Greater fracture risk seen with insulin vs. metformin use for adults with type 2 diabetes
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ATLANTA — Adults with type 2 diabetes who were prescribed insulin had greater risks for major osteoporotic and hip fractures than those prescribed metformin, according to study data.
“Patients using insulin or sulfonylurea are at a high risk of fractures compared to metformin-only users, and the risk could be higher in nonobese and well-controlled diabetic patients,” Sung Hye Kong, MD, professor in the department of endocrinology at Seoul National University College of Medicine, South Korea, told Healio. “[The risk] was attenuated in users with a combination of insulin and metformin.”
Kong and colleagues analyzed data from a common data model database, collected between 2008 and 2012, on 6,694 adults with type 2 diabetes aged at least 50 years (mean age, 65.8 years; 47.7% women). Patients were grouped according to medication they used for at least 1 year: metformin only; insulin only; sulfonylurea only; DPP-IV inhibitor plus metformin; insulin plus metformin; sulfonylurea plus insulin; sulfonylurea plus metformin; DPP-IV inhibitor plus sulfonylurea and insulin; and sulfonylurea and insulin plus metformin. The researchers compared fracture risks for patients in each medication category with those who used metformin alone. Follow-up was a median of 3.6 years.
Overall incidence of major osteoporotic fractures was 8.36 per 1,000 person-years and 1.53 per 1,000 person-years for hip fractures. After adjustments for age, sex, BMI, comorbidities and medications including anti-osteoporotic drugs, risks for major osteoporotic fracture were doubled (HR = 2.03; 95% CI, 1.32-3.11) and for hip fractures increased fivefold (HR = 5.33; 95% CI, 2.78-10.21) among patients prescribed insulin alone compared with those prescribed metformin alone. Analysis by subgroups revealed significantly increased risks in the insulin-alone group only for those with HbA1c less than 7% and those with BMI less than 25 kg/m2. The risks were not statistically significantly different for those prescribed insulin alone compared with those prescribed insulin plus metformin.
“The speculated mechanism for increased risk in insulin users is mainly because of the risk of hypoglycemia, and mechanisms for decreased risk in combination with metformin can be both protective effect of metformin on bone, or decreased dose of insulin when combined with metformin, which may reduce the risk of hypoglycemia,” Kong said.
“In clinical practice, clinical attention to the patients who use insulin or sulfonylurea is needed since fracture risks can be elevated in insulin or sulfonylurea users compared to metformin-only users,” Kong said. “Also, the fracture risk in insulin users was exaggerated in nonobese and well-controlled diabetic patients, suggesting that active fracture risk assessment, especially in these patients, might be needed.”
Editor's note: This article was edited on June 14, 2022 to reflect updated data.
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Bone disease is a long-described and not well-understood complication of diabetes. While the armamentarium of therapies for diabetes is expanding, little is known about the effect of different antihyperglycemic agents on bone. The notion is that insulin has a direct anabolic effect on bone. Data also suggest that metformin and DPP-IV inhibitors confer either a positive or neutral effect on bone mineral density and fracture risk. The negative influence of other antihyperglycemic agents on bone may be through an increase in bone turnover, the loss of osteoanabolic effects of insulin in insulin-resistant states and by augmenting the risk of falling due to hypoglycemia.
Intriguingly, several studies have reported that insulin use itself is associated with increased fracture risk compared with other antihyperglycemic medications. It is speculated that insulin use could be a marker for increased severity of diabetes, a surrogate for comorbidities that may warrant aggressive treatment strategy and preclude treatment with other medications, thus resulting in an increased risk of hypoglycemia and falls.
Kong and colleagues analyzed real-world data in adults with diabetes after stratifying them by antihyperglycemic medication use for at least 1 year. After adjusting for multiple variables, including age, sex, BMI, HbA1c, comorbidities and steroid use, the observed risk for major osteoporotic fractures and hip fractures was twofold and threefold, respectively, in insulin monotherapy group compared to metformin-alone users. This difference was not observed in the combination — insulin plus metformin — group.
The nature of this association between insulin use and excess fracture risk appears to be more than correlational, and where possible, randomized controlled trials are needed to confirm the causality. Current guidelines by the International Osteoporosis Foundation include insulin use as a risk factor for fractures in the recommendation for bone mineral density assessment in patients with diabetes. A systematic evaluation of risk factors for fractures may be prudent in patients with diabetes when considering initiating insulin therapy. The use of antihyperglycemic medications with a favorable effect on bone metabolism and falls should help reduce the risk of fractures in patients with diabetes.
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Kong SH, et al. OR01. Presented at: ENDO Annual Meeting; June 11-14, 2022; Atlanta (hybrid meeting).
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