They’re called sodium-glucose cotransporter-2, or SGLT2, inhibitors, and ever since they came on the market nearly a decade ago, they’ve proven to be one of the most effective and popular diabetes medications. Also known as gliflozins, this drug class includes empagliflozin (brand name Jardiance), canagliflozin (Invokana), ertugliflozin (Steglatro), and dapagliflozin (Farxiga). SGLT2 inhibitors lower blood sugar by stimulating the kidneys to remove sugar from the body through the urine.
But as useful as SGLT2 inhibitors have been shown to be, eyebrows were raised when a study published in 2017 reported that people who used them were more likely to experience bone fractures. The surprising nature of this finding prompted the researchers who published it to take a fresh look at the subject. The results of their reevaluation, which has just been published in JAMA Network Open, indicate that SGLT2 inhibitors do not in fact increase the chances of bone fractures. The lead author of the report was Elisabetta Palomo, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.
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For this most recent evaluation, the researchers used Medicare records to collect data on nearly half a million type 2 diabetes patients aged 66 and up who were just starting on certain diabetes medications. About three out of four (73%) were newly prescribed DDP-4 inhibitors, such as sitagliptin (Januvia), linagliptin (Tradjenta), alogliptin (Nesina), and saxagliptin (Onglyza), which are diabetes drugs that work by blocking the action of DPP-4, an enzyme that destroys certain gastrointestinal hormones. Fourteen percent of the patients were starting on GLP-1 receptor agonists, which work by mimicking the GLP-1 naturally made by the body that helps lower blood sugar levels after meals. This drug class includes dulaglutide (Trulicity), exenatide (Byetta), exenatide extended-release (Bydureon), semaglutide (Ozempic, Rybelsus), lixisenatide (Adlyxin), and liraglutide (Victoza). Finally, 13% of the patients were new users of SGLT2 inhibitors. The period in which the subjects began taking their new medications ranged from April 1, 2013, to December 31, 2017.
SGLT2 inhibitors not linked to higher risk of bone fractures
Far from being related to a higher bone fracture risk, the SGLT2 inhibitors actually had a slightly better record than the other two medications. Participants using DDP-4 inhibitors reported the highest fracture rate (7.55 per 1000 person-years). The second highest rate was among GLP-1 receptor agonist users (4.76 per 1000 person-years), and the lowest rate (4.36 per 1000 person-years) was among those who took SGLT2 inhibitors. The researchers reported similar results when they looked at specific conditions. SGLT2 inhibitors, for example, were not related to a higher risk of fractures whatever the fragility level of the subjects. Also, no safety issues with SGLT2 inhibitors were reported with regard to sex, age, and whether or not the patient used insulin. Patients taking SGLT2 inhibitors showed a considerably lower fate of falls and of low blood sugar (hypoglycemia), while the risk of syncope (fainting spells) was about the same. The risk of heart failure was lower among the SGLT2 inhibitor group, and no difference among the three groups was found when it came to diabetic ketoacidosis (DKA).
So why was it reported in 2017 that SGLT2 inhibitors were connected to a higher risk of bone fractures? The authors of the new study speculated that the urinary excretion promoted by the drugs might have something to do with the effect, but, they pointed out, “Although the adverse effects of SGLT-2i on bone health are biologically plausible, clinical studies on fracture risk are inconsistent.” The fractures reported in the 2017 study, they said, were “low-trauma fractures” and “there was no definitive explanation for the increased fracture risk.” Most important, later studies done by others did not report an increased risk of bone fractures, while a large Food and Drug Administration (FDA) safety analysis of reporting data from 2004 to 2019 “also showed no difference in fracture event reports for patients taking SGLT-2i vs SGLT-2i plus other diabetes agents.”
Want to learn more about SGLT2 inhibitors? Read “Diabetes Medicine: SGLT2 inhibitors.”
