Glucose-Lowering Drugs Linked to Increased Fracture Risk in Patients With Diabetes

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Researchers in Denmark have concluded that use of glucose-lowering sulfonylureas and glitazones within 90 days increased the risk for hip fractures in elderly patients with type 2 diabetes. Current use of sulfonylureas was also associated with an increased risk of other fractures including vertebral and forearm. “Current use of sulfonylureas and glitazones was associated with increased risk of a hip fracture, and the risk remained increased after adjustment for comorbidities and previous admissions due to falls and hypoglycemic events,” the researchers concluded (Bone 2017:95;136–42). “By contrast, hip fracture risk was not increased in ever users of glucose-lowering drugs among patients with incident type 2 diabetes.” Previous research has shown that patients with type 2 diabetes are at 1.4-fold increased risk for hip fracture, but there are conflicting data on the effect of sulfonylureas. Researchers led by Jakob Starup-Linde, PhD, selected 5244 patients from a cohort of diabetes patients (n = 501,724) entered into the Danish National Patient Register and the Register of Medicinal Product Statistics from January 1996 to December 2011. Patients with type 1 diabetes were excluded. Researchers followed the cohort from the time of diabetes diagnosis to time of fracture or date of death, emigration, or end of study. Mean follow-up was 5.5 years for patients with a hip fracture and 6.4 years for patients who did not have a fracture. Mean follow-up was 5.2 years for patients with a fracture at a major osteoporotic site, 5 years for any fracture, 5.2 years for vertebral fractures, and 5.2 years for forearm fractures. Compared with non-diabetic patients, major osteoporotic fractures and any fractures were more common than hip fractures in patients with type 2 diabetes. Patients who suffered a hip fracture were significantly older than those without a hip fracture, and women with type 2 diabetes were at greater risk for hip fracture than men. “The most plausible reason for an increased risk of fracture within sulfonylurea users are hypoglycemic events,” Dr. Starup-Linde, from the department of endocrinology and internal medicine, Aarhus University Hospital, Denmark, told Caring. “Sulfonylureas are known to cause hypoglycemia by increasing beta cell insulin release. Hypoglycemia may lead to falls and thereby fractures.” Previous and current use of sulfonylureas were associated with an increased risk for hip fracture in the unadjusted model (HR, 1.08). Current use of sulfonylureas increased the risk for hip fracture in all models. However, ever use of sulfonylurea use was associated with a lower fracture risk in the adjusted (HR, 0.81) and propensity adjusted (HR, 0.91) models. Ever use of glitazones was associated with a higher risk of a hip fracture in the unadjusted model (HR, 0.28) but the effect was neutral in the adjusted models. Current use of glitazones was associated with a lower risk of hip fracture in the unadjusted model, but researchers said glitazones were a strong risk factor for fracture in the 90-day propensity adjusted models (HR, 2.07). When researchers examined the effect of new use of a glucose-lowering drug, sulfonylureas (HR, 1.91) and glitazones (HR, 7.18) were associated with an increased risk for hip fracture. Current use of sulfonylureas was associated with an increased risk for any fracture (HR, 1.44), major osteoporotic fracture (HR, 1.54), vertebral fracture (HR, 1.47; 95% CI, 1.24–1.74), and forearm fracture (HR, 1.55). Current use of glitazones was associated with an increased risk for any fracture (HR, 3.01), major osteoporotic fracture (HR, 3.71), vertebral fracture (HR, 4.53), and forearm fracture (HR, 4.89). In contrast, current use of metformin, dipeptidyl peptidase IV-inhibitors, or peptide-1 receptor agonists was associated with reduced risk for decreased risk of any fracture, major osteoporotic fracture, vertebral fracture, and forearm fracture. “To the best of our knowledge, this is the largest study on incident hip and osteoporotic fractures among incident cases of type 2 diabetes,” the researchers wrote. “The present investigation is limited by the lack of information on bone mass, body mass index, lifestyle habits as smoking and daily alcohol consumption, vitamin D status, and other biochemical parameters. These factors are important to consider when interpreting the risk of fracture.” Jason Harris is a freelance medical writer based in Philadelphia.