Risks of adverse events with newer antidiabetic drugs identified
April 6 2016
An association between the diabetes drug pioglitazone and increased risk of bladder cancer has been identified in a new study. It found no similar risk with rosiglitazone.
The findings published in the British Medical Journal suggest that the risk increases with increasing duration of treatment and higher dose. While the number of patients likely to be affected is small, the effect is significant, so should be taken into consideration when assessing overall risks and benefits of the therapy, the researchers have advised.
Researchers analysed data for over 145,000 patients being treated for diabetes between 2000 and 2013. The data had been supplied by GPs to the UK Clinical Practice Research Datalink. Combined, and the accessed records amounted to nearly 700,000 person years of follow up.
From this, the study identified 622 patients as being newly diagnosed with bladder cancer, equivalent to a crude incidence of 90.2 per 100,000 person years. Pioglitazone was identified with an increased risk of bladder cancer, at 121.0 per 100,000 person years, compared to an average of 88.9 per 100,000 person years where pioglitazone was not used.
It equates to an overall 63% increased risk of incident bladder cancer, said the researchers. Rosiglitazone had a similar level of risk to non exposure at 86.2 compared to 88.9 per 100,000 person years.
The difference between the two glitazone drugs suggest the difference “is drug specific and not a class effect,” they concluded. Both pioglitazone and rosiglitazone entered the UK market in 2000 and were intended for the same target population. “Given their similarities, it is unlikely that confounding by indication or detection bias can explain the association observed with pioglitazone.
“Of note, although the biological mechanism for pioglitazone induced bladder cancer is not clear, this imbalance in the risk of bladder cancer between these two thiazolidinediones could likely be explained by pharmacological differences.”
The researchers point out that pioglitzaone has dual activity on the peroxisome proliferator activated receptors (PPAR) α and γ, while rosiglitazone is only active at PPAR γ.
“Although differences in PPAR activity are possible explanations for the observed association, additional studies are needed to better understand the biological mechanism behind the possible pioglitazone specific effect on the bladder.”
A second study, also published in the same issue of the BMJ has looked at diabetes medicines, particularly gliptins and glitazones, and the relationship to the risks of amputation, blindness, severe kidney failure, hyperglycaemia and hypoclycaemia.
This time the researchers assessed data from the QResearch database used in 1,243 GP practices in England, and covering almost 470,000 adults with type 2 diabetes between 2007 and 2015. The analysis found that 21,308 (4.5%) patients received prescriptions for glitazones and 32,533 (6.9%) received prescriptions for gliptins. It also looked at whether the drugs were given as monotherapy or in combination.
- there were significantly lower risks of hyperglycaemia among patients prescribed dual therapy involving metformin with either gliptins or glitazones compared with metformin monotherapy;
- triple therapy with metformin, sulphonylureas, and either gliptins or glitazones was associated with significantly higher risks of hypoglycaemia than those prescribed metformin monotherapy, but these risks were similar to those involving dual therapy with metformin and sulphonylureas;
- triple therapy with metformin, sulphonylureas, and glitazones was associated with a significantly reduced risk of blindness compared with metformin monotherapy.
Commenting on both studies, the BMJ said: “Both studies are observational so no firm conclusions can be drawn about cause and effect. However, the researchers say these results may have implications for prescribing, and suggest doctors and patients should be aware when assessing the overall risks and benefits of diabetes drugs.”
J Hippisley-Cox and C Coupland. ‘Diabetes treatments and risk of amputation, blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia: open cohort study in primary care’. BMJ 2016; 352: i1450