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The saga of whether pioglitazone (Actos) increases risk of bladder cancer took another turn with a new analysis of Medicare data showing an elevated risk compared with two other classes of type 2 diabetes drugs.

Patients taking pioglitazone had an incidence of bladder cancer of 308 per 100,000 person-years versus 204 per 100,000 person-years with dipeptidyl peptidase-4 (DPP-4) inhibitors for an adjusted hazard ratio of 1.57 (95% CI 1.23-2.00) in an "as-treated" analysis, found Elizabeth M. Garry, MPH, of University of North Carolina at Chapel Hill, and colleagues.

The rate with pioglitazone was also higher than for sulfonylureas (231 per 100,000 person-years; adjusted HR 1.32, 95% CI 1.02-1.70), they reported online in .

The increased risk was seen within the first 2 years of treatment compared with DPP-4s (adjusted HR 1.63; 95% CI 1.22-2.17). A trend for increased risk for pioglitazone within 2 years versus sulfonylureas just missed statistical significance (adjusted HR 1.32; 95% CI 0.98-1.78).

"We identified an increased risk of bladder cancer associated with pioglitazone treatment, as suggested by some, but disputed by others," stated Garry. "The risk emerged within the first 2 years of treatment and increased over time. Findings from our secondary and sensitivity analyses suggest that these results are unlikely to be explained by differential detection rates, cohort selection, outcome definitions or censoring approaches."

The FDA first required label warnings about the possible bladder cancer risk with pioglitazone in 2011, and later affirmed that ruling at the end of 2016.

Despite efforts from drug-maker Takeda to debunk the cancer link, the conclusion fell in line with a recent population-based cohort in the U.K. which found that people taking pioglitazone faced an increased risk of bladder cancer of 121.0 versus 88.9 per 100,000 person-years among those on other diabetes drugs (hazard ratio 1.63, 95% CI 1.22-2.19).

to settle thousands of lawsuits from patients and their family members over the increased risk of bladder cancer from the drug.

Garry and colleagues examined a 20% random sample of Medicare beneficiaries ages 66 years and older to compare bladder cancer incidence among 38,700 treated with pioglitazone, 82,552 with DPP-4s, and 126,104 with sulfonylureas. Mean age of participants was 75 and 41% were men.

All patients initiated treatment from 2007 to 2014 after at least 6 months without prescriptions for the drugs. Using the as-treated approach, they were followed from second prescription until bladder cancer outcome (two claims within 60 days) using a 6-month induction/latency period and censoring for treatment change, death, or end of 2014. An "initial-treatment" analysis that did not censor for treatment discontinuation was also performed.

Garry and colleagues found that 727 patients developed bladder cancer over a median of 1.2 treatment years.

Compared with patients taking DPP-4s in the initial treatment analysis, those on pioglitazone had an increased incidence of bladder cancer with rates per 100,000 person-years of 244.4 versus 195.7 (adjusted HR 1.22, 95% CI 1.02-1.47).

The risk appeared to vanish when treatment was discontinued within the first 2 years (adjusted HR 0.89; 95% CI 0.61-1.28).

No excess risk was seen with pioglitazone versus sulfonylureas in the initial treatment analysis.

Limitations included use of claims data that precluded control for smoking and workplace exposures (i.e., industrial chemicals), two known risk factors for bladder cancer. Other study limitations included detection bias, as well as the possibility of misclassification due to defining bladder cancer with administrative claims without pathological confirmation.

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