/publications/issue/2006/2006-10/2006-10-5916

GlaxoSmithKline's Avandamet

Author: Caryn Domenici, RPh; Alka Patel, PharmD; and Vishal Barot

According to the National Diabetes Information Clearinghouse, 20.8 million people in the United States have diabetes, which accounts for $132 billion in medical costs each year.1,2

Approximately 90% of people with diabetes in North America are classified as having type 2 diabetes mellitus (DM).1 These patients typically are treated with one or more oral hypoglycemic medications rather than with insulin. On July 11, 2006, GlaxoSmithKline announced the approval of Avandamet as first-line therapy to control glucose levels in patients diagnosed with type 2 DM when dual therapy is needed.3,4

Pharmacology

Avandamet (rosiglitazone maleate and metformin HCl) is a combination of 2 oral hypoglycemic agents consisting of a thiazolidine and a biguanide, respectively. The advantage of Avandamet lies within the additive effect of 2 different mechanisms of action. Rosiglitazone targets insulin resistance and decreases circulating insulin levels, whereas metformin reduces glucose production at the hepatic level.5 The metabolic processes also differ because rosiglitazone is primarily metabolized by the CYP450 isoenzyme 2C8 (2C9 minor) and metformin is primarily metabolized renally.5

Clinical Trials

A 32-week, randomized, double-blind trial to evaluate the efficacy and safety of Avandamet, compared with rosiglitazone and metformin as single agents, confirmed Avandamet's superiority in glycemic control over the 2 monotherapies.4 The inclusion criteria required patients with type 2 diabetes who were drug-naive. The study defined drug-naive as not having taken an oral hypoglycemic medication or insulin for more than 15 days within the 12 previous weeks.4

This study evaluated 468 patients between the ages of 18 and 70 years. The Avandamet treatment arm included a starting total daily dose of 2 mg/500 mg. The investigators were allowed to increase doses in increments of 2 mg/500 mg, with a maximum daily dose of 8 mg/2000 mg.4 Patients in the rosiglitazone arm were initiated at a total daily dose of 4 mg and could be titrated up to 8 mg. Those in the metformin treatment arm started at a 500-mg total daily dose, with a maximum dose of 2000 mg (titrated in increments of 500 mg).4

When test results were compared with baseline, the researchers found that Avandamet was superior to metformin and rosiglitazone in reducing hemoglobin A1C and fasting plasma glucose (FPG).

A second study was an open-label, single-arm, 24-week trial to evaluate the safety and efficacy of Avandamet in 120 drug-naive patients with type 2 diabetes. The inclusion/exclusion criteria were similar to those of the aforementioned 32-week trial, except that this open-label study included patients with A1C >11% or FPG >270 mg/dL.4 The Avandamet regimen included a starting dose of 4 mg/1000 mg, with the possibility of a dose increase to 6 mg/1500 mg at 4 weeks. The maximum dose allowed was 8 mg/2000 mg.4 The results showed that Avandamet reduced A1C by 4% and FPG by 139 mg/dL from baseline.4,5

Safety

The most common adverse events observed in the trials were nausea, vomiting, diarrhea, headache, and dyspepsia.4 An increase in weight also was reported. Avandamet is contraindicated in patients with renal dysfunction.5 A black-box warning has been issued for the risk of lactic acidosis due to the accumulation of metformin.5 Lactic acidosis is a rare but serious side effect; 50% of the cases are fatal. Rosiglitazone can cause edema, which can lead to or exacerbate heart failure. Avandamet is not recommended for patients in New York Heart Association Class III and IV because of an increased risk of cardiovascular events.5

Conclusion

It is important for patients with type 2 DM to have adequate glucose control. Nonpharmacologic treatment includes caloric restriction, weight loss, and exercise. It also is important for patients to be compliant with their medications and with routine doctor visits.

The total daily dose of Avandamet usually is prescribed in divided doses that are taken with meals to reduce gastrointestinal side effects.5 Alcohol should be avoided when taking Avandamet.5 Avandamet is available in the following strengths: 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg, 2 mg/1000 mg, and 4 mg/1000 mg rosiglitazone/metformin, respectively.

Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Mass. Mr. Barot is a sixth-year PharmD candidate from Northeastern University currently on clinical clerkship in the Investigational Drug Service at Brigham and Women's Hospital.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an e-mail request to: arybovic@ascendmedia.com.