DocTalk Podcast: Approval of Oral Semaglutide and PIONEER with Dr. Aroda

SEPTEMBER 23, 2019
Patrick Campbell
Flashback nearly a decade and a half ago, and GLP-1 receptor agonists and SGLT2 inhibitors were still considered novel therapies and had yet to become the fixtures in diabetes care that they have become today.

Many could argue endocrinology has yet to see an advance as monumental or practice-altering since. That is until the US Food and Drug Administration’s recent approval of oral semaglutide (Rybelsus).

While oral semaglutide has demonstrated it can hold its own against current standards of treatment during the PIONEER trials, Novo Nordisk’s newest approval is the FDA’s first for an oral GLP-1 receptor agonist.

As clinical trial investigator for multiple PIONEER trials, including PIONEER 1, few have had as intimate an experience with oral semaglutide as Vanita Aroda, MD, director of diabetes clinical research at Brigham and Women’s Hospital. To better understand the advantages of oral semaglutide and how its approval alters the current landscape of diabetes care, and what a potential cardiovascular approval in early 2020 could mean, MD Magazine® reached out to Aroda to take part in the DocTalk Podcast.
 
For more on that discussion, listen below. For more of the DocTalk Podcast, be sure to subscribe on iTunes.



MD Mag: Hello everybody and welcome to the DocTalk Podcast. I’m Patrick Campbell, associate editor with MD Magazine, and I will be your host for this edition of DocTalk. Today, we are joined by Dr. Aroda, of Brigham and Women’s Hospital, as we discuss the recent approval of Novo Nordisk’s oral semaglutide and the PIONEER trials.

Welcome to the DocTalk Podcast, Dr. Aroda. If you could just give our listeners a brief background on who you are and your expertise in diabetes we can dive into our chat.

Aroda: My name is Vanita Aroda and I am director of diabetes clinical research at Brigham and Women's Hospital. I am an endocrinologist with a focus on diabetes and I have been involved in diabetes clinical research, specifically clinical trials in the areas of diabetes prevention, and novel diabetes therapeutics for over 15 years now. In terms of disclosures, I've worked with a number of companies who have been involved in novel therapeutics and I have served as a clinical trial investigator and/or consultant with a number of those companies.

MD Mag: Could you describe your involvement with the PIONEER trials exploring oral semaglutide?

Aroda: I was a clinical trial investigator on 2 of the PIONEER clinical trials, PIONEER 1 and PIONEER 8. And I was also lead author of the manuscript describing the estimand methodology that was used across all of the PIONEER trials.

MD Mag: Okay, thank you for that. Now the first question we have for you today: There's been a total of 10, PIONEER trials—all of them really impressive in terms of proving the advocacy and the safety of oral semaglutide—in your opinion, which of these trials is most significant? Or what's the most significant takeaway from one of these trials?

Aroda: Thank you for that question, Patrick. For me, it's the totality of the picture. And I'll summarize it in basically 3 sentences. With the placebo-controlled trials—PIONEER 1, 5, and 8—we saw high glycemic efficacy, as well as the benefit of weight loss in early populations when we use the treatment early in the treatment of diabetes, as well as in late populations.

Sentence number 2, in the active-controlled studies, PIONEERs 2, 3, 4, and 7, we saw a greater glycemic efficacy compared to other oral agents that we might use with the addition of weight loss.

And sentence number 3, the cardiovascular safety study, pioneer 6 demonstrated cardiovascular safety with a non-significant 21% reduction in major adverse cardiovascular events. So, for me, it's the totality of the picture, which I think is important as we take care of our patients.

MD Mag: Okay, thank you for that. And now, the big thing I think everybody realizes with this approval is that there's now an oral GLP-1. For a long time, SGLT2 inhibitors have been preferred by some endocrinologist specifically because they're available in an oral form. What does this approval for an oral GLP-1 mean for physicians? And then as a second part to that question was it means for patients as well.

Aroda: The development of an oral GLP-1 is a significant scientific and clinical achievement in the field of diabetes and care of patients for type 2 diabetes. We have had this class of agents since 2005 And it's perhaps the most well-studied class of medications that we have —it ranks amongst the highest glycemic efficacy with the additional benefit of weight loss. So, now having an oral version that works and has preserved its efficacy, even in the oral form, is a significant achievement.

In part, because having the conversation about injectable therapy is challenging in the day-to-day clinic. So, having an oral formulation may allow the earlier introduction and discussion of this class for patients who might benefit. In terms of the second part of your question: How does this compare to an oral SGLT2 inhibitor? Studies have been done and the data is there. In PIONEER 2 for example, where oral semaglutide was compared with the empagliflozin—an SGLT2 inhibtior—and both were consistent with their class. So, greater glycaemic efficacy with oral semaglutide compared to empagliflozin and pretty similar weight reduction between the 2 and a different side effect profile with each class.

MD Mag: One of the things that, obviously, is the perk of oral therapies as opposed to injectables is increased patient compliance. What does this mean in terms of health outcomes for these patients, that a drug that that will resolve greater patient compliance is now available to them?

Aroda: That's a great question. We've actually seen studies where translation of clinical trials to real world clinical practice, the efficacy seen in the trials does not necessarily always translate to efficacy in the real world.

A big factor in that is adherence and compliance with the prescribed medications. So, to be able to have a choice to accommodate the different patient choices that are out there—no 2 patients are alike—I think is a significant advancement and should help advance patient adherence as well as patient outcomes by actually having the choice of being allowed to have the shared decision making conversation.

MD Mag: Okay, thank you for that. Now, this is a bit hypothetical, but looking forward oral semaglutide could also receive approval for cardiovascular conditions in early 2020—a bit of the same question from the last one—but what would this approval mean for physicians and patients? Especially as we see people trending more towards multidisciplinary teams for the treatment of diabetes?

Aroda: Thank you for that question, Patrick. Recognizing, as you said, that this is hypothetical as currently we don't have that information, should oral semaglutide receive an approval for cardiovascular indication that again—I think that speaks to the whole picture where then we would have at our fingertips something where we understood the physiology, where we understood the immediate clinical effects on A1C and weight loss, and had something that would help with long-term outcomes of interest for our patients with type 2 diabetes. Namely, the ability to reduce cardiovascular events. Having said that, though, there is a separate dedicated clinical trial, called the SOUL study, that is underway that is powered and designed to address the question of superiority of cardiovascular risk reduction with oral semgalutide compared to standard of care.

MD Mag: Okay, and that was about it on my end. Was there anything else you wanted to add about oral semaglutide that you think would be important to touch on for our listeners, before I let you go?

Yeah, I'll highlight a few points. So, number 1, with oral semaglutide across the PIONEER program, we saw A1C reductions on average in the 1.2 to 1.5% reduction range, which again, is greater than many of our other oral classes. We also saw weight loss reductions of about 3 to 4 kilograms and this was this was an additional benefit as these were not weight loss studies.

In addition, it's important to note that the side effect profile is consistent with what we already know about the GLP-1 receptor agonist and that is this early sense of satiety and fullness, which can translate to nausea during that initial dose escalation period, and we did see that it did diminish within the first few weeks and diminished over time. I think those are the big highlights.

The other interesting thing is just the scientific innovation. The way that this has been developed and to allow for gastro intestinal absorption is that it is co-formulated with an absorption enhancer called SNAC, which then protects the oral semaglutide from being degraded in the stomach and allows it to be absorbed transcellularly to then cross into the bloodstream and have its effect.

So, in order to optimize absorption and effect the dosing instructions that we gave participants in the trials, and that is, I believe, included in the prescribing information—the way we recommend that participants take oral semaglutide in the studies was that they should take it fasting, without any food in their stomach, and wait 30 minutes before consuming any other medications or food. When they took the medication, they were instructed to take it with up to half a glass or 120 milliliters of water, and that was, again, to support the oral absorption of the GLP-1 receptor agonist.

MD Mag: Thank you so much Dr. Aroda for sharing your insights with us on this edition of DocTalk Podcast, I know our listeners will be very excited to hear your takes on oral semaglutide and it’s potential impact.

Aroda: Thanks so much—it is. I would add that this is a big milestone not just for our patients, but I think for the clinicians and for the providers, to actually have this as a choice with the results that we've seen so far.

MD Mag: Thank you again to all of our listeners. For the latest in diabetes and endocrinology, be sure to head to MDMag.com. Thank you for listening.

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