EASD Day #2
Kelly here. I woke up so excited today, as if I knew ahead of time how many stars the day could hold! It was not disappointing for a second.
One thing that is good about Copenhagen – they don’t have decaffeinated coffee here. At least, I asked the bartender it tonight, and got a look like he thought I was crazy! I should have known they are too cool and style-y here to even consider having decaf around. It’s good, because the meeting is exhausting. One doesn’t want to miss a microsecond ...
So we wrote yesterday about the big-picture themes that have played into EASD so far – the intensifying focus on reduced glycemic variability, the increased post-prandial focus, the focus on earlier, more aggressive therapy, the focus on and the interest in avoiding complications, the growing disinterest in treating complications (granted they won’t disappear, but people really do want to avoid them altogether rather than just trying to treat), the move ever more toward reduced treatment targets, the evolving treatment pathways, the interest in more optimized outcomes, the intense interest in beta cell health, the interest in achieving normalcy. Or, better than normalcy.
Every day I find diabetes interesting, but every day, I don’t necessarily like being part of it. Sometimes I would prefer being a little more on the outside looking in. But I liked being part of diabetes today – even if I’m not really part of it, per se, as in part of the solution. Today, it seems there’s a feeling here that we can all do better – industry, doctors, patients. Doctors, patients, industry. Patients, doctors, industry. There’s a feeling here that we’re really doing pretty badly, that we won’t be able to fix everything at once, that many times we can't fix anything at once … (and I speak from the perspective of the US – try China) but that at least we should be trying and that we should be oh-so-completely going for it. We finally have some better tools, and it is just inspiring to watch, to say nothing of digging in.
So what I liked most of all today was the DREAM trial. I liked it not because of what it means commercially for GSK but because of what it meant for the disease. The PIs of this trial showed that they could change the course of this ravaging disease – what congratulations they deserve! They will look back, I hope, and be proud for moving forward the research that makes the world realize that it can be done. Yes, DPP and Tripod really taught us it could be done – but this strengthened it.
The cynic says that lifestyle can reduce progression 58% and Avandia reduces risk by 60% so why would you even consider gaining modest weight with modest CHF risk and use Avandia and
forget lifestyle? For sure, no one is saying to forget lifestyle. But from a public health (or any) perspective, lifestyle obviously doesn't work so well - we need other tools so that we can continue to generate other trials.
DREAM is not done perfectly by any stretch and there are some truly unsettling aspects of the trial results. But, here is what we care about. Despite everything that remains uncertain, the initial results in our view are promising enough that they should make Merck, Novartis, BMS, Lilly, and J&J (who must be very excited about the recent Metabolex deal) and others realize that the ROI on prevention might well be positive – and that they better go for it because if they don’t, someone else will – and because prevention is the right thing to do for past, future, and present patients.
It’s a whole new world in terms of companies working on metabolic disease – onward! The results of DREAM can be found in about one zillion places online so I won’t focus on that too much here. Here are ten thoughts on the trial:
1. Results suggest that underlying physiology can be changed. It’s not just about glucose, and it’s not just about getting good numbers somewhat consistently. It’s about avoiding the disease. There was a 62% reduction in progression to diabetes for the rosiglitizone treated group (versus the treatment arm) – in real life, that means that 10.6% of the 5,279 people in the trial progressed to diabetes compared to 25% of people on placebo.
2. Even better BETTER yet – there was also a return to real life (without diabetes) for people with pre-diabetes. Specifically, over half – half! – (51 percent) returned to normal blood glucose levels for the group, compared to about 30 percent of people on placebo. Amazingly to us this was seen after just a year, suggesting that other pre-diabetes trials mihgt well be faster than we had imagined.
3. In terms of safety, there were troubling results regarding congestive heart failure and weight gain. And, in a trial that people had hoped would provide cardiovascular benefits, none were seen.
4. 14 people in the study developed CHF who were in the treatment arm versus 2 in the placebo arm – that is a substantial difference in terms of relative risk, to be sure. The messaging seemed to focus more on “only 14 out of 5,279” than on relative risk. The math says that if 10 percent of those in the US estimated to have impaired glucose tolerance and impaired fasting glucose were treated with TZDs, 130,000 cases of diabetes would be prevented, many thousands more would move back to normal from pre-diabetes, and 4,500 cases of CHF would occur. And this math reflects the low-risk population, so in a more real life population, it’s probably a higher number who would get CFH and maybe a lower rate who would qualify!
5. Additionally, the weight gain seen by those treated with TZDs was an average 2.2 kg – while the placebo group lost a little weight - so again, were this normalized, probably the weight loss would be higher. The PIs spoke a lot about how this is the “good” weight and we get that theoretically, but back in the real world, it still brings up an illusion of someone saying, looking at you funny, “So I have pre-diabetes and now you want me to take a drug that is going to make me gain weight?! And, it’s possible I might have a heart attack? More possible than otherwise? Um, what?”
6. Of course there are many questions: 1) How can we learn more about the CHF (there were no deaths, but no matter – we wouldn’t be at the point of examining death yet, after only three years); 2) Is it possible to minimize weight gain and CHF? 3) How can we figure out the return on investment for the trial overall – we know avoiding risk overall is impossible, so it is just tradeoffs – which are the right ones?; 4) How is beta cell health? 5) What will GSK do - is this enough to submit to the FDA for registration for pre-diabetes? (We think not, because of all the safety concerns but we note a trial might not take as long as had been expected, perhaps two years.) 6) Will we see reimbursement?
7. One big bucket of questions concerns other diabetes companies. We think the results of the trial are a major signal to big pharma invest further in pre-diabetes. We really like the idea of DPP4s and GLP-1 being tested for prevention (since safety and tolerability seem to have a better record) and we oh-so-LOVE the idea of LAR being considered for prevention. Who knows what they will find, but I love the idea of such a potentially fruitful investment because n=1, but I have this disease and I loathe it. I talk a lot about how having it gives me the chance to be healthier than I otherwise might be, and I think most days I am pretty legitimately glass half full about it. But I also think it's wrong to ignore that people with diabetes also actively or passively resent that their bodies betray them every single day. It’s all super sub-optimal once you have this disease, with or without complications. It’s all a continuum that you really don’t want to be on, however bright you can say things are.
8. So, let’s also not let some random statistician deciding to take away others’ chances of prevention just because of a signal we don’t even know yet is weak or positive. Based on what we've seen, we'd say we would think it quite negative, but we're not so expert about that.
9. Epidemiologist Dr. Nick Wareham did an amazing job of pointing out some of the risks and helping us think about potential safety signals, cost effectiveness, etc - and his last slide said it all "INDEPENDENT."
10. So speculation is rampant - let’s not miss the forest for the trees. DEMAND is incredibly important work that has been done and it should be congratulated and taken oh-so-seriously – and then we should wait for more work on side effects – maybe they are enough to suggest people with pre-diabetes not take this, maybe they aren’t. It would probably be best if we don’t behave like any of us knows yet. On that note, we can’t wait to see washout data in South Africa to see what sort of picture is there …