SGLT2 Inhibitors

The next issue of The Medical Letter (1479; October 12, 2015) will include an article on 2 recent reports about SGLT2 inhibitors, one favorable and one a little worrisome. The SGLT2 inhibitors, which are used to treat diabetes, have been proliferating rapidly since 2013, when canagliflozin (Invokana) was the first to be approved. Dapagliflozin (Farxiga) followed in 2014, and later that year empagliflozin (Jardiance) was approved. Canagliflozin, dapagliflozin, and empagliflozin are also available in fixed-dose combinations with metformin (as Invokamet, Xigduo XR, and Synjardy, respectively), and empagliflozin is available in combination with the DPP-4 inhibitor linagliptin (as Glyxambi).

These drugs have an unusual mechanism of action for antidiabetic agents. They have no effect on insulin. Rather, they interfere with reabsorption of glucose in the kidney, which then is excreted in urine, lowering levels of glucose in blood. Diabetes clearly increases the risk of cardiovascular disease. No one has shown that lowering blood glucose levels decreases that risk, but a study published recently in The New England Journal of Medicine (September 17, 2015) found that empagliflozin reduced the risk of cardiovascular mortality significantly in patients with type 2 diabetes who had established cardiovascular disease. However, lower blood sugar levels may not be the mechanism for this positive outcome; empagliflozin also causes weight loss, lowers blood pressure, and has a diuretic effect. Increased sodium excretion could have contributed to the lower rate of hospitalization for heart failure reported in the study in patients treated with the drug.

Meanwhile, though, the FDA has found use of canagliflozin to be associated with a decrease in bone mineral density and an increased incidence of fractures, and published a safety warning to that effect. A higher incidence of fractures was reported earlier among patients with moderate renal impairment who took dapagliflozin, increasing the plausibility of the more recent report. Is that a class effect? The randomized controlled trial that produced the favorable cardiovascular results with empagliflozin found no more fractures with the active drug than with placebo, but fractures were not part of the primary endpoint of that study, which may not have been adequately powered to detect differences in their occurrence. We may be left with more questions than answers.

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  1. Barry S Gloger, MD says:

    Are we merely treating a marker with these drugs – that cause an increase of UTI’s refractory to treatment in the elderly?

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