Dr. Darren McGuire presents how regulatory requirements have dramatically altered the trial landscape of drug development for type 2 diabetes.
So I'm going to go through at a Very high altitude top level results from over a decade of clinical trials, outcomes. We started I guess in 2015 with the emperor the outcome. But remember we had a few trials before improving outcomes. So for um since about 2000 and 13 we've been having outcomes trials data um emerged from the anti hypoglycemic realm. And that's all based on this 2000 and eight announcement from the FDA that said from this day forward, All anti hypoglycemic agents being developed for type two diabetes have to undergo cardiovascular safety assessment. So this was a paradigm shift up until this guidance in 2008, you could get a drug to market in the United States for the treatment of type two diabetes with as little as 250 patient years of exposure, You only had to have 100 patients exposed for one year to get your drug to market for type two diabetes. And that's just absolutely insane. That's that's not even a pilot trial. Um but that that was the the coin of the realm at the time. And so the FDA flipped the switch and when this switch was flipped, this increased the Number of patient years of exposure to get a drug to market to stay on the market from 250 to 15,000. So this was a 70-fold increase in the patient year exposure for registration of diabetes drugs. Now why did that come about? A lot of people said, well that was all because of rosie glitches. Um and the myocardial infarction single. And I will say that rose egotism and the risk for my carl infarction was the reason that this actually came to the table. But we had been having and many others had been having conversations for over a decade prior to that with the F. D. A. Pushing them continually to amplify the thresholds for bringing drugs to market because with little patient your exposure, you simply cannot assess safety of a intervention. And so um so what happened behind that? 2000 and eight guidance? Well first there was an increasing incidence and prevalence of Type two diabetes. Um When I went through residency the type two diabetes prevalence in the United States was somewhere around 2%. And now it's estimated to be somewhere around 13 to 14% if we count the patients with undiagnosed diabetes. And so we have more than one out of 10 U. S. Adults with type two diabetes. So this is a public health catastrophe that we have to have evidence based data to know how best to handle. Um over those last 20 years there's been a growing awareness of cardiovascular impact on type two diabetes. When I was a second-year resident in 1995 I decided I wanted to focus on diabetes as a cardiologist as a cardiovascular disease and all of my cardiology colleagues thought I was crazy. Um Nobody was interested in diabetes at the time from a cardiovascular perspective and I would like to say I was really smart and I saw all of this coming. But I was just lucky at the right place at the right time. Um But as I went through residency we almost never, I don't remember ever talking about cardiovascular disease when we were dealing with diabetes. We were always just focused on the glucose and often secondarily on the kidney disease. But we know now today there's certainly as I just presented a clear relationship where really cardiovascular disease is the primary complication of diabetes. And then of course there were a number of examples of adverse drug effects. If you bring a drug to market with only 250 patient years of exposure, we are commonly seeing adverse events emerge in Pharma. Co surveillance after drugs are on the market that we didn't expect. Like tribalism causing liver failure or the TCDD is causing heart failure or the TCDD is causing macular oedema or the T. C. D. S causing small bone fractures. Um Rosie Glisan causing myocardial infarction. So it wasn't just rosy glow to zone. It was a lot of adverse drug effects across multiple classes of medicines causing the concern. And these were on target effects sometimes like hypoglycemia and weight gain. Um that are expected by the mechanism of action. But a lot of off target effects. And then finally um there was a proliferation of medications available. So as I went through residency, all we had was insulin and so funny area. And then in 1995 as I was a second year resident, Metformin came online and in 1997 the T. C. D. S. And so um from that point until now we now have more classes of medications. 13 different classes of medications for anti hypoglycemic therapies. That's more classes than anti hypertensive. And so we have this this whole uh cornucopia of of medications to choose from. So there's no longer a an imperative to rapidly get new drugs to market for an unmet clinical need. We have lots to choose from. So we now have the luxury of time to slow down and to actually test the new drugs. Sometimes new drugs versus placebo, sometimes new drugs versus old drugs. And as I mentioned about the Metformin Random Ization. I think it's time to test some of the old drugs against a placebo. This just shows you compared with the blue is the numbers of classes of medications to treat hypertension. And in the red are the numbers of classes of medications to treat hyperglycemia in Type two diabetes. And you can see that almost vertical line beginning in 1995 were, on average, once every two years, we've had a new class of medicines emerged for the treatment of type two diabetes. And I'll focus my comments on the three most recent and prevalent classes, the STL T two inhibitors, the DPP four inhibitors and the GLP one receptor agonists. Well, So let's start with the DPP four inhibitors for available on the market. Once daily tablets. These are the clipped in cities. Lipton sacks of Lipton, Alig, Lipton and Lena Clinton. They all have cardiovascular outcomes trials completed. This is a meta analysis or actually not a meta analysis a pulled plot of the primary outcomes of each of the DPP four inhibitor trials that have been completed. These are listed from top to bottom in the order with which they were completed. That the top is the savor timI 53 trial of Saxon captain versus placebo examine of Allah Lipton versus placebo, Ticos of civic Lipton versus placebo and car Molina with lena, Lipton versus placebo. And as you can see each individual trial and across the class, there's almost exact unity of the point estimates. 1.0, so it ranges from 0.96 to 1.2. So this is probably $2 billion spent to prove that these drugs are perfectly placebos. So they do not do anything at all to the cardiovascular risk. So, the good news here is we've proven with great statistical rigor that these are safe to use in very high risk patients. But we've also proven that none of them favorably affect cardiovascular risk. And so after we completed many of these trials, I was involved in all of these except for examine. And there was lots of criticism in the field that we're wasting our money. We're not making any progress. But I will say having safety data is a big step forward. It's not the wind that we were hoping for that. We would favorably affect risk. But we're certainly proving statistically we're not harming folks. And that's important when you look at this. So funny areas that to this day have a product labeled warning that these drugs may increase cardiovascular death. Um That's still in the every product label for every cell phone area today in the United States. We don't know about the cardiovascular safety of so funny areas. We don't know about the cardiovascular safety of uh the T. C. D. S. We think they're probably safe. There is a heart failure signal um that we can manage but we're uncertain with a lot of the therapies we use. So that's a step forward. And as was mentioned in the previous talk, we had a surprising finding in the savory to me, 53 trial at the top there's a statistically significant increased risk for heart failure. 27 increased risk and these were prospectively collected and centrally adjudicated events. So this is bona fide heart failure that we saw in the savor timI. 53 trial. We believe that this is a real finding that for some reason we don't understand sexy Clapton increases the risk for heart failure. The similar signal was seen in the examined trial with alec Lipton a point estimate and the adverse direction there were fewer events that, so this is a a less less powerful statistical analysis. Um but it doesn't achieve statistical significance. So the people who want, I believe in eric Lipton say there's no statistical difference, but I think the signal looks similar more similar to than different from that with sexy clipped and so I still have some concern about alec Lipton with regard to its safety for heart fire. Because of those observations, I was involved in the tacos and the caramel in a trial and I designed a c prospective statistical analysis plan for heart failure assessment. And so in the first two trials, that was an accidental finding that wasn't pre specified. So it was a bit of a data dredge. Again, I think it's legitimate, but we didn't plan for it. It's more statistically legitimate when you make a prospective statistical plans. And so we filed with the FDA and european medicines Agency. Our plan to analyze heart failure with citic Lipton and with lena clipped in and as you can see, there's no signal of harm with either of those two drugs. In fact, a favorable point estimate with Lena clinton, I wouldn't go so far as to say that Lena Krypton improves heart failure risk, but I'm pretty confident that neither of these two drugs increased heart failure risk. So The summary there is if you're going to use a DPP four inhibitor, it should probably be citic Lipton or lena Lipton then to the S. G. L. T. Two inhibitors integral flows in Canada flows in. Capital flows in an article flows. And now this class of medicines, as you know, has been a game changer in the field of Type two diabetes because of their cardiovascular benefits. And this is a meta analysis we published on the heels of the presentation of the various CV trial. So from top to bottom these are in Pickle flows in and temporary outcome. Cannibal flows in the canvas trials program. Capital flows in and the declared to me 58 trial again, Canada flows in in the credence trial and error to go flows in the verde CV trial. All of these trials enrolled patients with type two diabetes. All of these trials enrolled patients with prevalent atherosclerotic cardiovascular disease And the canvas trials program declaring credence also enrolled patients with multiple cardiac risk factors. These are the primary outcomes, cardiovascular death, M. I. And stroke from top to bottom you can see that both in empowering outcome. The canvas trials program and in the credence trial in Pickle flows in and chemical flows in statistically significantly improved risk for a. S. CBD based events. Capital flows in an article flows did not achieve statistical separation. So they were proven safe Because the upper confidence limit was within the 1.3 non inferiority margin to determine safety. So both irritable flows in and ethical flows in our safe but not incrementally beneficial with regards to the cardiovascular death in my and stroke stroke outcome. These are heart failure outcomes from each of the trials. Again in all of these trials, heart failure was captured prospectively and centrally adjudicated using exactly the same definitions across the trials. And as you can see here, a very different story from the prior slide that had a fair amount of heterogeneity between the trials Here there is extraordinary consistency from one trial to the next. So the independent of the population studied or the drug studied. Um there's almost identical effect on risk reduction for heart failure. Uphold estimate of 32% relative risk reduction. That's a huge reduction for a cardiovascular outcome. 32%. And then the bottom left without getting too statistically geeky. I'll tell you this I squared value. This is the estimate of the proportion of the difference from one trial to the next result. What proportion cannot be explained by chance alone? So the lower this I squared the more likely that any difference between the trials is just furious is just chance. So when you get an I squared value of zero that's extraordinary consistency in the estimate of the effect across the trials. And I'll just contrast that with the previous slide for a S. C. V. D. The I. Squared value is a moderate degree of heterogeneity between the trials 23% cannot be explained by chance alone And then finally for the composite chronic kidney disease outcome, this is sustained reduction of EGFRF 40% or renal replacement therapy or kidney related death. So when you harmonize the kidney composite outcome across the trials, each of these trials use slightly different definitions for their composites for the primary outcome. But in this slide we've made all of the definitions the same and again, look at the bottom left that I squared value is 0%. So extraordinary consistency with the effect across the class across the populations In the reduction and risk of progression of diabetic kidney disease. So both for heart failure and for kidney disease, these drugs are extraordinarily potent and all of them are more similar than they are different and that summarized here across the trials of type two diabetes for cardiovascular disease. Um, only infrared outcome achieved statistical reduction in death alone. Both infrared outcome in canvas and major adverse cardiovascular events. But all four of the trials and all four of the compounds achieve statistical significance for heart failure and for kidney disease related outcomes. Last class we'll talk about are the GLP one receptor agonist and they're listed here. I'm not going to read all of the names but on the left or the genetic generic names and on the right are the trade names. The only time I use trade names. These summary slides and as many of you know, we're now developing an oral GLP one receptor agonist that's on the market for the treatment of hyperglycemia. I'm chairing a cardiovascular outcomes trial called the Soul Trial where we have almost 10,000 patients enrolled with the same magnetite oral versus placebo to test the cardiovascular safety and efficacy of this new formulation. Um And that trials ongoing. We don't have outcomes evidence yet for that one. And here's the most recently published meta analysis. This is just a few weeks old. These are meta analysis that now include at the bottom the amplitude oh trial of FP glitter tied epic limited is not available are approved on the on the market but it is has been studied and repo reported from the amplitude Oh trial. And as you can see across the class this is cardiovascular death. Um I and stroke. The aggregate estimate of efficacy is a 14% relative risk reduction. But look again at the bottom left. Professor Sitar is also using the I squared value here is approaching 50. So this is twice the heterogeneity that we saw in the S. G. L. T. Two inhibitors for the same outcome. So there's much more heterogeneity across this class. And as was mentioned in the previous lecture. Um a lot of the heterogeneity is driven by the sustained six trial which now has a product labeled indication for some magnetite injectable for cardiovascular risk reduction. The leader trial which supports the Lord Raglan tied once daily injectable uh cardiovascular risk reduction indication and the rewind trial with dual blue tide which also has a cardiovascular risk reduction indication. Here's the heart failure analysis, a much lower point estimate of relative risk reduction. The class pull estimate. It does achieve nominal statistical significance. So barely excludes the line immunity with an upper confidence limit of 0.98 but an 11% relative risk reduction. Remember the STL T two inhibitors have a 32%. So three times more risk reduction with s guilty two inhibitors with regards to heart failure. But importantly, I think this plot shows us that GLP one receptor agonist in a patient population at high risk for heart failure. These appear to be quite safe drugs if not incrementally beneficial. Just one word of caution about the GOP one receptor agonist. We we still are not completely certain about the safety of their use in patients with advanced systolic heart failure. This is the fight trial that randomized patients with low ejection fraction, heart failure. Symptomatic with new york heart association class two or greater symptoms. Um, and they were randomized Galarraga tied versus placebo. These are patients with or without diabetes. And you can see the point estimate that Laura got eyes on the top. So numerically a higher risk for heart failure related outcomes. And a point estimate of 1.3 or 30 increased risk that barely misses statistical significance. And so this is a non definitive result because of the lack of statistical significance. But the point estimate is in an unfavorable direction for laura to tighten finally with the effects on the kidney disease outcome. The same composite outcome I showed you with the S. G. L. T two inhibitors and here the G. O. P. One receptor agonists failed to achieve statistical significance on reduction of kidney function risk. And if you take albumin urea Out of this outcome um you get a point estimate of almost exactly 1.0. So um there's no harm, it's safe to use all the way down to dialysis. There's no dose adjustment required but there's no clear incremental benefit of kidney disease progression with the G. O. P. One receptor agonists. So as was hinted at uh you've seen the standards of care and the previous talk, I'll show you a few additional guidelines. These are now these data are now completely saturating all of the endocrine and cardiology guidelines for the care of patients with type two diabetes very similar and parallel with the standards of medical care for patients with diabetes that was just presented this joint Society recommendation including the E. A. S. D. Now say if a. S. C. V. D. Predominance the same recommendation as before use one of the two classes of medications choosing the agents that have been our evidence based for risk reduction. If heart failure or CKD predominance SGL T two inhibitors are preferred. This is a cardiology recommendation. This is the a. C. C. Decision pathway recommending exactly the same thing. If the patient has Type two diabetes and A. S. C. V. D. At least a discussion is warranted if the patient should be on an S guilty two inhibitor or a GLP one receptor agonist and that's for cardiovascular risk indication. And just like the current the contemporary guidelines in the endocrine space, this is not predicated on the need for additional glucose control. This is simply adding these medications to patients who have just who have uh a minimal level of atherosclerotic vascular disease risk. And lastly, the european society of Cardiology, getting to the Metformin first question the E. S. C. Has fired a shot across the bow and said if the patient has newly diagnosed diabetes and is drug naive who has cardiovascular disease, consider starting as the first line therapy and SGL T two inhibitor or G. O. P one receptor agonist. If they don't have a CD or high risk Metformin monotherapy remains the first line therapy recommended on the right of the patients already on Metformin or on any other medications for glucose control, consider adding S GUILTY two inhibitor or GLP one receptor agonist for incremental cardiovascular risk reduction. And this is summarized all including blood pressure care and LDL cholesterol care and lifestyle modification is all summarized in a very recent update to the H. A. Society recommendations published in circulation last year. So I'll finish their we've studied now over 300,000 and I haven't done that calculation I suspect is getting closer to 400,000 patients in randomized trials. We have 11 trials proving safety and seven trial programs proving benefit. Uh And the benefits are associated with the S. E. A. L. T. Two inhibitors and the GOP one receptor agonist. And this has now directly impacted contemporary here and the guideline recommendations. So Athena um back to you. Yeah. Thank you Darren. That was fabulous. Um I really feel very fortunate that we have you with us as a real expert in this field and someone that's been deeply involved in all of these studies. Um Can you just comment a little bit more on the E. S. C. Recommendations and what you think? I mean they've kind of taken that leap. Um But maybe not without as much concrete data as we would like and evidence. What do you think? Yeah. I have to admit that I was I had a part in that. Um We had published a paper we had been invited to publish a paper um querying whether Metformin should be first. And so we published a fairly provocative opinion, most of which I believe. But we kind of went way to the extreme just to shake people out of their comfort zone. But we the end of that. We recommended that Metformin should probably be somewhere between 5th and 7th line, Wow. The evidence and the reality is we have more evidence for each individual DPP four inhibitor than we have for the totality of metformin randomized trials. Um and so we have much more confidence, at least in the safety. Um We've not even proven safety with statistical rigor with Metformin. Now I believe it's safe. Don't get me wrong. I'm not saying that it's not safe and I'm not even saying that it's not incrementally beneficial. I'm just saying we haven't studied it. We haven't rigorously put it to the test. Um And so and so um I shared that with Nico Marks, my good friend who is a co chair of that guideline writing committee, I shared my paper and Pope prodded him a little bit too to take that step. And they did they can't say they did it because of me. But but you know, a guideline is very different also than a consensus, right? And so the standards of medical care is not a guideline, it's a consensus statement. The A D A S C E S. D. S, a consensus statement. When you put it to the The formal guideline rig or metformin cannot be first line. It simply is not evidence based. You have to go statistically rigorously by the level of evidence available. And so I think as a guideline they got it right whether it's the right answer clinically. I don't know, let me just say one additional thing. A lot of people say. Well all of the new drugs were tested on the background of Metformin. I will tell you that as many as 40% of the credence trial, 40% of the patients were not on Metformin in every trial. At least 15% of the patients. So you take a trial like declare with 16,000 patients. 20% not on Metformin. Now you've got a subset not on Metformin. That's as big as the U. K. P. D. S trial. So a subset within a bigger trial. Not on Metformin. And we when we do sub analysis of Metformin background or not, we don't see any difference in the efficacy of the new drugs. And so the additional benefit of the new drugs is not predicated on the presence of Metformin. Mm hmm. And when you're saying ethics, you're talking about cardiovascular cardiovascular outcomes. Not like Not at all, glucose. No. And to that point and I didn't mention and I'm glad you raised that. Just to remind people all of these trials, I just presented every one of them was designed identically with regards to glucose. And that is we intended to test the cardiovascular effects and safety of the drug itself and not test glucose control. So all of these trials were intentionally designed to have what we refer to as glycemic equipoise. We wanted the two groups to have as close to identical a one CS as we can. So there's really no ability to test the efficacy with regards to glucose controlling these cardiovascular outcomes trials. And so we don't know if and what I suspect and we see it in all the trials, you know the placebo treated patients and all of these trials had more drop in anti hypoglycemic therapies. They had more initiation of insulin, they had more tea tray shin of insulin. They had more addition of other oral, anti hypoglycemic. That's because they were being managed for their glucose during the trials. So um I would say, you know, if you if you can get a patient who who has indication for an STL T two inhibitor and or a GLP one receptor agonist to your therapeutic target for that patient with one or two of those drugs. Um Then there's I'm not sure what the need for Metformin is and there are lots of patients like that. But I would certainly I would personally reach for matt foreman in that kind of patient probably after I had a patient on one of the two drugs and they weren't at goal. I'd probably go to Metformin before I added a second and that's based on cost access and cost more than anything. Do we need a study to look at that had had starting and we have uh this year at 88. Um the initial information was presented on grade which was glycemic reduction approaches and diabetes comparative effectiveness. Um but that was still second line to Metformin. It was not uh initial therapy and it had some interesting results. We I don't think I've seen the publication out yet for it uh with La Regla tied showing um some benefit there in cardiovascular outcomes will have to wait for the final paper on that. But um do we need that study? We need it. And and of course, as you, as you're hinting at, um there's such um there's such a passion for Metformin that a lot of people believe it would be unethical to randomize people not to get Metformin. But, you know, we've got a lot of other, much more aggressive trials. You know, back in when I was a fellow, my mentor was designing one of the hormone replacement therapy randomized trials. And you know, the epidemiology was so consistently and robust that how could you ever randomize a woman postmenopausal to placebo and look what we found out exactly. I remember that coming out fascinating. Sometimes you test your dogma, it gets a little bit uncomfortable, but at the end of the day it's much better to have confidence. What you're doing is the right thing. Yeah, yep. Um All right. I I don't see any other questions coming in from our audience at this time, uh anything any last comments you might want to make before we sign off? Well, I'll just sure, I'll make just a couple that we have a minute. You know, we're not done. We have a lot of cool stuff coming out. I think probably a lot of people have seen the heart failure results from typical flows in and capital flows. And that's exciting, both for patients with and without diabetes. As I mentioned, we're doing the outcomes trial for the oral some magnetite formulation. That will be interesting. I'm also on the executive committee of the outcomes trial for tourists appetite. I think that's a really exciting uh therapeutic, that's a dual GLP one G I. P agonist. So we're we're targeting two different in Cretan axes. Um the early data on glycemic control and on weight loss with hers appetite look really intriguing. Just three days ago, the surpass four trial was published in the Lancet showing better glycemic control versus thai traded insulin gar gene and substantial weight loss. I mean, the weight loss with this, this drug is approaching bariatric surgery. So, you know, there's there's still some interesting stuff coming around. I'm sure there's a lot more I don't know about, but absolutely no, I think that's fabulous. In addition to potential other risk factors that we're not addressing. You showed us 567 risk factors. But um later on, I think right after a break, we're gonna have Harpreet, who's going to talk a little bit about LP little a um there might be other things that we really need to consider too, continue to incrementally drop those um those risks if we could do it all all together, which is really the beauty of the steno, how do you, in a practical, real world environment, be able to control and administer all these medications in the way that they need to be done. Uh Yeah. Right. You come back. I was just gonna say, I think weight is weight management is going to re emerge. You know, it kind of ebbs and flows and our attention to weight loss management. But now as we have the GLP one receptor agonist and tricep it tight pins out. We're going to have some some therapeutic choices that not only induce weight loss, they sustain it and they also favorably affect outcomes and absolutely, absolutely. And and our tomorrow our entire half day is dedicated to obesity management. So all good points. Great. Until the link is also right in the mix there internationally in that space too. So, she may have some comments about obesity. Terrific. Well, thank you so much Darren. It was a pleasure to have you. We really appreciate it. Hope you have a great rest of the day there in texas and in Dallas and we'll be seeing you soon. Okay, look forward to seeing you
