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Are SGLT2 Inhibitors Increasing Fracture Risk in Patients With CKD?

  • Authors: News Author: Marlene Busko; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 6/24/2022
  • Valid for credit through: 6/24/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care physicians, endocrinologists, nephrologists, cardiologists, nurses, pharmacists, PAs, and other members of the healthcare team who care for adults who may be prescribed sodium glucose cotransporter-2 inhibitors.

The goal of this activity is for learners to be able to evaluate the risk for fracture associated with the use of sodium glucose cotransporter-2 inhibitors.

Upon completion of this activity, participants will:

  • Evaluate the potential risk for fracture associated with sodium glucose cotransporter-2 inhibitors
  • Compare rates of fracture among older adults receiving sodium glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors
  • Outline implications for the healthcare team


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News Author

  • Marlene Busko

    Freelance writer, Medscape


    Marlene Busko has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California


    Charles P. Vega, MD, has the following relevant financial relationships:
    Advisor or consultant for: GlaxoSmithKline; Johnson & Johnson

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    Associate Director, Accreditation and Compliance
    Medscape, LLC


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  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC


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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Are SGLT2 Inhibitors Increasing Fracture Risk in Patients With CKD?

Authors: News Author: Marlene Busko; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 6/24/2022

Valid for credit through: 6/24/2023, 11:59 PM EST


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.

Study Highlights

  • Study data were drawn from a provincial health database in Ontario, Canada. Researchers obtained demographic, chronic illness, and medication data from adults at least 66 years of age who received their initial prescription for DPP4 inhibitor or SGLT2 inhibitor between 2015 and 2019.
  • Patients who filled a medication within 2 days of hospitalization were excluded from analysis, as were those prescribed both SGLT2 and DPP4 inhibitors.
  • The main study outcome was hospitalization for fragility fracture, and the principal variable for the study analysis was the use of SGLT2 or DPP4 inhibitors. The study analysis was adjusted to account for patients' baseline variables. Researchers performed an analysis to determine whether reduced kidney function affected the main analysis.
  • 38,994 new users of SGLT2 inhibitors were compared with 105,700 new users of DPP4 inhibitors. The mean age of patients was 73 years, and most patients were men.
  • Patients who received SGLT2 inhibitors were younger and more likely to be men compared with the cohort receiving DPP4 inhibitors. More patients in the DPP4 inhibitor group were receiving bisphosphonates. Patients in the SGLT2 inhibitor cohort had higher rates of coronary artery disease, whereas patients in the DPP4 inhibitor cohort had more renal disease.
  • Mean continuous use of SGLT2 and DPP4 inhibitors was 428 and 501 days, respectively. Empagliflozin was the most popular SGLT2 inhibitor, whereas sitagliptin was the most commonly prescribed DPP4 inhibitor.
  • 342 fractures occurred within 180 days after the initial prescription; the fracture total by 365 days was 689.
  • The HR for fracture in comparing the SGLT2 inhibitor cohort with the DPP4i inhibitor group through 180 days was 0.95 (95% CI, 0.79-1.13). The respective HR at 365 days was 0.88 (95% CI, 0.77-1.00).
  • There was also no difference between groups when researchers compared specific skeletal sites of fracture.
  • Moreover, there was no difference between the SGLT2 inhibitor and DPP4 inhibitor groups for hospitalization for falls, hypoglycemia, or hypotension.
  • The analysis predicated on eGFR failed to change the study's main finding of a null risk for fracture with SGLT2 vs DPP4 inhibitors.


SGLT2 inhibitors, N = 38,994

DPP4 inhibitors, N = 37,449

Weighted HR

Fractures at 180 days

170 (0.44%)

172 (0.46%)


Fractures at 365 days

329 (0.84%)

360 (0.96%)



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.
Implications for the Healthcare Team
The healthcare team should not use the risk for fracture as a common reason to withhold SGLT2 inhibitors.

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