Actos and Avandia for PCOS

Background on Actos and Avandia

Actos (pioglitazone) and Avandia (rosiglitazone) belong to a class of medications known as thiazolidinidiones or TZDs. A third medication known as Rezulin (troglitazone) is no longer available in the United States. All three of these medications have been approved by the Food and Drug Administration for the treatment of diabetes. The use of Actos and Avandia for PCOS is considered an off label indication.

Because of the risks, TZDs such as Actos and Avandia are no longer recommended for the treatment of PCOS

Why diabetes drugs for PCOS?

There are many reasons why a woman may not ovulate regularly. It appears that some women are resistant to the hormone insulin. Insulin is normally thought of as a hormone that helps regulate blood sugar. Insulin is produced by cells that are located adjacent to the pancreas called the Islets of Langerhans. While this is true, insulin also has many other effects in the body. The ovary has receptors for insulin and thus insulin is capable of modifying hormone production from the ovaries.

The are several conditions that may result in a woman becoming resistant to the effects of insulin. Among these are PCOS (Polycystic Ovary Syndrome), genetics and obesity. When insulin resistance occurs, the body needs a higher level of insulin to accomplish the same tasks. High insulin levels are frequently seen in women with insulin resistance.

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return.

In fact some studies in women with PCOS demonstrated that thiazolidinidiones could be an effective treatment.

Rezulin in PCOS

Rezulin was the first TZD studied. Studies with Rezulin in PCOS patients demonstrated an improvement in some of the hormone abnormalities seen in PCOS.

In 2 other studies, Rezulin either alone or combined with clomiphene citrate induced ovulation in insulin and/or clomiphene-resistant patients with PCOS. Ovulation and pregnancy rate were 83% and 39% in 18 Clomid resistant patients, and in most of the patients, ovulation was achieved with Rezulin alone or in combination with low doses of CC.

Actos in PCOS

More recently, a well designed study using Actos in PCOS patients was published. The Actos study was a randomized, double-blind, controlled trial was to investigate whether Actos was capable of decreasing insulin resistance and the elevated levels of male hormones (androgens) that are common in women with PCOS. The Actos study also sought to determine whether the ovulation rate would improve in women with PCOS.

Forty pre-menopausal women with PCOS were assigned to treatment with either Actos (30 mg/d) or a placebo for three months. The results were very encouraging. The group which took Actos showed a decline in both fasting serum insulin levels and insulin response after giving them a high load of sugar.

This represented an increase in insulin sensitivity. In addition, Actos increased the levels of a protein called SHBG. SHBG binds up the male hormones in the circulation resulting in less “free” male hormones (androgens).

Treatment with Actos was also associated with higher ovulation rates.

Avandia in PCOS

A similar study using Avandia was published in March of 2005. The stated goal of this randomized, controlled, double-blind trial was to learn whether Avandia would improve the ovulation rate and androgen levels in non-obese women with polycystic ovary syndrome (PCOS). An interesting aspect of this study is that women were chosen based on the fact that all laboratory testing for insulin resistance was normal.

100 women with PCOS were enrolled in the study. The women received either 850 mg of Glucophage, 4 mg Avandia, a combination of both treatments, or a placebo twice a day for 6 months.

The results of this Avandia study are interesting. Women given Avandia gained an average of 1 kg (about 2.2 pounds). However, all treatment groups except the placebo group had a significant decline in their waist-to-hip ratio which implies a reduction in insulin resistance. Likewise, systolic blood pressure fell in all actively treated groups but not in those who received placebo.

Avandia and Glucophage treatment resulted in an increase in the number of times the PCOS patients ovulated. The highest rates of ovulation were found in the combined Avandia and Glucophage group and in the Glucophage only group.

The male hormone testosterone decreased significantly with active treatment.

Avandia dose for PCOS

Avandia 4 or 8 mg tablets. Maximum 8 mg daily

Actos dose for PCOS

Actos 15, 30 or 45 mg tablets. Maximum dose 45 mg daily.

Actos and Avandia side effects

Rezulin which is no longer available in the U.S. has been found to cause liver injury, jaundice and very rare cases of liver failure, liver transplants, and death. In early studies, Rezulin was noted to increase the levels of certain blood markers of liver injury (liver enzymes, AST, ALT). The other members of this class have not been found to cause similar problems. In fact, it is when Actos and Avandia were approved by the FDA that Rezulin was removed from the U.S. market. However, due to the close structural similarity of all these medications, it is strongly recommended that all patients undergo regular assessment of liver enzymes.

The incidence of other reported side effects in clinical trials of Actos and Avandia did not differ from that of placebo (sugar pills).

In a small percentage of people, Actos or Avandia may cause fluid retention. Others may notice swelling in the lower extremities during use.

Because of the possible risks, you should not take Actos or Avandia if:

1. You have known liver problems
2. You drink alcohol excessively
3. Heart disease

Patients who develop nausea, vomiting, abdominal pain, fatigue, loss of appetite, dark urine, light colored stools, or yellowing of the whites of the eyes should immediately report these symptoms to us.

Newly reported possible risks of Actos and Avandia

Takeda pharmaceuticals recently performed an analysis of its clinical trial database of Actos with a special focus on fractures, comparing patients treated with Actos or a comparator (either placebo or a different medication). The results suggest that Actos users are at higher risk for fractures. In the analysis, the maximum duration of Actos treatment was up to 3.5 years. There were more than 81 00 patients in the Actos-treated groups and over 7400 patients in the comparator-treated groups. The majority of fractures observed in female patients who received Actos were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia).

Based on their calculations, if 1000 women took Actos for one year, 19 fractures would be expected compared to 11 expected fractures in the comparison group. There was no increased risk of fracture identified in men.

Avandia was shown in a separate study published in the New England Journal of Medicine in May 2007 to possibly be associated with an increase in the risk for myocardial infarction (heart attack) and cardiovascular death. However, the study did not separate diabetics from PCOS patients and incldued both men and women. It is not clear at this time whether PCOS patients have a similar increase in risk.

Actos and Avandia: Effects on pregnancy

Rezulin and Avandia are considered pregnancy category B.

Animal studies in rats and rabbits at very high doses did not result in a higher than expected incidence of birth defects. At extremely high doses, body weights of fetuses were decreased. Postnatal development, attributed to decreased weight was delayed.

Actos is pregnancy category C. Delayed parturition and postnatal development and embryo toxicity (as evidenced by increased post-implantation losses, delayed development and reduced fetal weights) were observed in rats and/or rabbits when given very high doses.

There are no good, well-controlled studies in women. It is recommended that Actos or Avandia be stopped immediately upon the diagnosis of pregnancy.