SAN FRANCISCO – Adults who started taking sulfonylurea drugs for diabetes were 9% more likely to develop fractures within 5 years, and patients starting thiazolidinediones were 9% more likely to have fractures, compared with patients on other medications in a retrospective study of 99,892 adults.
Those significantly increased risks emerged after adjusting for the effects of multiple factors including age, gender, region, medical conditions, and concomitant medications, Sandhya Mehta, Ph.D. and her associates reported at the annual scientific sessions of the American Diabetes Association. Patients had no prior history of fracture.
The longitudinal retrospective analysis of a large administrative claims database found a 10% incidence of fracture on sulfonylureas and 11% on thiazolidinediones, compared with 7% on biguanides (metformin), 8% on dipeptidyl peptidase-4 (DPP-4) inhibitors, 11% on meglitinide analogues, and 6% on incretin mimetic agents. After adjusting for the confounders, the hazard ratios for each of the other three types of drugs hovered around 1 and were not statistically significantly different but increased to 1.09 for sulfonylureas and 1.4 for thiazolidinediones, reported Dr. Mehta of Inovalon Inc. in Bowie, Md., a health care data analytics company.
In the cohort as a whole, 7% of patients developed fractures. Roughly 15% of patients started sulfonylureas, 3% took thiazolidinediones, 78% were on metformin, 3% took DPP-4 inhibitors, 1% were on incretin mimetics, and 1% took meglitinides.
Previous reports have shown an increased risk of fracture in patients on thiazolidinediones, compared with those on metformin, and the current results support the hypothesis that thiazolidinediones decrease bone mineral density, stimulate adipocyte and osteoclast differentiation, and inhibit osteoblast differentiation to make fracture more likely, Dr. Mehta said.
The association between sulfonylureas and increased fracture risk appears to be new, however, and deserves further study, she added.
The study did not look at the effects of combination drug therapy.
Data came from the Medical Outcomes Research for Effectiveness and Economics (MORE) Registry, which is owned by Inovalon, drawing from the years 2008-2012.
Dr. Mehta reported having no financial disclosures.
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Dr. Amanda Adler
Dr. Amanda Adler
This study confirms that we observe more fracture risks with thiazolidinediones. To my knowledge, this is the first time that this has been shown for sulfonylureas.
Dr. Amanda Adler
One concern about the study is so-called residual confounding. The confounders were not entirely clear in the presentation. One possible confounder is what might have preceded the fracture. If, in fact, patients on sulfonylureas were having more low blood glucose values and consequently fell, then that would be interesting to know. Unfortunately, the investigators couldn’t tell us that.
With thiazolidinediones, I’ve been told that a cell that hasn’t decided yet whether it’s going to be a bone cell or a fat cell might, in the presence of a thiazolidinedione, go on to be a fat cell instead of a bone cell. In which case, you would possibly have a problem with fewer bone cells. This study set out to look at bone metabolism but, to be fair, it could not show anything about that. That was rather ambitious.
I think there is no clinical message from this as yet. The investigators might want to look back at trials that randomized people to sulfonylureas or something else and meta-analyze that to see if there were differences in fractures.
The study suggests that the other second-line agents are okay, but again, we can’t really know what they’re doing to bones without knowing if there’s something else going on. If you took a drug that made you more likely to topple over, your bones could be equally strong as those who didn’t fall over, yet you end up with a fracture.
I’m not going to change my practice on the basis of this study.
Dr. Amanda Adler is consultant physician at Cambridge University’s Addenbrooke’s Hospital and chair of the technology appraisals committee for the National Institute for Health and Clinical Excellence in England. She gave these comments in an interview at the meeting.