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Patients with type 2 diabetes newly initiated on a sodium-glucose cotransporter-2 (SGLT2) inhibitor did not have an added risk of fracture at 6 months or 1 year compared with patients started on a dipeptidyl peptidase-4 (DPP-4) 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, cost of advair 500 50 without insurance 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.

These findings add “to the growing body of evidence related to the safety of SGLT2 inhibitors,” Mirela Dobre, MD, agrees in an accompanying editorial.

But 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 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, 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 of 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.

“It would probably not be wise to interpret this fact as reassurance with respect to risks associated with chronic use of the drug (for example, longer than 5 or 10 years),” added Taylor of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore.

“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, Cowan and colleagues note that patients with CKD “have a two- to fivefold higher risk of fracture compared with the general population.”

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

However, in some randomized, placebo-controlled trials, SGLT2 inhibitors have been associated with a higher risk of skeletal fractures, possibly related to secondary hyperparathyroidism and increased bone turnover (also common in CKD), the researchers note.

And so they investigated whether fracture risk was greater with SGLT2 inhibitors than with DPP-4 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 and older, researchers identified 38,994 outpatients newly prescribed an SGLT2 inhibitor and 105,700 outpatients newly prescribed a DPP-4 inhibitor between July 1, 2015 (the earliest date that SGLT2 inhibitors were covered) and September 30, 2019.

They excluded those with advanced CKD and those on 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 DPP-4 inhibitor, followed by linagliptin and saxagliptin.

The researchers used propensity scores to match 38,994 SGLT2 inhibitor users with 37,449 DPP-4 inhibitor users. The patients in each propensity-matched group were a mean age of 72 and 40% were women.

At 180 days, the number of fractures was similar in each group: 172 fractures in the DPP-4 inhibitor group and 170 fractures in the SGLT2 inhibitor group (weighted hazard ratio [HR], 0.95; 95% CI, 0.79 – 1.13).

The number of fractures at different sites, as well as hospital visits due to 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 DPP-4 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 four eGFR categories:

  • ≥ 90 mL/min/1.73m2 (17% of patients)

  • 60 to < 90 mL/min/1.73m2 (60% of patients)

  • 45 to < 60 mL/min/1.73m2 (17% of patients)

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

Again, in each kidney function category, the risk of fracture after 180 days or after 365 days was similar in patients who had received an SGLT2 inhibitor or a DPP-4 inhibitor.

Jury Still Out on Risk for Moderate or Severe CKD

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.   

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 taking an SGLT2 inhibitor had an eGFR < 45 mL/min/1.73m2.

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,” 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 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. 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. Taylor is a consultant for Ionis Pharmaceuticals.   

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

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