Sulfonylureas May Up Fracture Risk in Diabetes, Along With TZDs

Miriam E. Tucker

June 15, 2014

SAN FRANCISCO — The oral diabetes drug classes of thiazolidinediones (TZDs) and sulfonylureas both boost the risk for fractures compared with metformin, a large database analysis has found.

The observational study confirms previous findings of increased fracture risk with TZDs but is the first to compare multiple classes of glucose-lowering agents and the first to suggest a possible increased fracture risk for sulfonylureas, Sandhya Mehta, PhD, an investigator with Inovalon, a technology company specializing in large data analytics, told the American Diabetes Association (ADA) 2014 Scientific Sessions today.

Dr. Mehta said her study findings should be taken into consideration in prescribing antidiabetic drugs, especially in those patients already at higher risk for fracture.

"Be more careful with TZDs, to be sure, and also with sulfonylureas," she told Medscape Medical News, but she added that the association with sulfonylureas needs confirmation.

Indeed, session moderator Amanda I. Adler, MD, PhD, of Addenbrooke's Hospital, Cambridge University, United Kingdom, and chair of the Technology Appraisal Committee of the United Kingdom's National Institute for Health and Care Excellence (NICE), told Medscape Medical News that despite the investigators' attempts to control for many potential confounders, "One concern is residual confounding, that patients who take sulfonylureas are at higher risk for fractures than those who don't take sulfonylureas."

More Work Needed to Drill Down into Sulfonylurea Fracture Risk

Dr. Mehta and colleagues retrospectively analyzed 2008–2012 data from Invalon's Medical Outcomes for Effectiveness and Economics (MORE) registry of more than 100 million individuals. A total of 99,892 adults were identified as new users of glucose-lowering drugs: metformin (77.8%), sulfonylureas (15.3%), dipeptidyl peptidase-4 (DPP-4) inhibitors (2.7%), TZDs (2.7%), incretins (0.81%), and meglitinides (0.6%).

Within the 5-year follow-up period, 7353 patients (7.4%) had evidence of fracture.

The incidence of fractures was 6.8% among the total 76,924 patients taking metformin, 10.9% among the 2679 taking TZDs, and 9.7% in the 15,162 on sulfonylureas. Rates for other glucose-lowering agents ranged from 6.1% of 799 individuals taking incretin drugs to 10.7% of the 626 on meglitinide.

After adjustment for age, gender, region, a variety of medical conditions and other medications, the hazard ratios for fracture risk compared with metformin were 1.40 for TZDs (P < .0001) and 1.09 for sulfonylureas (P = .0054). The increase in fracture risk for the other drug classes compared with metformin did not reach statistical significance.

In her presentation, Dr. Mehta noted that the findings support the hypothesis that TZDs increase fracture risk by decreasing bone-mineral density, stimulating adipocytes and inhibiting osteoclast differentiation.

She noted, however, that previous epidemiologic studies have not found an increased fracture risk with sulfonylureas. "The present study points to the need of further investigation on the association between sulfonylureas and the risk of fractures."

Dr. Adler told Medscape Medical News that what preceded the fracture is important information. "If they were having more low blood sugars and consequently fell, it would be interesting to know, but unfortunately she couldn't tell us."

She also noted that although the findings for the other glucose-lowering drugs are reassuring, "We can't really know what they're doing to bones without knowing what else is going on. If you took a drug that made you more likely to topple over, your bones could be equally as strong as the group that didn't fall over, but [you could still] still have more fractures."

Dr. Mehta and Dr. Adler have no reported no relevant financial relationships.

American Diabetes Association 2014 Scientific Sessions; June 15, 2014. 165-OR

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