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Diabetes drug alters vitamin D levels, possibly explaining increased bone fracture risk

Scientists found that the diabetes drug canagliflozin reduces vitamin D levels and calcium uptake, which may explain why this drug can increase the risk of bone fractures. Canagliflozin is one of a class of drugs called sodium glucose cotransporter-2 (SGLT2) inhibitors, which lower blood glucose (sugar) levels by preventing glucose reabsorption from urine in the kidney. Several SGLT2 inhibitors are FDA-approved to treat type 2 diabetes, and they can also reduce kidney and heart complications, two major causes of death in people with diabetes. However, SGLT2 inhibitors such as canagliflozin can also have detrimental side effects, including an increased risk of bone fractures.

In a study led by NIDDK, in conjunction with other NIH Institutes, scientists hypothesized that canagliflozin may affect bone health by reducing calcium uptake. In addition to its effects on glucose, the SGLT2 protein transports sodium into kidney cells. Inhibiting SGLT2 lets sodium build up outside the cells, causing another transporter to increase the cells’ uptake of phosphate. Based on results from previous studies, the researchers suspected that this increase in phosphate could trigger body-wide signals that ultimately reduce calcium absorption in the gastrointestinal tract. To test this theory, 9 female and 16 male healthy, non-diabetic volunteers received courses of canagliflozin and a placebo for 5 days each, with participants blinded to which course they received first. The participants ate a standardized diet before and during the study, so the researchers could investigate how canagliflozin affects levels of nutrients like phosphate, sodium, vitamin D (which promotes calcium absorption in the gut), and calcium. Consistent with their prediction, canagliflozin rapidly increased phosphate uptake, resulting in signals that, on average, reduced vitamin D levels in the blood as well as calcium uptake from food. The magnitude of these reductions varied from person to person, however, and were generally small enough that they might only affect the health of certain people with already low vitamin D and/or calcium levels. Though the study was too brief to measure bone fracture risk, canagliflozin’s effects on calcium uptake, a key contributor to bone health, provides a likely explanation for the increased fracture risk with canagliflozin use observed previously.

The researchers noted that it is not yet known if all SGLT2 inhibitors affect vitamin D to the same extent. Future research will also be required to confirm whether baseline vitamin D levels affect fracture risk when taking SGLT2 inhibitors, and, if so, whether modifying vitamin D levels could help protect bone health. Overall, this research revealed new insights about a possible side effect of a commonly-prescribed, heart-protective diabetes drug that could be crucial to people and their doctors seeking to personalize their diabetes treatment.

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