Patients with type 2 diabetes who were newly started using a sodium-glucose transporter-2 (SGLT2) inhibitor had no additional risk of fracture at 6 months or 1 year compared to patients who started using a DPP-4 inhibitor. 4).
Importantly, this is true regardless of the estimated glomerular filtration rate (eGFR) in patients with mild chronic kidney disease (CKD) associated with diabetes but also less severe or moderate CKD, in this large, older outpatient study. 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 wrote.
“And that provides more real-world confirmation of that [SGLT2 inhibitors] It can be prescribed safely without the risk of fracture,” they concluded in their article published online May 22 Clinical Journal of the American Society of Nephrology.
These findings add “to the growing body of evidence regarding the safety of SGLT2 inhibitors,” Merella Dupree agrees in an accompanying editorial.
But Dupree, as well as the researchers and another expert, noted limitations of the study, such as the one-year follow-up.
The study should encourage “ongoing baseline and clinical studies to determine the potential risk of fractures with greater certainty, particularly in individuals with advanced chronic kidney disease (eGFR <30 mL/min/1.73 m)."2) who were excluded from this study, adds Dupree, of Case Western Reserve University, Cleveland, Ohio.
“If such a risk is found, interventions to mitigate it may include phosphate binders to mitigate phosphate buildup, active vitamin D supplementation to suppress parathyroid hormone and subsequent bone remodeling, and last but not least, recommendations for a low-phosphate diet. Rich in fruits and vegetables.
Studies on long-term use of SGLT2 inhibitors and fracture risk are needed
Dobre adds that greater use of SGLT2 inhibitors “is likely to tilt the balance of benefit versus side effect profile in the coming years and may prove or refute their role in bone metabolism and increased fracture risk.”
“Until then, we will continue to walk a fine line in an effort to provide our patients with advanced chronic kidney disease with the best possible care,” she concludes.
Invited for comment, Simeon I. Taylor, MD, PhD, was not involved in the research, agreed. “For me, the main takeaway from this study is that there does not appear to be a significantly increased risk of fractured bone that may appear 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.
Taylor added from 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 increases fracture risk in susceptible patients, it would be beneficial to be able to identify patients most at risk and design strategies to mitigate risk. In the meantime, it may be too early to be reassured. Therefore, it may be constructive to remain vigilant and aware of the potential for risk.”
High risk of fractures at baseline in CKD
In their article, Kwan and colleagues note that patients with CKD “have a two- to five-fold greater risk of fracture compared to the general population.”
At the same time, given their proven benefits in preventing heart and kidney disease, recent guidelines recommend starting SGLT2 inhibitors in all patients with diabetic kidney disease and eGFR >30 mL/min/1.73 m.2.
However, in some randomized, placebo-controlled trials, SGLT2 inhibitors were associated with a higher risk of skeletal fracture, which is likely related to secondary hyperparathyroidism and increased bone turnover (also common in chronic kidney disease), the researchers note.
So they investigated whether the fracture risk was greater with SGLT2 inhibitors than with DPP-4 inhibitors (which are not associated with increased fracture risk).
They hypothesized that if this were true, the risk would be greater in patients with more severe CKD (low eGFR).
In the Comprehensive Health Insurance Prescribing Database for the Ontario, Canada population of 66 years or older, researchers identified 38,994 outpatients who were recently prescribed an SGLT2 inhibitor and 105,700 outpatients who were recently prescribed a DPP-4 inhibitor between July 1, 2015 (the earliest date for SGLT2 inhibitors was 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 common SGLT2 inhibitor, followed by canagliflozin and dapagliflozin. Sitagliptin was the most common 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 mean age of patients in each trend-matching group was 72 years and 40% were women.
At 180 days, the number of fractures was similar in each group: 172 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 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).
Patients were also classified into four categories of eGFR:
≥ 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 category of renal function, the risk of fracture after 180 days or after 365 days was similar in patients who received an SGLT2 inhibitor or a DPP-4 inhibitor.
“The jury is still out“ At risk of moderate or severe chronic kidney disease
Kwan and colleagues acknowledge that the study lacks statistical power to be able to stratify patients by type of SGLT2 inhibitor. Most prescriptions for this type of drug have been for empagliflozin, which is associated with minimal hyperphosphatemia and hyperparathyroidism. There may be residual confounding factors that have not been taken into account and fractures may have occurred after one year.
Dupre notes that investigators “gathered a robust cohort of individuals with moderate 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/1.73 m2.
She speculated that “with prolonged use of SGLT2 inhibitors, beyond one year, in individuals with more advanced CKD, we may observe an increased bone fracture burden in the coming years.”
Also, “canagliflozin, the drug associated with the largest number of fractures reported in randomized trials, was taken by only a third of the group,” says Dobre, while empagliflozin, which is associated with the fewest number of bone metabolic abnormalities, represented most prescriptions and may be have paid off to the end 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 appears to be an inflection point in the risk curve at approximately 24 weeks,” Taylor said.
“The drug-related increase in fracture incidence was most pronounced between 24 and 104 weeks,” he said. “This indicates that the 180-day endpoint in the current study was almost certainly too early to be beneficial. Likewise, the 365-day endpoint would likely be relatively early for the time course if the goal was to assess the effect of a drug on fracture risk. bones.”
This study was supported by ICES with funding from the Ontario Department of Health and Long-Term Care. Cowan reported his work at the University of Western Ontario and received support from the Department of Nephrology, Lawson Health Research Institute, Physician Services Foundation, and Schulich College of Medicine and Dentistry. Other authors’ disclosures are listed in the article. Taylor is a consultant to Ionis Pharmaceuticals.
Clean J Am Sok Nephrole. Published online May 26, 2022. Editorial Article
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