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SGLT-2 inhibitors were deemed safe for the bones in older patients with type 2 diabetes, a new study reassured.

No significant differences were seen in regards to fracture risk when comparing new SGLT-2 inhibitor users versus new DPP-4 inhibitor users (HR 0.90, 95% CI 0.73-1.11) or GLP-1 receptor agonist users (HR 1.00, 95% CI 0.80-1.25), reported Elisabetta Patorno, MD, DrPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues in .

This safety reassurance was consistently upheld when the researchers looked more closely at specific patient populations. For example, SGLT-2 inhibitors weren't tied to any increased risk of nontraumatic fracture -- the primary outcome -- for patients of any frailty level (non-frail, pre-frail, or frail based on the claims-based frailty index). They also appeared to be safe for both sexes, all ages, and users and non-users of insulin.

As for secondary outcomes, new users of SGLT-2 inhibitors did see a significantly lower rate of falls (HR 0.82, 95% CI 0.77-0.87) and hypoglycemia (HR 0.75, 95% CI 0.67-0.84) versus DPP-4 inhibitor users. Risk of syncope was similar between the two groups.

Comparing SGLT-2 inhibitors with GLP-1 receptor agonists, there were no significant risk differences for falls, hypoglycemia, or syncope.

Risk for diabetic ketoacidosis was not significantly different between any of the medication groups. Not surprisingly, though, the risk for heart failure hospitalization was lower for SGLT-2 inhibitor users compared with DPP-4 inhibitor users (HR 0.42, 95% CI 0.37-0.48) and GLP-1 receptor agonist users (HR 0.69, 95% CI 0.59-0.80).

These findings were welcome news, as Patorno's group previously found a significantly higher incidence of bone fractures among those on the SGLT-2 inhibitor canagliflozin (Invokana) versus placebo in the 2017 CANVAS trials.

"This increased risk of fracture, however, was not observed in other large randomized clinical trials of canagliflozin or other SGLT-2 inhibitors," the group pointed out.

The possible explanation behind the findings in CANVAS could be the mechanism of how this class of antidiabetic drugs reduce blood glucose. "SGLT-2 inhibitors lower blood glucose levels by promoting urinary glucose excretion. [They] also augment urinary phosphate reabsorption, triggering the parathyroid hormone and fibroblast growth factor 23; this action has the potential to harm bone health," the researchers explained.

For this population-based study, Patorno and colleagues focused on older adults (66 and older) with type 2 diabetes and used Medicare claims data from Parts A, B, and D. All patients were newly prescribed an SGLT-2 inhibitor, a DPP-4 inhibitor, or a GLP-1 receptor agonist from April 2013 -- after canagliflozin was the first SGLT-2 inhibitor to gain FDA approval -- through December 2017.

A total of 466,933 patients were included: 13% were new SGLT-2 inhibitor users, 73% were new DPP-4 inhibitor users, and 14% were new GLP-1 receptor agonist users. Older adults newly prescribed an SGLT-2 inhibitor tended to have a lower prevalence of comorbidities and were less likely to be frail. Those prescribed DPP-4 inhibitors tended to be older, while those prescribed GLP-1 receptor agonists were more likely to also be insulin users.

Before participant matching, patients on DPP-4 inhibitors saw the highest incidence of fractures (7.55 per 1,000 person-years), followed by GLP-1 receptor agonist users (4.76 per 1,000 person-years), and SGLT-2 inhibitor users (4.36 per 1,000 person-years). For the main analysis, patients were matched based on a 1:1:1 three-way propensity score.

The primary outcome was a composite endpoint of nontraumatic pelvic fractures; hip fractures requiring surgery; or humerus, radius, or ulna fractures requiring intervention within 30 days.

Some limitations to the study included a lack of data on "relevant clinical variables," such as duration of diabetes, HbA1c levels, vitamin D and parathyroid hormone levels, and body mass index. The researchers also noted that their propensity score matching may have possibly excluded patients who were at the highest risk for fractures.

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