Are Thiazolidinediones (TZDs) Safe?

Pharmacology Watch

In this issue: Are thiazolidinediones safe? New study shows Zometa reduces risk of hip fractures and improves survival; Merck HIV vaccine proven ineffective in clinical trials; no causal association found between exposure to mercury from thimerosal; and FDA approvals.

There's no hotter topic in medicine right now than the safety of the thiazolidinediones (TZDs) rosiglitazone (Avandia) and pioglitazone (Actos). Several meta-analysis have pooled data from multiple clinical trials and come to different conclusions regarding the safety of the drugs. The September 12 issue of JAMA contained two papers, both meta-analysis, the of first which suggests that pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. An increase in heart failure was noted, although no increase in mortality (JAMA 2007; 298:1180-1188).

The second paper looked at rosiglitazone and noted that in patients with impaired glucose tolerance or type 2 diabetes, use of rosiglitazone for at least 12 months was associated with a significantly increased risk of myocardial infarction and heart failure, again without a significant increase risk of cardiovascular mortality (JAMA 2007; 298:1189-1195). This followed on conflicting meta-analysis regarding the risk of rosiglitazone published in the New England Journal of Medicine in June and July, the first of which suggested the rosiglitazone was associated with an increase risk of myocardial infarction and increased risk of death from cardiovascular causes (NEJM 2007; 356:2457-2471), while the second showed an increased risk of heart failure but no increased risk of myocardial infarction or death from cardiovascular causes (NEJM 2007;357:28-38). The studies led to congressional hearings, multiple editorials in medical journals and eventually led the FDA to recommend black box warnings regarding the risk of heart failure for both drugs in July. But despite cries from consumer groups suggesting that this was the Cox-2 debacle redux, the FDA stopped short of taking rosiglitazone off the market. The most recent entry into the fray is a new meta-analysis from the Lahey Clinic in Boston. This review analyzed over 3000 studies of which 7 were used for the analysis—all randomized double-blind clinical trials of drug-related congestive heart failure in prediabetic or diabetic patients given either rosiglitazone or pioglitazone. In over 20,000 patients, 360 had congestive heart failure, 214 on TZDs and 146 on comparators. As with other studies there was an increase risk of heart failure associated with both drugs (relative risk 1.72, 95% CI 1.21-2.24, P= 0.002), but again no increase in cardiovascular death was noted with either drug (RR 0.93). The authors suggest that TZDs cause worsening heart failure, but are not associated with progressive systolic or diastolic dysfunction of the left ventricle that leads to death. They also suggest that more studies are needed (Lancet 2007;370:1129-1136). The take home message from all the studies is to use caution in TZDs in patients with diabetes and heart failure (NYHA I and II), and to carefully monitor patients for worsening signs and symptoms including weight gain and edema. Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated.

Zometa and hip fractures

A single 5 mg infusion of zoledronic acid (Zometa) within 90 days of a hip fracture reduced the risk of new fractures and improved survival according to new study. Zoledronic acid is a long acting bisphosphonate that is approved for once yearly treatment of postmenopausal osteoporosis. The drug is effective at reducing vertebral, hip, and non-vertebral fractures in women with osteoporosis. In this current study, 1065 men and women with hip fractures were assigned to receive yearly intravenous zoledronic acid 5 mg IV or placebo, the infusions were administered within 90 days of surgical repair of a hip fracture. All patients received vitamin D and calcium. Mean age was 74.5 years, with approximately 75% women. The rate of new clinical fracture was 8.6% in the zoledronic acid group and 13.9% in the placebo group (35% risk reduction, P = 0.001). The respective rates of new clinical vertebral fractures were 1.7% vs 3.8% (P = 0 .02) and for non-vertebral fractures 7.6% vs 10.7% (P = 0.03). The death rate was 28% less in the zoledronic acid group (101 of 1054 [9.6%] vs 141 of 1057 [13.3%], P= 0.01). No cases of osteonecrosis of the jaw were reported and no adverse effects of healing fractures were noted. The authors conclude that an annual infusion of zoledronic acid within 90 days of a low trauma hip fracture was associated with reduced rate of new fractures and improved survival (published early at September 17, 2007).

Merck HIV Vaccine Ineffective in Clinical Trial

After years of development and clinical trials Merck has announced that their HIV vaccine is ineffective in a large clinical trial, and the company has halted further test vaccinations. Other HIV vaccines have also failed but many had hoped that the Merck vaccine, which worked by stimulating T cells, might be more effective. The trial, which was begun in 2004 vaccinated 3000 uninfected volunteers in the US and Latin America. Among 741 patients who received a least one dose of the vaccine, 24 new HIV infections were identified, compared to 21 infections in 762 patients who received placebo. Work continues on other HIV vaccines, currently 30 worldwide are in clinical trials, but the failure of the Merck vaccine is seen is a major setback for HIV researchers.

Thimerosal and Mercury Exposure

Thimerosal has been the subject of intense scrutiny for years regarding its potential link to various neuropsychological deficits in children. Thimerosal has been used as a preservative in vaccines and gamma globulin for decades, although it is rarely used now because it is metabolized to mercury and thiosalicylate, potentially leading to high mercury levels in children. In a new study from the CDC and several large HMOs, 1047 children between ages of seven and 10 years were enrolled and tested for 42 neuropsychological outcomes, then the medical records were examined for history of exposure to mercury from thimerosal. Prenatal mercury exposure from thimerosal was associated with better performance on one measure of language and poor performance on one measure of attention and executive functioning. Exposure in infancy up to seven months old was associated with better performance in one measure, fine motor coordination, and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination. The authors conclude that they could not find a causal association between early exposure to mercury from thimerosal and deficits in neuropsychological functioning at age 7 to 10 years (NEJM 2007; 357: 1281-1292).

FDA Actions

Eli Lilly has received approval from the FDA to market raloxifene (Evista) for the indication of reducing the risk of breast cancer in postmenopausal women with osteoporosis and postmenopausal women who are at high risk for invasive breast cancer. Raloxifene is a selective estrogen receptor modulator (SERM) that is already approved for prevention and treatment of osteoporosis in postmenopausal women. The drug was recently required to add labeling regarding an increased risk of fatal strokes in women taking the drug. It also carries a black box warning regarding risk of thromboembolism in women who are at high risk (those with an active or past history or thromboembolism).

Just in time for the winter flu season, the FDA has approved nasal influenza vaccine (FluMist) for use in children between the ages of 2 and 5. Previously the vaccine was only approved for children 5 years old and older and adults up to age 49. The CDC is recommending all children between the ages of 6 months to 59 months receive a flu vaccine. Children ages 2-8 who have never received a flu vaccine will initially require two doses of fluMist at least one month apart.

The FDA has approved a new oral granules form of terbinafine for the treatment of tinea capitis (ringworm) in children. The preparation may be sprinkled on food, allowing easier administration to children who may not otherwise take medicine over the two weeks required to treat tinea. Terbinafine granules are indicated for the treatment of tinea capitis in children age 4 years and older. It is marketed by Novartis AG as Lamisil Oral Granules.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5413. E-mail: