Medical Discussions

 To see the Lancet summary of this article click here

 The Big Picture

• GlaxoSmithKline recieved a patent on rosiglitazone in 1991 and released the drug under the trade name Avandia  in 1999
• According to IMS health, in 2002, Avandia had annual sales of $1.1 billion
• The patent for Avandia will expire in 2015
• It is estimated that approximately 10 to 15 percent of Americans have either impaired glucose tolerance or impaired fasting glucose.
  • A drug that would prevent these Americans from developing diabetes would be very profitable.
• The risk of developing diabetes in patients with impaired glucose tolerance has been found to be from 3.6 to 8.7 percent per patient year
• This study was funded by the Canadian Institute of Health, Sanofi-Aventis, GlaxoSmithKline, and King Pharmaceuticals

Background

• Type 2 diabetes affects 5 percent of adult worldwide
• Acarbose and metformin reduce the incidence of diabetes by 25-30 percent
• More importantly, lifestyle intervention reduce the incidence of diabetes by 50 percent.
• Rosiglitazone is a approved in patients with established type 2 diabetes
  • activates peroxisome proliferator-activated gamma receptors which play a role in insulin resistance
  • increase hepatic and peripheral insulin sensitivity
  • promote pancreatic beta cell health

Methods

• 24,592 people aged 30 yo or older were assessed for elgibility with a 75 g oral glucose tolerance test between July, 2001 and August, 2003
• Inclusion criteria
  • impaired fasting glucose defined as fasting glucose between than 110.9 mg/dl and 127.27 mg/dl and a 2 hour plasma glucose concentration less than 202 mg/dl or
  • impaired glucose tolerance defined as a fasting glucose between fasting glucose as less than 110.9 mg/dl and a 2 hr plasma glucose concentration between 127.27 and 202 mg/dl
• Exclusion criteria
  • People with a history of diabetes (except gestational diabetes), cardiovascular disease (including heart failure and known decreased ejection fraction), or intolerance to either ACE inhibitors or thiazolidinediones.
• If patients were deemed eligibile, they entered a 17 day run in period and if patients took at least 80 percent of run in meds they were enrolled for randomization.
• All patients were provided with advice about healthy diets and lifestyle habits to reduce diabetes
• Patients randomized to recieve initially 4 mg and then titrated up to 8 mg of rosiglitazone.  Patients were also concurrently randomly assigned to either  ramipril (titrated to 15 mg) or placebo with a 2×2 factorial design
• Composite primary endpt –> incident diabetes or death from any cause during active treatment period
• Secondary endpt–>regression to normal fasting and 2h glucose tolerance, renal events, glucose concentrations, and a composite of cardiovascular events (myocardial infarction, stroke, a CV death, revascular procedure, heart failure, new angina with evidence of ischemia, or ventricular arrhythmia)

Results

• 5269 people with a mean age of 54.7 (SD 10.9) years were randomly assigned to recieve either placebo or rosigiltazone
  • 57 percent had isolated had isolated impaired glucose tolerance and 14 percent had isolated impaired glucose tolerance and 29 percent had both
  • Patients were followed for a median of 3 years
• 72 percent of the patients were compliant in the experimental group while  75 percent of patients were compliant in the placebo group.  Compliance was defined as 80 percent adherent to the drug regimen
• Reasons for stopping the drug (% of experimental grp vs % placebo grp)
  • patient refusal 18.9 vs 16.7
  • edema 4.8 vs 1.6
  • physician advise 1.9 vs 1.5
  • weight gain 1.9 vs 0.6
• Primary outcome of diabetes or death was seen in 11.6 percent in the rosiglitzone grp as opposed to 26 percent in the placebo group – an absolute risk reduction of 14 percent
  • This reduction was entirely due to a reduction in the incidence of diabetes as death rates in the two groups were similar
• There was slight increase cardiovascular complications in the rosiglitazone group 2.9 percent compared to placebo at 2.1 percent that was not statistically significant (p=0.08)
  • This was almost entirely due to an increase in confirmed heart failure  0.5 percent in the rosiglitazone vs 0.1 percent in the placebo group (p=0.01), which occured equally irrespective of whether they were taking ramipril.
• Patients with a BMI <28, decreased waist-to-hip ratio, decreased waist circumference, and decreased hip circumference did better in the placebo group

Discussion

• This study shows that 8mg of rosiglitazone along with lifestyle recommendation decreases the risk of diabetes in patients with impaired fasting glucose or impaired glucose tolerance.
• There was an increase in patients developing confirmed CHF who were taking rosiglitazone.
• The reduction is similar to reductions which have seen in patients who make lifestyle changes
  • It is greater, though, than changes seen with metformin or acarbose.
• Patients with increased BMI and increased waist to hip ratios developed diabetes at the same rate as patients with lower BMIs and decreased waist to hip ratios.

THE BOTTOM LINE: Rosiglitazone in combination with lifestyle conselling decreased the incidence of the developing diabetes in patients without diabetes who have impaired fasting glucose levels or glucose tolerance.  There is, however, a small, but statistically significant, increase in the development of documented congestive heart failure in patients taking rosiglitazone.