Few classes of drugs have managed to simultaneously take the endocrinology, nephrology, and cardiology worlds by storm like the sodium-glucose cotransporter 2 inhibitors (SGLT2is). It almost seems too good to be true, but so far, rigorously designed randomized controlled trials and large prospective observational studies continue to reaffirm their pleiotropic effects in a variety of patient populations, including those afflicted by CKD.
The discovery of the glucose transport through the rat kidney tubules in the 1980s laid the foundation for the detection of two proteins belonging to a new class of glucose transporters: sodium-glucose cotransporter 1 (SGLT1) and SGLT2. Although SGLT1 is found in the intestine, kidneys, and other organs, SGLT2 is specific to the kidney and is responsible for reclaiming sodium and approximately 90% of the total filtered glucose (approximately 180 g/d) in the proximal tubule.
Half a century prior to the discovery of SGLTs, phlorizin, a nonselective SGLT inhibitor derived from the root bark of the apple tree, was shown to lower the serum glucose level by preventing the renal reabsorption of glucose. Its effects were not limited to the kidneys, and because it had a low intestinal absorption and interfered with glucose transport in other organs, it was not feasible for human use. However, phlorizin triggered interest in diabetes drugs development. Over the subsequent decades, large industry-sponsored trials found SGLT2is to be safe and effective at improving glucose control in adults with type 2 diabetes. However, their role in glucose control was somewhat overshadowed by the impressive reduction in cardiovascular morbidity and mortality and kidney disease progression in a variety of patient populations. This led to changes in clinical practice guidelines for the treatment of both heart failure and diabetic kidney disease.
Like any other pharmacologic compound, SGLT2is are not free of side effects, including genitourinary infections, AKI, ketoacidosis, lower limb amputations, loss of bone mineral density, and bone fractures. The bone fracture complication was first reported in 13 participants with and without CKD taking dapagliflozin (1), and subsequently, in 114 CANVAS study participants taking canagliflozin (2). In people over 65 years old with both diabetes and CKD, which individually increase skeletal fragility, adding a therapy that could elevate fracture risk may seem hazardous. In January 2016, the Food and Drug Administration issued a warning regarding the increased risk of bone fractures with canagliflozin and stated that a class effect of these drugs is under investigation.
In this issue of CJASN, Cowan et al. (3) help shed further light on the potential association between SGLT2i and fracture risk and included CKD populations for which this association might be most applicable. The investigators examined the association between initiation of SGLT2i versus dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy and subsequent 180- and 365-day hospital encounters for fragility fracture. The added benefit was the examination of secondary outcomes: hospital encounters for falls, hypoglycemia, and hypotension, all of which could trigger an increase in fracture risk. The comparison groups were well balanced on indicators of baseline health using inverse probability of treatment weighting and examined the association of interest in prespecified eGFR subgroups. The authors started with the premise that if a higher risk of fracture was observed with SGLT2is, the risk would be greatest in patients with advanced CKD. However, important to note is that only 6% of the SGLT2i users had eGFR <45 ml/min per 1.73 m2. The study found that the weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of SGLT2is versus a DPP-4i (wHR, 0.95; 95% confidence interval, 0.79 to 1.13 and wHR, 0.88; 95% confidence interval, 0.88 to 1.00, respectively) with no interactions by eGFR categories.
The Canadian universal access to insured hospital and physician services and universal prescription drug coverage for residents over 65 years old allowed for the assembly of a large cohort of outpatient users of a SGLT2i (canagliflozin, empagliflozin, or dapagliflozin) or DPP4-i (saxagliptin, sitagliptin, or linagliptin). Population demographics were reasonably representative of individuals followed in most primary care outpatient settings. The use of outpatient laboratory values, which are more accurate in identifying individuals with CKD, was a plus; however, a single eGFR measurement just prior to the event could lead to some misclassification. The findings are in line with a recently published cohort study (4) and a meta-analysis of 67 RCTs, where SGLT2is were not found to have an increased risk of fractures over placebo or other commonly used antidiabetic medications (5).
Cowan et al. (3) assembled a robust cohort of individuals with mild CKD; however, the jury is still out regarding the effect of SGLT2is on bone metabolism and fractures in individuals with advanced CKD (eGFR=15–30 ml/min per 1.73 m2). Although dual-energy x-ray absorptiometry bone mineral density (DXA BMD) is unable to discern bone turnover type, it is associated with fracture risk in adults with CKD stages G3a to G5D (6). As such, a baseline DXA BMD could have helped identify individuals at higher fracture risk and may be a useful risk stratification tool in clinical setting prior to SGLT2i initiation, especially in individuals with other risk factors. Is it reasonable to postulate that fractures that occurred in the first 180 days post–SGLT2i initiation happened in individuals with an already deranged bone metabolism? Baseline DXA BMD was not ascertained in this study.
Whether 1-year follow-up time is sufficient to study bone fracture risk is another point to discuss. Acknowledging potential crossover that may occur with longer follow-up, alteration in bone quality is a change that takes much longer to manifest clinically. With prolonged use of SGLT2is in individuals with more advanced CKD, we may observe an increase in bone fracture burden in the years to come. Emerging technologies aimed to overcome the limitations of DXA BMD to assess bone turnover in CKD, including high-resolution microcomputed tomography and micromagnetic resonance imaging, that allow noninvasive, three-dimensional evaluation of bone microarchitecture are currently under development and may become part of the clinical armamentarium in the future.
An additional consideration relates to the study’s inability to accurately ascertain medication adherence and the role of individual SGLT2is. Canagliflozin, which is the drug associated with the most reported fractures in randomized trials (2), was taken by only a third of the cohort, whereas empagliflozin, which is associated with the lowest number of bone metabolism abnormalities, represented the most prescriptions and may have driven the final results.
There are several mechanisms responsible for the alteration in bone metabolism by SGLT2is, including directly affecting calcium-phosphate homeostasis and indirectly increasing bone turnover by causing weight loss. The increase in the serum phosphate level is known to be a class effect of SGLT2is, and it was first reported with phlorizin in 1944 (7). This effect is potentially facilitated by the increase in phosphate transport via the sodium-phosphate cotransporter in the proximal tubule. Sodium loss leads to an increase in phosphate reabsorption and urinary calcium excretion. In a randomized crossover study performed in healthy volunteers, administration of canagliflozin 300 mg/d triggered the FGF23/1,25-dihydroxyvitamin D/parathyroid hormone (PTH) axis by increasing the mean serum phosphate level up to a peak of 0.61 mg/dl after 36 hours of drug administration. It also led to increases in plasma FGF23 and PTH by 20% and 25%, respectively, and a decrease in plasma levels of 1,25 dihydroxyvitamin D by 10% (8). The increase in phosphate is likely to have triggered FGF23 stimulation, which would cause phosphaturia and 1,25-dihydroxyvitamin D inhibition to maintain phosphate homeostasis. The downstream effect is inhibition of calcium absorption from the gastrointestinal tract, a reduction in serum calcium level, impairment in skeletal mineralization, and the development of secondary hyperparathyroidism. In most cases, patients with an indication for SGLT2is also have concomitant comorbidities, including CKD, diabetes, or postmenopausal osteopenia or osteoporosis, all of which can augment the above alterations in bone health.
However, the evidence for SGLT2is causing bone fractures is lacking. Of the proposed mechanisms, a higher risk of falls through volume depletion/postural hypotension, hypoglycemia, and an increased bone turnover due to weight loss are the most discussed. Such changes are particularly relevant in individuals with CKD who are susceptible to changes in bone quality due to a predisposition to CKD mineral bone disorder.
In summary, deciphering the mechanisms of SGLT2i influence on bone metabolism and fracture risk in individuals with CKD will help design interventions to reduce these devastating consequences. The report by Cowan et al. (3) adds to the growing body of evidence related to the safety of SGLT2is; however, it 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 per 1.73 m2). 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 PTH and its subsequent bone remodeling, and, last but not least, recommendations to follow a low-phosphate diet rich in fruits and vegetables. The widespread use of SGLTs 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.
M. Dobre reports consultancy agreements with CareDx, Inc.
M. Dobre is supported by National Heart, Lung, and Blood Institute grant NIH/NHLBI R01HL141846.
The author is grateful for critical review of the manuscript by Dr. Thomas H. Hostetter, Professor of Medicine, University of North Carolina.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
M. Dobre conceptualized the study, was responsible for data curation, wrote the original draft, and reviewed and edited the manuscript.
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