Study Compares Fracture Risk Among Antidiabetes Medication Regimens

Sung Hye Kong, MD

Analysis of real-world data patients suggests patients with diabetes who were using insulin had an increased risk of major osteoporotic and hip fractures compared to metformin users.

Results of the study, which leveraged data from more than 6500 patients, indicate risk of major osteoporotic fracture was nearly doubled and risk of hip fracture was more than tripled among patients using insulin, but these associations were attenuated among patients with diabetes who were using a combination of metformin and insulin therapy.

“Patients using insulin or sulfonylurea are at a high risk of fractures compared to metformin-only users, and the risk could be higher in non-obese and well-controlled diabetic patients,” said Sung Hye Kong, MD, of Seoul National University Hospital in South Korea, in a statement.

As patients age, the threat to quality of life and life expectancy posed by fracture grows in unison, particularly patients with diabetes. Although observational data suggesting patients with diabetes were at increased fracture risk, little is known about the influence of different antidiabetic medication regimens on this risk. With this in mind, Kong, with a team of colleagues from Seoul National University Hospital and the Seoul National University College of Medicine, sought to compare the risk of fracture among patients with diabetes using different classes of medications compared to those using metformin.

Using the common data model database from 2008-2012, investigators identified a cohort of 6694 patients aged 50 years and older who used the same antidiabetic medications for over a year for inclusion in their analyses. This cohort had a mean age of 65.8 years, 47.7% were women, and the median follow-up duration was 6.1 years. Overall, the incidence rates of major osteoporotic fracture and hip fracture among this cohort were 8.36 and 1.53 per 1000 person-years, respectively.

For the purpose of analysis, patients were grouped according to medication use. These groups were defined as metformin alone, insulin alone, sulfonylurea alone, dipeptidyl-4-inhibitor (DPP4i) plus metformin, insulin plus metformin, sulfonylurea plus insulin, sulfonylurea plus metformin, DPP4i with sulfonylurea and insulin, and sulfonylurea with insulin and metformin. The primary outcomes of interest were the risks of major osteoporotic fracture and risk of hip fractures in each group, which were assessed using Cox proportional hazards models with the metformin group serving as the reference cohort. Investigators noted these models were adjusted for multiple factors, including age, sex, BMI, HbA1c, history of fracture, secondary osteoporosis, rheumatoid arthritis, cardiovascular disease, cerebrovascular disease, dementia, chronic kidney disease, and use of steroids, proton pump inhibitors, or warfarin.

Upon analysis, results indicated insulin users had a greater risk of major osteoporotic fractures (HR, 1.96 [95% CI, 1.28-3.02]) and hip fracture (HR, 3.06 [95% CI, 1.21-7.77) compared to metformin users in fully adjusted models. However, further analysis demonstrated this increase in risk became insignificant when assessing use of insulin plus metformin for risk of both major osteoporotic fractures (HR, 1.32 [95% CI, 0.77-2.27]) and hip fractures (HR, 2.68 [95% CI, 0.56-12.8)]) in the same models. In subgroups analyses, results suggested insulin users a significantly higher risk for major osteoporotic fracture was observed among insulin users compared to metformin users only among patients with an HbA1c greater than 7% or a BMI greater than 25 kg/m2.

“From real-world data using the common data model, we found that insulin users were at elevated risk of major osteoporotic and hip fracture compared to metformin users, which was attenuated in users with a combination of insulin and metformin,” Kong said.

This study, “Increased Fracture Risk in Patients Using Insulin Compared to Metformin, Attenuated in Patients Using Combination of Insulin and Metformin: Based on Common Data Models,” was presented at ENDO 2022.