Clinical Context

There is little doubt regarding the benefits of a sodium-glucose cotransporter-2 (SGLT2) inhibitor for conditions such as heart failure and chronic kidney disease. However, the issue of long-term adverse effects of SGLT2 inhibitor use are more controversial. The authors of the current study review what is known regarding SGLT2 inhibitor use and the risk for fracture.

In the randomized, placebo-controlled CANVAS trial, canagliflozin was associated with a significantly higher risk for fracture vs placebo, although the relative risk was modest (15.4 vs 11.9 fractures per 1000 person-years, respectively). Subsequent trials have failed to find an association between the use of SGLT2 inhibitors and fracture, and there is a suggestion that persons with reduced renal function might be at a particularly increased risk for fracture when receiving an SGLT2 inhibitor. The current study reevaluates the safety of SGLT2 inhibitors, using a large cohort sample.

Study Synopsis and Perspective

Patients with type 2 diabetes newly initiated on a SGLT2 inhibitor did not have an added risk for fracture at 6 months or 1 year compared with patients started on a dipeptidyl peptidase-4 (DPP4) inhibitor. 

Importantly, this held true regardless of estimated glomerular filtration rate (eGFR) in patients with mainly mild chronic kidney disease (CKD) associated with diabetes, but also less severe or moderate CKD, in this study of a large cohort of older outpatients in Ontario, Canada.

"To our knowledge, this is the first study of its kind to specifically examine fracture risk in patients with CKD," Andrea Cowan, MD, Western University, London, Ontario, Canada, and colleagues write.

"This provides further real-world assurance that [SGLT2 inhibitors] can be safely prescribed without a higher risk of fracture," they conclude in their article, published online May 22 in the Clinical Journal of the American Society of Nephrology.^[1]

But Dr Dobre, as well as the researchers and another expert, have pointed out study limitations, such as the 1-year follow-up.

The study "should encourage continued basic and clinical studies to determine with more certainty their potential risk of fractures, especially in individuals with advanced CKD (eGFR < 30 mL/min/1.73m²)" who were excluded from this study, adds Dr Dobre, from Case Western Reserve University, Cleveland, Ohio.

"If such risk is found, interventions to alleviate it may include phosphate binders to attenuate the accumulation of phosphate, active vitamin D supplements to suppress parathyroid hormone and its subsequent bone remodeling, and, last but not least, recommendations to follow a low-phosphate diet rich in fruits and vegetables," she suggests. 

Studies on Long-Term Use of SGLT2 Inhibitors and Fracture Risk Needed

Greater use of SGLT2 inhibitors, Dr Dobre adds, "is likely to tilt the balance of the benefit versus side effect profile in the coming years and may prove or disprove their role in bone metabolism and increased fracture risk."

"Until then, we will continue to walk the fine line in an attempt to provide our patients with advanced CKD with the best possible care," she concludes.

Invited to comment, Simeon I. Taylor, MD, PhD, who was not involved with the research, agreed. "For me, the main takeaway message from this study is that there does not appear to be an enormously increased risk for bone fracture that would be manifest after taking SGLT2 inhibitors for a very short period of time--less than the time required to obtain the expected benefits from the drug," he noted in an email to Medscape Medical News.

"If it eventually turns out that chronic use of these drugs does increase fracture risk in susceptible patients, it would be valuable to be able to identify the patients at greatest risk and to design risk mitigation strategies. In the meantime, it may be premature to be reassured. Rather, it may be more constructive to remain watchful and to be mindful of the possibility of risk," he added.

Heightened Fracture Risk at Baseline in CKD

In their article, Dr Cowan and colleagues note that "[p]atients with CKD have a two- to five-fold higher risk of fracture compared with the general population."

At the same time, because of the proven cardio- and reno-protective benefits of SGLT2 inhibitors, recent guidelines recommend starting the inhibitors in all patients with diabetic kidney disease and eGFR levels higher than 30 mL/min/1.73 m².

However, in some randomized, placebo-controlled trials, SGLT2 inhibitors have been associated with a higher risk for skeletal fractures, possibly related to secondary hyperparathyroidism and increased bone turnover (also common in CKD), the researchers note. Therefore, they investigated whether fracture risk was greater with SGLT2 inhibitors than with DPP4 inhibitors (which are not linked to increased fracture risk).

They hypothesized that if this were true, the risk would be greatest in patients with more severe CKD (lower eGFR).

In a universal health insurance database of prescriptions for residents of Ontario, Canada, aged 66 years and older, researchers identified 38,994 outpatients newly prescribed an SGLT2 inhibitor and 105,700 outpatients who were newly prescribed a DPP4 inhibitor between July 1, 2015, which was the earliest date that SGLT2 inhibitors were covered, and September 30, 2019. They excluded those with advanced CKD and those receiving dialysis, as SGLT2 inhibitors were contraindicated in these patients during the study period.

Empagliflozin was the most commonly prescribed SGLT2 inhibitor, followed by canagliflozin and dapagliflozin. Sitagliptin was the most commonly prescribed DPP4 inhibitor, followed by linagliptin and saxagliptin.

The researchers used propensity scores to match 38,994 SGLT2 inhibitor users with 37,449 DPP4 inhibitor users. The patients in each propensity-matched group were a mean age of 72 years, and about 40% were women.

At 180 days, the number of fractures was similar in each group: 172 fractures in the DPP4 inhibitor group and 170 fractures in the SGLT2 inhibitor group (weighted hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.79-1.13).

The number of fractures at different sites, as well as hospital visits resulting from falls, hypoglycemia, or hypotension, were also similar in each group.

At 365 days, the number of fractures was also similar in each group: 360 fractures in the DPP4 inhibitor group and 329 fractures in the SGLT2 inhibitor group (weighted HR, 0.88; 95% CI, 0.77-1.00).

The patients were also grouped into 4 eGFR categories:

• ≥90 mL/min/1.73 m² (17% of patients)
• 60 to <90 mL/min/1.73 m² (60% of patients)
• 45 to <60 mL/min/1.73 m² (17% of patients)
• 30 to <45 mL/min/1.73 m² (6% of patients).

Again, in each kidney function category, the risk for fracture after 180 days or after 365 days was similar in patients who had received an SGLT2 inhibitor or a DPP4 inhibitor.

"Jury Still Out" on Risk for Moderate or Severe CKD

Dr Cowan and colleagues acknowledge that the study lacked statistical power to be able to stratify patients by SGLT2 inhibitor type. Most prescriptions for this drug type were for empagliflozin, which is associated with the least hyperphosphatemia and hyperparathyroidism. There may have been residual confounders that they did not account for, and fractures may have occurred after 1 year. 

Dr Dobre notes that the investigators "assembled a robust cohort of individuals with mild CKD," but stressed that "the jury is still out" regarding the effect of SGLT2 inhibitors on bone metabolism and fractures in individuals with advanced CKD, and only 6% of those receiving an SGLT2 inhibitor had an eGFR lower than 45 mL/min/1.73 m².

She speculated that, "with prolonged use of SGLT2 inhibitors, beyond 1 year, in individuals with more advanced CKD, we may observe an increase in bone fracture burden in the years to come."

Also, "canagliflozin, which is the drug associated with the most reported fractures in randomized trials, was taken by only a third of the cohort," Dr Dobre says, "whereas empagliflozin, which is associated with the lowest number of bone metabolism abnormalities, represented the most prescriptions and may have driven the final results."

"In the analysis of fractures in CANVAS, canagliflozin was associated with a very small increase in the incidence of fractures early in the study, but there appeared to be an inflection point in the risk curve at around 24 weeks," said Dr Taylor.

"The drug-associated increase in incidence of fractures was most apparent in the time period between 24 and 104 weeks," he continued. "This suggests that the 180-day endpoint in the present study was almost certainly too early to be informative. Similarly, the 365-day endpoint was likely relatively early relative to the time course if the objective is to assess the impact of a drug on risk of bone fracture."

This study was supported by ICES, which is funded by the Ontario Ministry of Health and Long-Term Care. Dr Cowan has reported employment with the University of Western Ontario and was supported by the Division of Nephrology, the Lawson Health Research Institute, Physicians Services Incorporated, and the Schulich School of Medicine and Dentistry. Disclosures for the other authors are listed in the article. Dr Taylor is a consultant for Ionis Pharmaceuticals. 

Clin J Am Soc Nephrol. Published online May 26, 2022.

Clinical Implications

• SGLT2 inhibitors might promote a higher risk for fracture because of their known effects in reducing circulatory volume and promoting lower serum glucose levels. In addition, SGLT2 inhibitors might disturb the metabolism of calcium and phosphate as well as promote weight loss, both of which can contribute to bone loss. In the randomized, placebo-controlled CANVAS trial, canagliflozin was associated with a significantly higher risk for fracture vs placebo. Subsequent trials have failed to find an association between the use of SGLT2 inhibitors and fracture.
• The current study failed to find a higher risk for fracture with new prescriptions for SGLT2 vs DPP4 inhibitors through 365 days. This outcome remained valid regardless of patients' eGFR.

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