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Lilly's Retatrutide Eased Sleep Apnea in Two Phase 3 Trials, NEJM Study Reports · GLP-1 Newspaper: Daily Ozempic, Zepbound & Weight-Loss Drug News

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  Welcome to the GLP-1 Newspaper, your daily update
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  on the news shaping GLP-1 and weight loss medications.
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  Visit glp1newspaper.com to see today's stories
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  and sign up for email alerts. So if you follow
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  the daily developments in this space, you know
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  it is just incredibly crucial to look directly
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  at how clinical data is actually structured.
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  Yeah. That is especially true today. We are looking
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  at a highly specific set of phase three clinical
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  trial results focusing on the investigational
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  pipeline for weight loss medications, specifically
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  in the context of moderate to severe obstructive
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  sleep apnea. Right. But before we even touch
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  that investigational pipeline, we really need
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  to establish the current regulatory baseline.
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  You know, to understand the new clinical data,
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  you have to know what is already available to
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  patients. Absolutely. Grounding the conversation
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  in the established facts is, well, it's the only
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  way to accurately read pipeline developments.
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  If we skip that baseline, we completely lose
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  the context of the regulatory environment. I
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  mean, let's look back at December 2024. The FDA
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  approved Zepbound, which is tirzepatide, for
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  the treatment of moderate to severe obstructive
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  sleep apnea in adults with obesity. Right. And
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  that approval, it represents the established
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  baseline we are operating from today. And when
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  we look at the clinical studies that actually
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  led to that December 2024 FDA approval for Zepbound,
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  we have to look really closely at the trial demographics.
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  Yeah, those demographics are key. Exactly. The
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  approval was based on two studies involving a
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  total of 469 adults. And I want to pause on those
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  469 adults because there is a very defining boundary
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  to that specific data set. Those two foundational
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  studies for Zepbound enrolled adults without
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  type 2 diabetes. Right. Without type 2 diabetes.
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  And that is a critical piece of the regulatory
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  landscape. When you read clinical trial results,
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  the inclusion criteria tell you exactly who the
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  data applies to. Right. It sets the boundaries.
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  Yeah. In the case of the Zepbound approval
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  data from December 2024, the researchers maintained
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  a strict boundary, focusing exclusively on participants
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  without type 2 diabetes. And within that specific
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  population, they also structured the trials around
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  the existing standard of care, didn't they? Like
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  one study exclusively enrolled participants who
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  were using positive airway pressure or PAP therapy?
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  Yeah, that's right. Meanwhile, the other study
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  specifically enrolled participants who were unable
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  or unwilling to use pap therapy. Got it. So by
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  setting it up that way, the researchers created
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  two distinct cohorts. They observed the medication's
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  effects under those different standard of care
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  conditions, but, again, always within that defined
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  population of adults without type 2 diabetes.
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  Which, you know, brings us to a major question
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  for the investigational pipeline. Since that
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  foundational FDA-approved option from December
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  2024 was tested specifically in adults without
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  type 2 diabetes, how are researchers designing
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  clinical trials to capture data on people who
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  do have type 2 diabetes? Well, we actually now
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  have the trial design and the data to answer
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  that. We are looking at the phase 3 clinical
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  trial results for a pipeline medication called
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  retatrutide. Just to be absolutely clear on the
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  status here for you listening, retatrutide is
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  an investigational, unapproved weekly injection.
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  Right. It is strictly investigational at this
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  point. In terms of its structure, retatrutide
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  acts as a triple agonist. A triple agonist. Okay.
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  Meaning what exactly? That means the medication
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  targets three specific receptors, GIP, GLP-1,
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  and glucagon receptors. Okay. Got it. And Eli
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  Lilly funded two phase three clinical trials
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  to gather data on this investigational drug,
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  right? Yeah, they did. These trials were designed
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  for adults with moderate to severe obstructive
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  sleep apnea and a body mass index of at least
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  27. Right. And this is where we see exactly how
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  the clinical trial design addressed that question
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  of patient populations. To capture the necessary
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  data, the trials were structured to deliberately
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  split participants by diabetes status. Let's
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  break down the numbers on that split, because
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  across these two Eli Lilly-funded trials, they
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  enrolled a total of 691 participants. Yes, 691
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  total. The first trial is designated as TRIUMPH-1-OSA.
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  This specific trial enrolled 243 participants.
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  Following the inclusion criteria, these were
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  adults without type 2 diabetes. Okay, so that's
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  TRIUMPH-1-OSA. And running alongside that, you
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  have the second trial designated as TRIUMPH-2-OSA.
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  Exactly. This was a larger cohort enrolling
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  448 participants. And this group specifically
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  consisted of adults with type 2 diabetes. So
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  we have two strictly defined groups within the
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  691 total participants. And for both TRIUMPH-1-OSA
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  and TRIUMPH-2-OSA, the trial duration
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  was set at 80 weeks, I believe. Yeah. 80 weeks.
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  Which is a substantial timeline for gathering
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  clinical data. During that period, what were
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  the participants randomly assigned to receive?
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  Participants in both of these 80-week trials
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  were assigned to receive either a placebo or
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  retatrutide. For those receiving the investigational
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  medication, they were given one of three specific
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  doses. And those doses were? They were 4 milligrams,
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  9 milligrams, or 12 milligrams. Okay. With the
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  trials separated by diabetes status and lasting
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  for 80 weeks, what exact reductions in the apnea-hypopnea
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  index did they report for each group
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  compared to the placebo? Well, it is really important
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  to report these findings exactly as they are
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  presented in the data, which is as reductions
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  versus placebo at the 80-week mark. So we will
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  look at each trial independently. Sounds good.
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  Let's begin with TRIUMPH-1-OSA, which, again,
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  is the trial involving the 243 participants without
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  type 2 diabetes. So for the participants in TRIUMPH-1-OSA
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  assigned to the 4 mg dose of retatrutide,
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  what was the reported reduction? At the 4 mg
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  dose, retatrutide resulted in an AHI reduction
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  versus placebo of minus 13.0 events per hour.
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  Minus 13.0. Okay. Moving to the next dose level
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  in that same trial, what did they report for
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  the 9 milligram dose? For the participants on
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  the 9 milligram dose in TRIUMPH-1-OSA, the
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  reported AHI reduction versus placebo was minus
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  24.4 events per hour. Minus 24.4. And for the
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  highest dose administered in that trial, the
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  12 milligram dose. At 12 mg, retatrutide resulted
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  in an AHI reduction versus placebo of minus 21.9
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  events per hour. Okay, I just want to make
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  sure you have those primary findings clearly
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  documented for TRIUMPH-1-OSA. For the adults
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  without type 2 diabetes, the trial reported AHI
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  reductions versus placebo of minus 13.0 events
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  per hour at 4 milligrams, minus 24.4 at 9 milligrams,
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  and minus 21.9 at 12 milligrams. Yeah, those
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  are the reported figures for the first trial.
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  Now we look at the data reported for TRIUMPH-2-OSA.
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  This is the trial involving the 448
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  participants with type 2 diabetes. Right. We
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  will go through the exact same dose increments
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  for this group. At the 80-week mark, what did
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  the trial report for the 4-milligram dose? In
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  TRIUMPH-2-OSA, the 4-milligram dose of retatrutide
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  resulted in an AHI reduction versus placebo of
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  minus 8.9 events per hour. Minus 0.9. And for
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  the participants assigned to the 9-milligram
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  dose? At the 9-milligram dose, the reported
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  AHI reduction versus placebo was minus 14.4
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  events per hour. Okay. Finally, what was the
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  reduction reported for the 12-milligram dose
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  in the type 2 diabetes cohort? For the 12-milligram
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  dose in TRIUMPH-2-OSA, the trial reported an
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  AHI reduction versus placebo of minus 15.1 events
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  per hour. So beyond reporting the raw reductions
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  in events per hour, trials often establish specific
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  categorical outcomes. Did these trials report
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  how many participants reached the study's own
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  definition of no or mild sleep apnea? Yes, they
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  did. And to understand those results, we really
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  have to use the study's exact definition for
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  that outcome. Right. We can't just guess what
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  that means. Exactly. The trials defined reaching
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  no or mild sleep apnea using very specific parameters
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  based on the apnea-hypopnea index and a secondary
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  metric. Let's lay out those parameters for you.
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  To meet the study's definition, a participant
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  first had to reach an AHI of fewer than 5 events
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  per hour? Right. Alternatively, if a participant
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  had 5 to 14 events per hour, the study introduced
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  a second requirement to meet the definition.
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  Okay, what was the second requirement? They also
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  had to have a score of 10 or less on the Epworth
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  sleepiness scale. Got it. So that combined metric,
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  fewer than five events per hour or five to 14
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  events with an Epworth sleepiness scale score
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  of 10 or less, that is the study's own strict
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  definition for the outcome of reaching no or
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  mild sleep apnea. Yeah. And by adhering to that
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  specific clinical definition, we can look at
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  the reported outcomes for both trials. Starting
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  again with TRIUMPH-1-OSA, the trial for participants
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  without type 2 diabetes. How many participants
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  on retatrutide reached that defined outcome?
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  In TRIUMPH-1-OSA, between 26.3% and 51.6%
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  of participants on retatrutide reached no or
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  mild sleep apnea based on the study's definition.
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  Okay, and for the placebo comparison in that
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  trial? In the placebo group for TRIUMPH-1-OSA,
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  12.5% of participants reached that outcome.
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  Okay, now applying that exact same definition
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  to TRIUMPH-2-OSA, the trial for participants
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  with type 2 diabetes. In TRIUMPH-2-OSA, between
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  24.3% and 39.5% of participants on retatrutide
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  reached the study's definition of no or mild
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  sleep apnea. And the placebo group for that trial?
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  For the placebo group in TRIUMPH-2-OSA, 12.6%
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  of participants reached that outcome. Wow.
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  Okay. These trials also track changes in body
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  weight over the 80 weeks as a secondary endpoint,
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  right? We need to report those figures as well
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  to reflect the data provided. Yeah, we do. Looking
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  at the body weight metrics for TRIUMPH-1-OSA,
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  retatrutide produced mean body weight reductions
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  ranging from 12.5% to 22.2%. Compared to the
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  placebo group? The placebo group in TRIUMPH-1-OSA
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  had a mean body weight reduction of 4.8%.
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  Okay. And moving to the body weight changes reported
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  for TRIUMPH-2-OSA. In TRIUMPH-2-OSA, retatrutide
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  produced mean body weight reductions ranging
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  from 12.1% to 18.5%. And the placebo comparison
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  there? This is versus a 5.6% mean reduction
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  for the placebo group in TRIUMPH-2-OSA. Now,
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  I have to mention, these are just clinical trial
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  numbers and definitely not a reason for anyone
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  to change their treatment. Always talk to a doctor.
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  But before we wrap up, if we look strictly at
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  the safety results reported for these two sleep
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  apnea trials, what did they find? Well, we will
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  look strictly at the safety data reported for
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  these specific populations in TRIUMPH-1-OSA
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  and TRIUMPH-2-OSA. In TRIUMPH-1-OSA, adverse
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  events were reported by 88 to 93 percent of participants
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  on retatrutide. And for the placebo group
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  in TRIUMPH-1-OSA? Adverse events were reported
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  by 76% of participants on placebo. Okay. Now
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  looking at the second trial, TRIUMPH-2-OSA.
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  In TRIUMPH-2-OSA, adverse events were reported
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  by 73% to 84% of participants on retatrutide.
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  Right. And this compares to 71% of participants
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  on placebo who reported adverse events. So the
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  trial reports provide context on the nature of
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  these adverse events, right? Like they were mostly
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  gastrointestinal and they were generally mild
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  to moderate? Yeah, exactly. The safety reporting
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  also specifies the timing, noting that these
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  adverse events were most frequent during dose
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  escalation. And finally, we need to report on
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  trial discontinuations. The data states that
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  discontinuation because of adverse events occurred
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  at similar frequencies with retatrutide and placebo.
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  Right. That reflects the safety reporting for
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  these specific trials. The discontinuation rates
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  due to adverse events occurred at similar frequencies
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  between the medication and placebo groups. Thanks
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  for listening to the GLP-1 Newspaper. This show
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  is for information only and is not medical advice,
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  so always talk to your doctor before starting,
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