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Clinical Trials

Fewer Die – But Why?

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. . .

20 comments on “Fewer Die – But Why?”

  1. Biggie Mac says:

    The drug reduces blood pressure. Other anti-diabetic agents don’t. Not surprising this one has a mortality benefit. Many diabetics have systolic blood pressure over 120 mmHg. A recent NIH study suggested that further lowering of systolic BP below the 140 mmHg target towards the 120 mmHg range has a mortality benefit. Physicians argue good luck even getting patients down to 140.

  2. Kelvin says:

    If anything this just confirms that serendipity is still way way ahead of our very limited understanding of human biology and disease. Now, if only we could develop and implement systems that capture that serendipity more efficiently rather than relying on our inflated ego and belief that we know what we are doing.

  3. James McRedmond says:

    I wonder would there be a benefit in a non-diabetic population – there is plenty of skepticism about the benefits of lowering blood glucose, but could there be some beneficial pleiotropic effect?

  4. Mark Thorson says:

    Type 2 diabetes is also associated with a much greater risk of Alzheimer’s disease. Someone should check if this drug has a favorable impact on that, too.

  5. Tuck says:

    If I understand this correctly, it causes the body to dump a toxin (excess glucose) out of the body. Other mechanisms for reducing blood glucose control do not remove the toxin from the body.

    Why is it surprising that removing a toxin should reduce the negative effects of that toxin?

    The dose-response problem you note implies that the higher dose is much higher than is required, if it has no extra effect.

    What this drug does is mimic the effects on diabetes of a low-carb diet through, literally, the back door. Lower excess glucose in the body is less harmful to the body.

    The variation in glycemic target versus effect shouldn’t be to surprising either, given the wide variation in glucose toleration in the population.

    And to the commenter above, high blood pressure is simply a symptom of excess serum glucose. It’s well demonstrated that the body’s reaction to glucose in solution (in the gut or the blood) is to attempt to dilute it by adding water. See Yancy’s comparison of orlistat to a low-carb diet.

  6. dearieme says:

    There are serious arguments that the good statins do, when they do any good at all, is not related to their lowering of cholesterol readings, but to some other mechanism. The case sounds to be analogous.

  7. Anonymous says:

    I’m glad we have Tuck here to explain to us how this is all so simple.

  8. Anonymous says:

    Yep, good ol’ toxic glucose. If only there were a way to keep that from running around the bloodstream.

  9. milkshake says:

    The drug is a pretty good diuretic – when you dump lots of glucose (up to 100g a day) in your urine, you pass it together with lots of water, and this results in weight loss and lowering blood pressure. Incidentally, diuretics are favorite add-on for heart failure patients…

  10. flem says:

    the drug is approved to lower blood glucose. it improves CV mortality but not apparently due to quantitative glucose control. Could it be that unlike cholesterol, or BP, the benefits of blood glucose lowering is HOW you lower it rather than how much it is lowered?
    When are J&J’s CVOT due?

  11. anonymous says:

    The drug lowers glucose, blood pressure, and body weight. My bet is on the blood pressure and body weight loss as factors in the positive cardiovascular outcomes. As a sodium-dependent glucose transport inhibitor, the drug blocks both sodium and glucose reabsorption in the proximal tubule, providing diuretic effect via both osmolytes. While some of the sodium will later be absorbed in the distal tubule, where normal loop diuretics function, sodium excretion increases over placebo even without them. If these patients were also on diuretics, as some hypertensive diabetics are, it is possible that SGLT2 inhibitors in combination with loop diuretics are additive for sodium excretion. It would be interesting to see if survival rate is enhanced over the total patient population in patients who were on loop diuretics for BP control.

    I don’t think this is a huge medical mystery requiring off-target effects or mysterious, as yet undiscovered effects of renal glucose absorption physiology on cardiovascular function. I think it is, as expected, the impact of small, incremental decreases in blood pressure over a long period of time. It has long been known that relatively modest blood pressure reduction in diabetics will have a positive impact on cardio outcome above aggressive glycemic control alone. In the ADVANCE study of over 11,000 patients “Compared with placebo, additional blood pressure lowering of 5.6/2.2 mmHg was associated with reductions of 9% in the primary endpoint (P = 0.041), 18% in cardiovascular death (P = 0.027), 14% in total mortality (P = 0.025), and 21% in total renal events (P < 0.01)."

  12. Eric says:

    Anonymous: ” I think it is, as expected, the impact of small, incremental decreases in blood pressure over a long period of time.”

    If this were primarily the result of reduced BP wouldn’t one expect that strokes would be decreased in the trial? (they weren’t) I’m sure reduced BP played a role, but I’d be cautious of oversimplifying the outcome. Perhaps it’s a combination of reduced BP, weight loss, and glucose reduction.

    I do find it somewhat interesting that the Kaplan-Meier curve for the primary outcome shows some separation between empagliflozin and placebo within the first 6 months and then the two curves are essentially parallel for the next 42 months. Furthermore, the separation is due to an uptick in the placebo group rather than a drug-related decrease. Some of the other curves (death from CV causes for example) look more like what one would expect. It may not mean anything, but it’s odd.

  13. Tuck says:

    “I’m glad we have Tuck here to explain to us how this is all so simple.”

    I read up a few years ago on how to reverse diabetic kidney failure. It turns out a ketogenic diet does it in rodents, and as they discovered by accident, in humans. It happens in weeks.

    One of the leading experts commented “It is too simple to say that kidney failure could be prevented by diet alone…”

    Yet Jason Fung, a Canadian nephrologist is doing just that. Why should that be surprising? It was the standard, and very effective, treatment prior to the discovery of insulin. Harvard’s Joslin Center for Diabetes is named for a prominent proponent of dietary treatment of diabetes.

    Diabetes is a disease of carbohydrate intolerance. Remove the cause, remove the symptoms.

    Sometimes it really is simple.

  14. PharmaHeretic says:

    Care to comment?

    Company hikes price 5,000% for drug that fights complication of AIDS, cancer.(

    “Turing Pharmaceuticals of New York raised the price of Daraprim from $13.50 per pill to $750 per pill last month, shortly after purchasing the rights to the drug from Impax Laboratories. Turing has exclusive rights to market Daraprim (pyrimethamine), on the market since 1953. Daraprim fights toxoplasmosis, the second most common food-borne disease, which can easily infect people whose immune systems have been weakened by AIDS, chemotherapy or even pregnancy, according to the Centers for Disease Control.”

  15. Andy II says:

    First to PharmaHeretic

    Most interesting quote is the last 2 paragraphs in the USA Today’s article. I don’t think it is convincing enough…

    “A Turing spokesman, Craig Rothenberg defended Daraprim’s price, saying that the company will use the money it makes from sales to further research treatments for toxoplasmosis. They also plan to invest in marketing and education tools to make people more aware of the disease.

    “There has been no innovation in dealing with toxoplasmosis,” Rothenberg said. “That has been a long neglect in the patient community.”

    Re Jardiance story, it is fascinating and sounds not simple until we have a full set of patient data to figure out any correlations between drug, drug MOA (supposed), and unexpected outcome. In the meantime, we may weigh these positives and potential nagatives: this SGLT-2 inhibitor for Type 2 diabetes has warning of causing ketoacidosis, fatal swelling of the brain, severe dehydration, coma, pancreatic and prostate cancer (or even a potential treatment option for these cancers as these cancer cells express SGLT-2 for glucose uptake,, and increasing bone fracture. Both Jardiance and Invokana are C-glucoside derivatives while Ertugliflozin (Merck and Pfizer) is a sort of C-glucoside with an additional ring on the glucose frame.
    We will see what this finding would change the choice of drug for diabetes: insulin, PPD-4 or SGLT-2.

  16. JFT says:

    I think the lesson from this is the same one we can draw from the relative failure of the statins to reduce mortality-an easy endpoint for determining drug efficacy is changing some serum number. But just because we can lower the cholesterol, increase the insulin, change the serotonin levels doesn’t mean we are doing anything. In many cases it is clear that these values are correlated with pathogenic states but it is NOT clear that they cause the pathogenic state. I always think about this like the air conditioner control in my PhD. lab. The room was a temperature. The readout on the thermostat was correlated to the temperature of the room initially when left untouched. However, when we changed the values on the thermostat, although the readout changed, the temperature of the room reamined unaffected. The thermostat didn’t actually feedback to the power plant to change the climate-control in the room. No effect was noted. So, a preliminary study would have shown that hot rooms had high temperature readouts on the thermostat, and cold rooms had low temperatures on the thermostat and the correlation was 100 %. There appeared to be a clear mechanism of action as well-the thermostats were well known to affect the temperature of the room in residential settings. However, by finding an intervention that could routinely, reliably, and reproducibly lower the thermostat (ie hitting the buttons repeatedly) we had no impact on the climate conditions. Both the room temperature and the thermostat were symptoms of the same underlying cause-the perversity of the incompetent engineers at the physical plant, and were not directly related to each other. I feel a lot of drugs are doing just this-turning down a reading without actually affecting the underlying condition-and then we all get surprised when mortality remains unchanged despite the numbers getting better. It is nice to see that the opposite happens sometimes too.

    I think the best example is the SSRIs. They work. They reduce serotonin re-uptake. But they don’t seem to help the vast majority of people based on the new meta studies. This might very well be because people are not depressed because there is too little serotonin in the synapse. They have too little serotonin in the synapse because they are depressed.

    The erectile dysfunction pills suffer from the same problem. Very few prescriptions are renewed because most users suffer erectile dysfunction because of life dysfunction, not because their circulatory systems don’t work.

    We need these blockbuster drugs to sell to pay for drug development, and our drug development process is something we all strongly believe in-it is the best way we currently have, but we need to be far more careful and selective and thoughtful about our biological targets. The debates in Alzheimer’s and Parkinson’s research right now are excellent-we need to know if we are chasing the right target before rushing in and spending a few billion going after beta-amyloid and prions if we figure out that they are simply a symptom of the disease-like the neurodegeneration-rather than the underlying cause.

  17. steve says:

    Clearly there is something interesting going on here. Lot’s of drugs control glucose levels without effects on mortality so Tuck’s comments are irrelevant (besides which, you remove the “toxin” and you go into hypoglycemia and die so just getting rid of glucose is not an answer). Lot’s of diabetics are on diuretics so I find it hard to believe that a simple diuretic effect would answer the question nor would just reduction in BP seem to be the answer as these patients were on BP meds as well.

    Sometimes it pays to read the actual publication before voicing an opinion. As it says in the Discussion, “These benefits were observed in a population with established cardiovascular disease in whom cardiovascular risk factors, including blood pressure and dyslipidemia, were well treated with the use of renin–angiotensin–aldosterone system inhibitors, statins, and acetylsalicylic acid. The reductions in the risk of cardiovascular death in the empagliflozin group were consistent across subgroups according to baseline characteristics.”

  18. steve says:

    Don’t know why my spell-checker kept adding an apostrophe in “Lots”; sorry about that.

  19. flem says:

    Let’s face it most Dr’s prescribe on the basis of biomarkers (BP, A1C, LDL). When the 4S study was published it confirmed for the first time that you can reduce CV event by reducing LDL in a secondary prevention. This made LDL a cardiology concern in addition to an endocrinologist issue. I don’t know what biomarker will be used to use SGLT2 given this outcome. Until more is understood or confirmed, I suspect “early adopters” will simply add this drug (after metformin) in diabetic patients with heart failure given the outcomes.

  20. Vader says:

    Oh, yes, let’s get that toxic glucose out of the bloodstream. It turns out we already have quite a few drugs that do that; we’re evidently just not using a high enough dose.

    I’ll wager any amount of money that, if you eliminate glucose from the bloodstream of a sample of patients, they will show zero mortality from adverse cardiovascular events ten years down the road.

    (Knocks on side of head) “Is this thing working?”

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