Activity Transcript

Filip K. Knop, MD PhD: Hello, I'm Filip Knop, head of the center for clinical metabolic research at Gentofte Hospital, University of Copenhagen in Denmark. Welcome to this program titled 'A Digestive Latest Clinical Data with GLP-1 Receptor Agonists'. Joining me today is Subodh Verma who is a professor of surgery, and also pharmacology and toxicology, at the University of Toronto, and also Canada Research Chair in cardiovascular surgery. Welcome to you, Subodh.

Subodh Verma MD, PhD, FRCSC, FAHA: It's my pleasure to join you here from Toronto. Thank you very much for the opportunity.

Dr Knop: It's great to have you on board. So today, Subodh, we're going to discuss latest updates in GLP-1 receptor agonists, looking at data and new insights, including those just presented at the American Diabetes Association Scientific Sessions, 2020. So there has been a lot of fuss about GLP-1 receptor agonists, I guess we have a lot to cover, but first, let's look at glycemic control. What have we learned from the recent ADA meeting about glucose control with GLP-1 receptor agonists?

Dr Verma: I was particularly intrigued by the LIRA-PRIME study, which was, as you know, an open-label phase 4 trial that was done in primary care setting in nine countries. And the question that was being addressed here was, "In a randomized open-label setting, is liraglutide better, or is oral antidiabetic therapy intensification better, in patients with type 2 diabetes not controlled on metformin?"

So what they've done here is they've randomized patients to LIRA or any other oral antidiabetic agent, including alpha-glucosidase inhibitors, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas, thiazolidinediones, and I think that the most commonly used agent for intensification was either a SGLT-2 inhibitor or a DPP-4 inhibitor. And the primary endpoint was the time to inadequate glycemic control defined as an A1C of greater than 7%. And this was studied at two consecutive visits, 12 weeks apart, after the first 26 weeks of treatment.

And what they found here was that a strategy of liraglutide significantly reduced the risk of inadequate glycemic control compared to another strategy of intensification with an oral antidiabetic therapy. However, the rates of serious AEs and hypoglycemia episodes were similar, but from a GI standpoint, there seemed to be a numeric increase in the GI side effects with a liraglutide-based regimen.

Another very interesting sub-analysis came from the PIONEER program, and this was an exploratory analysis of PIONEER 1 through 5, and then PIONEER 7 and 8 to assess the effect of age at baseline on efficacy, safety for oral semaglutide versus comparators, sitagliptin, empagliflozin, liraglutide, or placebo in people with type two diabetes. The key efficacy outcomes were the change from baseline A1C, and also changes in body weight. And what they found was that the reductions in A1C were comparable across the various age groups, less than 45, 45 to 65, over the age of 65, and were generally larger with oral semaglutide than comparators irrespective of age. Body weight reductions were greater for oral semaglutide versus comparators, but without association between age reductions in body weight. The proportions of patients with AEs and AEs leading to treatment discontinuation were greater in the over 65 year age group versus those that were below 65 years of age. Now, continuing along the PIONEER sub-analyses, there was another sub-analyses looking at race and ethnicity. And I found this particularly interesting, Filip, because, as we know, we live in a global community where everyone is affected by diabetes, and sometimes the rates of diabetes in certain racial and ethnic groups are higher. And whether these therapies actually are generalizable in terms of efficacy towards the broader population is often an important question that clinicians have.

So they looked at white, Asian, black African American patients, and then evaluated the A1C and weight efficacy of oral semaglutide, again, across the PIONEER program. And what they found was that in PIONEER 1, 4 and 8, there was a significant interaction between the oral semaglutide treatment with race, but specifically, with a greater A1C reduction that seemed to be occurring in those of Asian ethnicity and background. Overall, the body weight reductions were greater for oral semaglutide versus comparitor regardless of ethnicity or race. And I think this gives us some insights around the overall generalizability, but also raises some very intriguing questions about why individuals of Asian ethnicity seemed to respond to a greater degree with A1C reduction with this strategy.

And lastly, let me mention the A1C body weight in post-hoc analysis of the SUSTAIN trial, SUSTAIN 1 through 5 and SUSTAIN 7 through 10, and this is with once-weekly semaglutide. Evaluated here was the change from baseline to end of treatment in A1C and body weight with once-weekly with semaglutide versus comparitor therapy. And in general, the estimated treatment difference for the change in A1C were greater with once-weekly subcutaneous semaglutide versus competitor in most subgroups and for body weight in all subgroups across the BMI specific cut points.

So I think that we had some very interesting analyses from these studies and I think it's generated a lot of excitement, but maybe I could ask you, Filip. There's been a lot of talk around A1C and body weight, but there's recently been a trial published that is specifically focused on weight loss, and maybe you could tell us a bit about that?

Dr Knop: Yeah, thank you. You have extracted a lot of good knowledge from the recent ADA meeting, I must say congratulations on that.

So one set thing about the obesity epidemic is that it has a particularly high impact on young people, children and adolescents, and currently we have very few things we can actually intervene with, with regard to obesity in adolescents and children. These investigators randomly assigned, in a 1:1 rate, these young people to receive liraglutide in 3.0 milligrams once-daily, or placebo administered subcutaneously on top of their lifestyle therapy.

So the primary endpoint was a change from baseline in body mass index. And in this study, there was a greater reduction in BMI on treatment with liraglutide plus lifestyle compared to placebo plus lifestyle. And the change from baseline and BMI standard deviation score at week 56 was estimated to -0.22, and that was highly significant with a P value of .002.

And one important thing about obesity in young people, is that we know from quality of life studies, that these young people suffer from a very low quality of life, actually at the level of adolescents or children treated for cancer. So this is hopefully something that really will help this group of people.

Obviously, when you treat obesity with these GLP-1 receptor agonists, including liraglutide, it comes at the expense of side effects, and the most common side effects with GLP-1 receptor agonist are these gastrointestinal side effects. And also in this group of people, gastrointestinal side effects were more common in the liraglutide-treated compared to the placebo-treated. But I think this really opens up for treating (even younger people with obesity) with GLP-1 receptor agonists, and that's really something that we highly need.

So can I pose a question to you, Subodh, because now we have talked about glycemic control and body weight and how to combine these drugs with other glucose-lowering drugs. Anything at the ADA we can extract and learn from, you think?

Dr Verma: There was some data on exenatide and renal outcomes in type 2 diabetes and DKD, and these were a small number of patients, 92 patients in four general hospitals from China. The patients with type 2 diabetes, a GFR of more than 30, also with a 24-hour urinary albumin: creatinine ratio of greater than 0.3 grams, were randomized to receive exenatide twice-daily plus glargine versus a lispro insulin and glargine for 24 weeks.

And the primary outcome here was really looking at 24-hour UACR from baseline. And what they found was that exenatide, when administered twice-daily plus glargine for 24 weeks, was associated with a significant reduction in albuminuria and patients with type 2 diabetes and DKD. So that was some data that came out from a small study in China.

And then there was another study looking at a post-hoc analysis from the trial that, I'm sure all of our viewers and yourself, are aware of, which was a cardiovascular outcome trial called EXSCEL, and looking at once-weekly extended-release exenatide 2 milligrams. And this was an evaluation looking at a subset of the EXSCEL participants with respect to eGFR slope. And essentially what was found here was that once-weekly exenatide may reduce UACR, improve eGFR slope, but that was specifically seen in patients with elevated baseline UACR.

So those were some of the sub-analyses, but I was intrigued, Filip, by the REWIND sub-analyses that I saw, particularly on cognitive impairment, and maybe you could tell our viewers about that one?

Dr Knop: So in a very recent publication just published in The Lancet Neurology and exploratory analysis of the cardiovascular outcome rewind trial was presented. And interestingly here, the focus was cognitive function. So, in more than 8000 patients around 4500 treated with dulaglutide and for 4400 treated with placebo had their cognitive function tested at baseline and at end of treatment. And what was found here was dulaglutide treatment actually caused a 14% improvement in cognitive function compared to placebo. And that number was highly significant. And that really emphasizes the GLP-1 receptor agonists, not all is about improving glycemic control and causing weight loss. They may have a very broad spectrum of functions, including cognitive function. And perhaps, we need to focus on new degenerative diseases and tier-2,1 receptor agonist in the future.

Dr Verma: Wow, that's really exciting, Filip.

Dr Knop: Yeah, so it really gives a perspective on whether the companies should start, or we should start, designing dedicated trials investigating this field.

In addition to GLP-1 receptor agonist, we also have GIP/GLP-1 receptor agonist in making one molecule that activates both receptors. And one of these GIP/GLP-1 receptor agonist is tirzepatide, which is furthest in development. And we know from the phase two studies that tirzepatide has a strong effect on body weight, and also a very strong effect on HbA1c. And when these compounds reduce body weight, there's also a big chance that they will have beneficial effect on non-alcoholic fatty liver disease. And in this study, which was a post-doc analysis from the phase two studies of tirzepatide, the investigators could actually show that tirzepatide improved circulating markers of fatty liver disease, including alanine aminotransferase and aspartate aminotransferase plus, keratin-18 and procollagen-3 which are considered important markers of a non-alcoholic fatty liver disease. So these patients were receiving tirzepatide had lower levels of these important markers.

But now we have talked about clinical trials and some of the post-hoc analyses that provide some interesting data, but we also have some real world evidence data that may interest some of the viewers.

Dr Verma: So thanks, Filip, I think we only have a few minutes left and I'll summarize one of the real-world comparisons of GLP-1 oral antidiabetic agents and insulin. And this was trying to ask the question, in a real-world setting, whether GLP-1 RA therapy, or a strategy of either a non-GLP-1-based therapy, either oral strategies or insulin, were more likely to facilitate A1C of less than 7%.

And essentially what was found is that a GLP-1 RA approach, in the real-world versus oral antidiabetic therapy or insulin, was more likely to achieve a better A1C control and also better weight loss. So I think that was quite interesting. There were similar types of real-world analysis, some done in people already on two agents, but I think the theme is very sort of consistent that a GLP-1 RA strategy, either in randomized trials or in the real-world, seemed to facilitate improved A1C control and better weight loss.

Dr Knop: Yeah, I agree. It's really good that we now have evidence that these compounds not only work in the control trials, but actually also work in our outpatient clinics out there for the patients. It's really promising, I think.

So, we've covered some really broad territory, including data just presented at the ADA and also very recently published data. And we've covered glycemic control and effects way beyond that, including effects of GLP-1 receptor agonists and renal function, and even cognitive function and liver function. We've also looked at trial data and also covered some important real-world evidence data. We clearly have seen the GLP-1 have multifactorial effect beyond HbA1c.

So with that, I would like to thank you, Subodh, for taking part in this great discussion.

Dr Verma: Thank you so much. It was wonderful speaking with you and thanks for the opportunity.

Dr Knop: And also thanks to you, the viewers, for participating in this activity. Please remember, continue on to answer the questions that follow and complete the evaluation of this activity. Thank you very much.

This transcript has been edited for style and clarity.