From the Journals

Are vitamin D levels key to canagliflozin’s fracture risk?



Vitamin D deficiency appears to render people more vulnerable to canagliflozin’s adverse effects on bone health, whereas vitamin D3 supplementation appears protective of individuals with vitamin D deficiency.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are beneficial for treating type 2 diabetes and reducing cardiovascular and kidney disease risk. However, some, but not all, trial data have linked the SLGT2 inhibitor canagliflozin to increased fracture risk. That particular agent has been reported to accelerate loss of bone mineral density, which could contribute to fracture risk. Other drugs in the class have also been implicated in worsening markers of bone health.

The new findings, from a small study of Amish adults with vitamin D deficiency (≤ 20 ng/mL) but without diabetes or osteoporosis, suggest that physicians consider screening for vitamin D deficiency prior to prescribing SGLT2 inhibitor. Alternatively, these patients can simply be prescribed safe, inexpensive, OTC vitamin D supplements without being screening, Zhinous Shahidzadeh Yazdi, MD, of the division of endocrinology, diabetes, and nutrition at the University of Maryland, Baltimore, and colleagues wrote.

“Something as simple as OTC vitamin D might protect against bone fractures caused by chronic multiyear treatment with a drug,” study lead author Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, said in an interview.

In the study, published in the Journal of Clinical Endocrinology and Metabolism, 11 adults with vitamin D deficiency underwent two canagliflozin challenge protocols of 300 mg/d for 5 days, once before and once after vitamin D3 supplementation (either 50,000 IU per week or twice weekly for body mass index < 30 kg/m2 or ≥ 30 kg/m2, respectively), to achieve 25(OH)D of at least 30 ng/mL.

When the participants were vitamin D deficient, canagliflozin significantly decreased 1,25(OH)2D levels by 31.3%, from 43.8 pg/mL on day 1 to 29.1 pg/mL on day 3 (P = .0003). In contrast, after receiving the vitamin D3 supplements, canagliflozin reduced mean 1,25(OH)2D levels by a nonsignificant 9.3%, from 45 pg/mL on day 1 to 41 pg/mL on day 3 (P = .3).

“Thus, [vitamin D3] supplementation provided statistically significant protection from the adverse effect of canagliflozin to decrease mean plasma levels of 1,25(OH)2D (P = .04),” Yazdi and colleagues wrote.

Similarly, when the participants were vitamin D deficient, canagliflozin was associated with a significant 36.2% increase in mean parathyroid hormone (PTH) levels, from 47.5 pg/mL on day 1 to 58.5 pg/mL on day 6 (P = .0009). In contrast, after vitamin D3 supplementation, the increase in PTH was far less, from 48.4 pg/mL on day 1 to 53.3 pg/mL on day 6 (P = .02).

Therefore, the supplementation “significantly decreased the magnitude of the canagliflozin-induced increase in mean levels of PTH (P = .005),” they wrote.

Also, in the vitamin D deficient state, canagliflozin significantly increased mean serum phosphorous on day 3 in comparison with day 1 (P = .007), while after supplementation, that change was also insignificant (P = .8).

“We are saying that SGLT2 inhibitors, when superimposed on vitamin D deficiency, is bad for bone health. This group of people have two important risk factors – vitamin D deficiency and SGLT2 inhibitors – and are distinct from the general population of people who are not vitamin D deficient,” Dr. Taylor noted.

The findings “raise interesting questions about how to proceed,” he said in an interview, since “the gold standard study – in this case, a fracture prevention study – will never be done because it would cost more than $100 million. Vitamin D costs only $10-$20 per year, and at appropriate doses, is extremely safe. At worst, vitamin D supplements are unnecessary. At best, vitamin D supplements can protect some patients against a serious drug toxicity, bone fracture.”

The study was funded by the National Institutes of Health. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals and receives an inventor’s share of royalties from the National Institute of Diabetes, Digestive, and Kidney Diseases for metreleptin as a treatment for generalized lipodystrophy. Dr. Yazdi disclosed no relevant financial relationships.

A version of this article first appeared on

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