The elevated fracture risk seen with the type 2 diabetes drug canagliflozin (Invokana, Janssen) appears to be a class effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors and is potentially modifiable, new research suggests.
The findings, from a single-blind randomized crossover study involving 25 healthy adults, were published online April 19 in JCI Insight by Jenny E. Blau, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and colleagues.
SGLT2 inhibitors, which reduce plasma glucose levels by inhibiting renal proximal tubular glucose reabsorption, are the newest class of oral therapies approved for type 2 diabetes.
When given canagliflozin 300 mg/day for 5 days, the participants experienced an immediate increase in serum phosphorus and subsequent downstream increases in fibroblast growth factor 23 (FGF-23) and plasma parathyroid hormone (PTH), as well as a decrease in 1,25-dihydroxyvitamin D. These changes could adversely affect bone health, Blau and colleagues say.
“While we studied only canagliflozin, there is strong reason to believe this is a class effect, as all the drugs in the class increase serum phosphorus. That does not imply, however, that the magnitude of the changes would be identical for all drugs in the class,” principal investigator Simeon I. Taylor, MD, professor of medicine at the University of Maryland School of Medicine in Baltimore, told Medscape Medical News.
Canagliflozin the Only SGLT2 Inhibitor With Fracture Warning
Although canagliflozin is the only SGLT2 inhibitor with a US Food and Drug Administration (FDA) fracture warning, an increase in fractures was also seen with dapagliflozin (Farxiga/Forxiga, AstraZeneca) in a 2014 study of patients with type 2 diabetes and moderate renal impairment (Kidney Int. 2014;85:962-971), the authors note.
This would make sense, because patients with chronic kidney disease also have increased levels of FGF-23, decreased 1,25-dihydroxyvitamin D, and increased PTH. FGF-23 blocks the kidney’s ability to form 1,25-dihydroxyvitamin D, leading to decreased absorption of calcium from the gastrointestinal tract, which in turn triggers increased PTH secretion, Taylor explained.
And although there are no reports of an association between another SGLT2 inhibitor, empagliflozin (Jardiance, Boehringer Ingelheim), and fracture risk in the current peer-reviewed literature, the FDA has suggested longer trials might be needed to detect an increase in risk, say Blau and colleagues.
Further, empagliflozin was associated with double the incidence of upper extremity fractures compared with placebo (1.0% vs 0.5%) in the EMPA-REG trial, they add.
Potential Mitigation in Certain Subgroups?
In the current study, because there was significant variation among the 25 healthy participants in magnitude of hormonal responses to canagliflozin, it is possible that patients with type 2 diabetes who have the largest decreases in 1,25-dihydroxyvitamin D and/or greatest PTH increases would be at greatest risk for fracture, the authors hypothesize.
This suggests some potential mitigation strategies in that subpopulation, they say. Either SGLT2 inhibitors could be withheld entirely from those at high risk, or calcitriol could be given with the SGLT2 inhibitor to restore 1,25-dihydroxyvitamin D levels to normal.
Alternatively, 1,25-dihydroxyvitamin D levels could be measured in patients prior to prescribing an SGLT2 inhibitor, and those found deficient could be advised to take an over-the-counter vitamin D supplement.
“One could argue that should be done anyway,” Taylor noted.
However, he cautioned, “None of these hypotheses are proven. Before actually recommending any of these mitigation strategies, additional research would be required.”
Taylor is a consultant for Ionis Pharmaceuticals, has research support provided to the University of Maryland School of Medicine by Regeneron and owns stock in Celgene, Amgen, and Abbott Laboratories.
JCI Insight. Published online April 19, 2018. Full text
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