A recent study published in BMJ found that higher levels of RANKL (Receptor activator of nuclear factor kappa-Β ligand, also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11)) were associated with a fourfold increased risk of type 2 diabetes over a five-year follow-up period, based on electronic health records from the IQVIA Medical Research Data (IMRD) UK primary care database. The study involved emulating a randomized target trial and included a cohort of individuals who had received an antiosteoporosis drug between January 1995 and December 2021.
The researchers selected a study cohort from this cohort comprising individuals who had initiated denosumab or received oral bisphosphonate between July 2010 and December 2021. The researchers then stratified the denosumab users into two types: those who switched to denosumab (prevalent new users) and those who were incident new users. The index date was considered the switching date or date of incident use.
For every individual who switched to denosumab, the researchers matched up to five people who continued an oral bisphosphonate and had used the oral bisphosphonate for the same duration at the time of the index date. For incident new users, the researchers matched each denosumab user with up to five incident new users of an oral bisphosphonate in the treatment naïve populations. The modified new user design enabled the researchers to emulate an analysis of a hypothetical trial comparing switching to denosumab or continuing an oral bisphosphonate.
After excluding specific individuals, such as those under 45 years of age, enrolled for less than 365 days, with Paget disease of bone, history of type 1 or type 2 diabetes, or previous anti-diabetes drug use before the index date, the study analyzed 4350 new users of denosumab. Among the potentially eligible population, 4350 individuals switched to or initiated denosumab, while 207,481 initiated an oral bisphosphonate. The denosumab users were mostly younger and female, and had a higher proportion of participants with a history of major osteoporotic fracture compared to the oral bisphosphonate users.
The study’s main focus was on incident type 2 diabetes, which was defined by diagnostic codes and the date of diagnosis. However, an alternative definition of incident type 2 diabetes was also considered, which included at least two prescriptions for the anti-diabetes drug or meeting specific criteria for fasting blood glucose, random glucose level, glucose tolerance test result, or glycated hemoglobin A1c level.
The study conducted on the IMRD database in the UK revealed that individuals who switched to or initiated denosumab had a 32% lower risk of developing type 2 diabetes compared to those who used oral bisphosphonates in a propensity score-matched cohort. The findings suggest that denosumab may be a more effective option for individuals at high risk of type 2 diabetes.
The study also highlights the association between RANKL levels and type 2 diabetes risk, providing important insights into the disease. It also highlights the potential benefits of denosumab use in reducing the risk of type 2 diabetes compared with oral bisphosphonates.