SB/Bristol Avandia Lipid Adverse Effect Diminishes Over Two Months - Label

The adverse effect of SmithKline Beecham/Bristol-Myers Squibb's antidiabetic Avandia (rosiglitazone) on patient lipid profiles appears to level off after one to two months, labeling indicates.

As with Warner-Lambert/Pfizer's Rezulin (troglitazone), a rise in low-density lipoprotein cholesterol is seen for patients initiated on therapy. However, the escalation for Avandia patients levels off and is buffered by continuing rises in high-density lipoproteins.

"Increases in LDL occurred primarily during the first one to two months of therapy with Avandia and LDL levels remained elevated above baseline throughout the [one year] trials," labeling states.

"In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after two months of therapy and then appeared to decrease over time."

Rezulin labeling, by comparison, notes that "as monotherapy or in combination, an increase in LDL (up to 13%), HDL (up to 16%), and total cholesterol (up to 5%) occurred while total-C/HDL and LDL/HDL ratios did not change."

The difference could help distinguish Avandia from Rezulin. Avandia, approved May 25, is the second thiazolidinedione class antidiabetic, and will attempt to carve into Rezulin's established market ("The Pink Sheet" May 31, p. 3).

Avandia labeling states that cholesterol levels changed, "with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These differences were statistically significantly different from placebo or glyburide controls." The lipid changes were similar for Avandia monotherapy or in combination with metformin (Bristol's Glucophage), labeling adds.

The cholesterol effect is not stated to be a class effect. A third entrant in the "glitazone" class, Takeda/Lilly's Actos (pioglitazone) is claiming a different lipid profile ("The Pink Sheet" April 26, p. 8). Actos has a priority review deadline of July 15.

Avandia, as with other "glitazones," is associated with weight gain. Labeling relates the adverse effect to the efficacy of the drug, stating, "reduction in hyperglycemia was associated with increases in weight."

The combination of rosiglitazone with metformin increases efficacy and has the additional advantage of somewhat abating the weight gain effect.

"In the 26-week trials, the mean weight gain in patients treated with Avandia was 1.2 kg (4 mg daily) and 3.5 mg (8 mg daily) when administered as monotherapy" compared to".7 kg (4 mg daily) and 2.3 kg (8 mg daily) when administered in combination with metformin." Metformin or placebo alone were associated with weight loss of about 1 kg.

Avandia functions as an "insulin sensitizer" because it acts as an agonist for peroxisome proliferator-activated receptor gamma, regulating transcription of insulin-responsive genes in charge of glucose production and utilization, labeling explains. The PPAR-gamma receptors are found in adipose tissue, skeletal muscle, and the liver.

This results in another relationship between lipids and efficacy: "In monotherapy studies, a greater therapeutic response was observed in females," labeling states, noting that "for a given body mass index, females tend to have a greater fat mass than males." Labeling observes that "in more obese patients, gender differences were less evident."

The durability of the "glitazone" mechanism of action is demonstrated by a 52-week rosiglitazone monotherapy study vs. glyburide active control. The trial tested Avandia 2 mg b.i.d. and 4 mg b.i.d. against glyburide titrated over 12 weeks to a maximum of 15 mg per day, with a median titrated dose of 7.5 mg.

"The initial fall in [fasting plasma glucose] with glyburide was greater than with Avandia; however, this effect was less durable over time," labeling states. After 52 weeks, the reduction in FPG was 40.8 mg/dL for Avandia 8 mg, 25.4 mg/dL for Avandia 4 mg, and 30 mg/dL for glyburide.

Labeling notes that "for HbA1c, the difference between Avandia [8 mg] and glyburide was not statistically different at week 52." HbA1c was lowered by .53 percentage points by Avandia 8 mg, by .27 percentage points by Avandia 4 mg and by .72 percentage points by glyburide. Again, glyburide demonstrated a quicker decrease and a trend towards returning to baseline (after about 26 weeks) while Avandia showed a slower reduction that tended towards baseline at the 52-week timepoint.