Well, here’s an interesting situation: a drug that seems to have a definite benefit, but not for the reasons anyone expected, and not for reasons that anyone even understands. The drug is Jardiance (empagliflozin), for diabetes, and the benefit is a flat-out survival benefit, a significant effect on cardiovascular mortality. As Matthew Herper correctly points out here, people have been looking for such an outcome from diabetes drugs for a long time, without finding all that much. Type II diabetes certainly seems to be a significant factor raising cardiovascular risks (through effects on blood vessel walls, and probably other mechanisms as well), so you’d think that the various means of keeping blood glucose levels under control would show up on that very important bottom line. But to a great extent, they don’t seem to.
Until now. Here’s the paper in the NEJM, and it’s hard to argue with. Of the hard endpoints, which one is more stony than death? De mortuis non disputandum est. Out of about 7000 patients, death from any cause was at 5.7% in the pooled drug treatment group, and 8.3% in the controls. No significant adverse event differences were seen between the two groups, outside of “genital infection”, which it’s kind of early in the morning to be writing about (urinary tract infection itself did not increase). Out of every million patients, then, you might hope for as many as 25,000 of them who don’t as soon as they otherwise would. But why? There are several strange features to the data.
For one thing, there doesn’t seem to be a dose-response; both doses of the drug came out about the same. The rates for myocardial infarction, hospitalization for unstable angina, and stroke were also within error bars across the two groups. Overall cardiovascular death, though, was down, as well as hospitalization from heart failure and rates of renal failure. So there’s a cardiovascular benefit, but it’s more heart failure than heart attack (or stroke). Many of the patients, though, didn’t reach their glycemic targets, and there seems to be no good correlation between these good outcomes and the lowering of blood glucose (as measured by glycosylated hemoglobin). So, as the authors themselves admit, “the mechanisms behind the observed benefits are speculative“.
Empagliflozin is an inhibitor of sodium glucose co-transporter 2 (SGLT-2), a mechanism that causes blood glucose to be dumped into the urine (thus the watch for urinary tract infection and kidney function). But there must be something else going on, because there are other therapies that lower blood glucose that don’t show these kinds of numbers. Seeing if the other SGLT inhibitors have this effect, and tracking down its mechanism, has now moved onto the agenda in metabolic disease. Of course, there’s the outside chance that this is due to chance, but we should find that out pretty quickly, no matter what. . .