Here are some data to file under “Drugs do things that we don’t expect”. The SGLT-2 inhibitors are a class of diabetes medications that work by inhibiting the sodium/glucose transporter 2 protein in the kidneys. That keeps glucose from being reabsorbed there; instead, more of it is removed in the urine, and that lowers circulating glucose levels. One side effect, as you might imagine, is an increased risk of urinary tract infections, but overall, the class seems to have a lot of beneficial effects.
Too many beneficial effects, actually. One of the major drugs in this category, Jardiance (empagliflozin) from Boehringer and Lilly, has recently been the subject of a big outcomes trial by the two companies. And the results were good – the drug reduced cardiovascular mortality, all-causes mortality, and hospitalizations from heart failure. Good news! But when the team dug further into the data, things got weird. You’d think that these benefits would be due to reductions in glycosylated hemoglobin (HbA1c), lower LDL cholesterol, lower blood pressure, etc. But when they corrected for all these factors, the effects persisted.
“It’s quite clear that the results that we see” from the drugmakers’ Empa-Reg Outcome study—including the 38% reduction in the risk of cardiovascular death—“really is not explained through these classical risk factors we have all been aware of for some decades now,” Thomas Seck, Boehringer’s VP of clinical development and medical affairs for its primary care unit, said in an interview.
So what the heck is it explained by? At this point, no one knows. This is reminiscent of the situation with statins, whose good outcomes are not completely explained by their reduction of LDL levels. This should serve as a reminder that (1) there are a lot of biochemical mechanisms that we don’t know about yet and (2) the ones that we know about aren’t necessarily as important as we’ve made them out to be.
Meanwhile, at the same ADA meeting where these results where released, J&J presented data on their own SGLT-2 inhibitor, Invokana (canaglifozin). And with this one, too, patients were notably less likely to suffer cardiovascular events, which is good news. But there was also an unexpected increased in the risk of amputation (which is already a risk in advanced Type II diabetes patients). This is not something that’s turned up with the other SGLT-2 compounds so far, and is also a mystery.
We do not know what a new drug is going to do, not really, until it’s gone into a large patient population. And that means, most of the time, until it’s made it to the market. Clinical trials are absolutely necessary to clear out the biggest, most noteworthy problems, and will show you the biggest, most noteworthy benefits that can be shown in the time it takes to run the trial. But the longer, more subtle things (or the ones that happen in very low incidence) will only appear once the drug is out there in the real world, being taken by a large number of people under all kinds of conditions.