these guidelines, but I have become much more selective in how I prescribe TZDs.
What Changed My Practice
In 2007, a controversial meta-analysis showed a statistically significant increase in myocardial infarction, in patients taking rosiglitazone. Subsequent post-hoc analyses of other large studies, including ACCORD and VADT, failed to confirm this effect. Furthermore, a prospective analysis of the RECORD study showed no increased risk of death or hospitalization for cardiovascular disease (CVD) in patients taking rosiglitazone. However, because most of these studies were not originally designed to examine CV risk in patients taking rosiglitazone, the data is considered inconclusive and the question has not entirely been answered. During this period, another side effect emerged; increased risk of distal bone fractures in women on TZDs. This finding was first observed in the ADOPT trial in 2006 and subsequently seen in other TZD trials. These fractures are uncommon and do not appear to be related to osteoporosis and are not observed in men taking TZDs.
What I Do Now
To summarize: 1) the evidence for CV risk with TZDs is limited and the data is not conclusive; 2) TZDs improve glycemic control; but 3) there are other options for treating diabetes (including insulin). Consequently, my approach to this problem might be characterized as “proceed with caution”. I continue to prescribe TZDs for certain patients, such as younger (<50 years) men, who are failing metformin monotherapy, with A1C levels > 8.5% and no history of heart disease (either CVD or CHF). I avoid TZDs in patients with established CVD or who are at high risk of CVD (≥ 2 non-diabetes risk factors). I no longer prescribe TZDs for patients with any degree of heart failure (NYHA Class I through IV). Furthermore, I do not prescribe TZDs in post-menopausal women, or any woman at risk of fracture (e.g. smoking, family history of fractures, hyperparathyroidism, etc). If I am considering a TZD (usually as a second or third line agent), I discuss the treatment options with my patient, weighing the risks/benefits, including the risks of poor glucose control on microvascular complications. Until more definitive data emerges, I tend to err on the side of caution when it comes to CV risk and diabetes.
References: (Note: Direct article downloads and article requests require a login ID with the BC College of Physicians website)
- The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008; 358: 2545-59. (Article Request Form)
- Duckworth W. Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med 2009; 360: 1-11. (Article Request Form)
- Home PD, Pocock, SJ, Beck-Neilsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomized, open-label trial. Lancet 2009; 373: 2125–35. (Full Article)