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Lilly's Retatrutide Beat Ozempic 2 mg on Blood Sugar and Weight Loss in Head-to-Head Diabetes Trial · 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, today we are
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  looking right at Eli Lilly's announcement. Right,
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  the top line results from their TRANSCEND-T2D-2
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  clinical trial. Exactly. And, you know, if
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  you've been following the development of these
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  medications, the bar for demonstrating efficacy
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  has really been moving. It definitely has. Yeah.
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  So today we are looking at data that compares
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  an unapproved investigational drug directly against
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  one of the most established treatments out there.
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  Yeah, that is exactly the focus of the data released
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  today. We're examining a head-to-head phase
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  three clinical trial. Which is always really
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  interesting to dig into. It is. Yeah. This specific
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  trial evaluates retatrutide, which is an unapproved
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  investigational drug against the highest approved
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  dose of a Zempik, which is the two milligram
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  dose in adults diagnosed with type two diabetes.
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  Well, I want to start by asking just a foundational
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  question about the trial design itself. Sure.
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  Like, why do companies conduct these head-to-head
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  trials instead of just testing a new drug
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  against a placebo? What's the specific value
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  of testing an investigational drug against Ozempic
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  2mg? Well, the value of head-to-head trials
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  is that they compare a potential new medicine
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  directly with the treatment that's already in
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  use. Right. So by testing against the highest
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  approved dose of Ozempic, The trial is designed
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  to give patients and physicians evidence that
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  reflects the actual medical choices they face
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  every day. Making it more applicable to the real
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  world. Exactly. Rather than simply proving the
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  drug is, you know, better than taking nothing
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  at all. That makes sense. So to really understand
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  these top line results, we need to know exactly
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  who was in this trial, what treatments they were
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  given, and how the researchers actually measured
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  the data. Definitely. Let's start with the participants.
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  Who exactly was enrolled in TRANSCEND-T2D-2? So
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  the trial enrolled 1,298 adults, and the baseline
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  requirement for these participants was that they
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  had type 2 diabetes that was inadequately controlled
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  with metformin. And the trial defines that baseline
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  metformin use very specifically, right? They
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  do, yeah. It required at least 1,500 milligrams
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  per day, and I think they were allowed to be
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  on an SGLT2 inhibitor as well? That is correct.
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  They had to be taking at least 1,500 milligrams
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  of metformin a day with or without an SGLT2 inhibitor.
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  Okay, got it. And beyond their existing medication,
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  the trial established very specific physical
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  and metabolic baseline parameters for these 1
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  ,298 adults. What were those parameters? Well,
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  they entered the trial with an average A1c ranging
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  from 7.0% to 10.5%. And in addition to the
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  A1C range, there were specific weight and body
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  mass requirements to enter the study too, right?
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  Yes. Participants had to have a stable weight
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  for 90 days prior to their screening, and they
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  had to have a body mass index or BMI of 25 or
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  higher. Right. But why would a clinical trial
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  require a participant's weight to be stable for
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  90 days beforehand? Well, establishing a stable
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  weight for 90 days ensures that any weight loss
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  observed during the 80 weeks of the trial is
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  directly attributable to the investigational
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  drug. Oh, I see. Or the comparator drug. Exactly.
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  Rather than being the result of a recent diet
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  or like a lifestyle change or another underlying
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  factor that was already causing them to lose
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  weight before the trial even started. That makes
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  a lot of sense. So that brings us to the treatments
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  themselves. This was a head-to-head trial.
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  So we need to contrast the two sides. Right.
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  Let's look at them. On one side, you have Ozempic.
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  And Ozempic targets the GLP-1 pathway. Yes.
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  On the other side, you have retatrutide. And
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  retatrutide is often referred to by the nickname
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  triple G because it's a single molecule that
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  activates three distinct hormone receptors. Right.
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  The GLP-1, GIP, and glucagon receptors. Exactly.
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  But it is absolutely critical to clarify the
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  regulatory status of retatrutide before we discuss
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  the data. Definitely. Retatrutide is an unapproved
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  investigational molecule. It cannot be legally
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  sold or marketed for human use anywhere. Right.
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  That's an important distinction. Okay. So we
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  have our 1,298 participants, and we have the
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  treatments they received. Yes. But before we
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  get into the exact efficacy numbers at the 80-week
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  mark, we really have to look at the methodology.
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  The way they measured it, yeah. Right. The trial
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  data is reported based on a specific statistical
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  term called the efficacy estimate. I want to
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  be very precise here. Can you define exactly
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  what an efficacy estimate is according to the
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  trial parameters? Yes. The efficacy estimate
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  represents the efficacy had all randomized participants
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  remained on study intervention with possible
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  dose interruptions and modifications for 80 weeks
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  without initiating additional anti-hyperglycemic
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  medication. Okay. So if you are listening and
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  wondering how to interpret that definition, It
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  essentially means the researchers are calculating
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  the pure effect of the drugs. Right. They're
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  measuring the data as if every single participant
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  stayed on their assigned treatment for the entire
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  80 weeks without adding any new blood sugar medications
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  to their routine. Exactly. That's the baseline
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  for the data. Okay. So with that methodology
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  defined, we can look exactly at how the two drugs
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  performed against each other at 80 weeks. Let's
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  look at the top-line efficacy data, starting
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  with the primary endpoint, which was A1C reduction.
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  Okay, so the trial tested two different doses
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  of retatrutide against the 2 mg dose of a Zembik.
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  Right. The data shows that both the 9 mg and
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  12 mg doses of retatrutide lowered A1c by an
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  average of 2.2%. Okay, and compared to a Zembik?
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  That's compared to a 1.8% reduction with a
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  Zembik 2 mg. I noticed that the statistical distinction
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  between those two retratratate doses is delineated
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  very carefully in the data when compared to Ozempic.
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  Yeah, they are handled quite differently. The
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  12 milligram dose and the 9 milligram dose are
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  treated differently from a statistical standpoint.
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  They are. So the 12 milligram dose of retratratate
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  achieved superiority versus Ozempic. Okay. In
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  statistical terms, that means it reached a p-value
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  of less than 0.001. Wow. But the 9 milligram
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  dose of retatrutide met non-inferiority for
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  change in A1c as a key secondary endpoint. Meaning
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  it wasn't worse. Right. Showing nominal statistical
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  significance versus Ozempic. Okay. So for listeners
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  who don't read biostatistics daily, superiority
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  means the data demonstrated the 12 milligram
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  dose was statistically better than the comparator.
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  Exactly. And that p-value of less than 0.001
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  indicates an extremely high level of confidence
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  in that specific binding. Yes, it does. Well,
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  non-inferiority means the trial demonstrated
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  that the 9 milligram dose was not statistically
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  worse than the comparator drug, achieving what
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  they call nominal statistical significance. That
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  is the precise literal translation of the trial
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  data regarding the A1C reductions. Okay, great.
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  Now, let's move to the weight loss numbers, which
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  was tracked as a key secondary endpoint. We know
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  the participants entered the trial with a stable
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  weight for 90 days. Right. Their average baseline
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  body weight at the start of the trial was 225.8
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  pounds. Right. So from that average baseline
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  of 225.8 pounds, the participants taking the
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  9 milligram dose of retatrutide lost an average
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  of 44.3 pounds. Yeah, that represents a 19.5
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  percent reduction in their body weight over the
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  80 weeks. And what were the exact numbers for
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  the participants taking the highest dose, you
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  know, the 12 milligram dose of retatrutide?
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  Participants taking the 12-milligram dose lost
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  an average of 47.4 pounds, which represents
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  a 20.9% reduction in body weight. Okay. Then
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  we have the comparator arm of the trial. What
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  were the results for the participants taking
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  Ozempic 2 milligrams? The participants taking
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  Ozempic 2 milligrams lost an average of 20.9
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  pounds, or 9.4% of their body weight from that
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  same 225.8-pound baseline. So looking at those
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  exact numbers side by side, the unapproved investigational
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  drug retatrutide resulted in more than double
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  the weight loss of Ozempic 2 milligrams in 80
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  weeks. Yes, it did. When Eli Lilly announced
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  this data, how did they characterize these specific
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  results? Kenneth Custer, who is the executive
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  vice president and president of Lilly Cardiometabolic
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  Health, made a direct statement regarding the
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  data. What did he say? He stated that based on
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  these results, retatrutide, if approved, could
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  shift the treatment paradigm for people living
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  with type 2 diabetes, obesity, and related cardiometabolic
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  conditions. The trial didn't just measure blood
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  sugar and body weight, though, right? It also
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  tracked other specific risk factors. Yes, absolutely.
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  And this broader data ties directly into how
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  financial markets are currently evaluating this
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  investigational GGG drug. Let's look at the specific
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  cardiovascular risk factors that were tracked
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  in the TRANSCEND-T2D-2 trial. Well, the top-line
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  data reports that retatrutide delivered greater
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  improvements than Ozempic across certain cardiovascular
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  risk factors. Which ones specifically? The results
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  specifically name non-HDL cholesterol, triglycerides,
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  and systolic blood pressure as the markers where
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  retatrutide showed greater improvements. To understand
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  why financial analysts are watching these specific
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  markers and the overall trial results so closely...
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  We really have to put this in the proper market
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  context. Context is everything here. GLP-1 medicines
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  have been on the market for over 20 years now,
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  but developers are pushing hard for multiple
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  targets. We just established that retatrutide
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  activates three receptors. Exactly, the triple
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  G. And Novo Nordisk also has three-pronged candidates
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  that are currently in phase two trials. So given
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  these phase three results comparing retatrutide
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  to Ozempic, how are analysts viewing the long-term
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  financial prospects of retatrutide? We
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  have a specific analysis from Leerink analyst
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  David Risinger. Okay. According to Risinger,
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  these top-line results strengthen the case for
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  ritatratreed's long-term differentiation in
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  the market. He stated that the data justifies
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  a branded premium for the drug ahead of the 2032
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  U.S. patent expiration of semaglutide. Let me
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  make sure I am following the logic there. The
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  U.S. patent for semaglutide expires in 2032.
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  Correct. Analysts... Anticipate that will change
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  the market dynamics significantly. But Risinger
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  is arguing that these trial results demonstrate
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  enough differentiation that an unapproved investigational
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  drug like retatrutide could maintain a branded
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  premium even when that patent expires. Yes, that's
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  exactly what he's arguing. Did he provide specific
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  sales estimates based on that evaluation? He
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  did provide specific estimates. Risinger expects
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  annual retatratreed sales to reach $15 billion
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  in the year 2032. Wow. $15 billion. Yeah. And
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  to put that figure in context, the current consensus
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  among Wall Street analysts for retatratreed sales
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  in 2032 is $10 billion. So his evaluation of
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  this trial data puts his estimate $5 billion
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  higher than the general Wall Street consensus.
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  It does. But, you know, evaluating any clinical
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  trial data requires looking at the complete picture.
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  Higher efficacy in clinical trials often comes
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  with a tradeoff in tolerability. Yes, that is
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  very common. We really need to examine the adverse
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  events recorded in TRANSCEND-T2D-2. So the announcement
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  states that the majority of the adverse events
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  reported during the trial were mild to moderate
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  in severity, and they typically resolved during
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  the course of the treatment. Which is pretty
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  standard. Right. And consistent with this class
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  of medications, the most common adverse events
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  were gastrointestinal related. We have the exact
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  percentages for the incidence of these side effects
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  across all three study arms. Yes, we do. That's
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  the 9 mg dose of ritatrateed, the 12 mg dose
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  of ritatrateed, and the Ozempic 2 mg dose. Let's
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  go through the gastrointestinal events exactly
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  as they were reported in the data, starting with
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  diarrhea. Okay. For diarrhea, the incidence was
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  28.3% for participants on ritatrateed 9 mg
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  and 32.7% for those on ritatrateed 12 mg. versus
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  26.4% for participants on Ozempic. And what
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  were the reported incidence rates for nausea?
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  The incidence of nausea was reported at 21.2
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  % for ritatrate 9 mg and 23.8% for ritatrate
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  12 mg versus 21.3% for Ozempic. Okay, and I
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  see that constipation showed a slightly different
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  pattern across the study arms. Yes, the incidence
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  of constipation was recorded at... 14.2% for
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  retatrutide 9 mg, and 13.1% for retatrutide
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  12 mg. And for Ozempic? That was versus 19.8
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  % for Ozempic. The trial data also includes specific
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  rates for vomiting. Vomiting occurred in 10.2
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  % of participants taking retatrutide 9 mg, and
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  15.0% of participants taking retatrutide 12
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  mg, versus 13.2% of those taking Ozempic. And
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  the final common gastrointestinal event listed
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  in the top line result is dyspepsia. The incidence
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  of dyspepsia was recorded at 10.4% for retatrutide
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  9 mg, 8.5% for retatrutide 12 mg, versus 11.6
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  % for Ozempic. So aside from those gastrointestinal
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  events, the trial results also noted the specific
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  incidence of dysesthesia and urinary tract infections.
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  That is correct. The trial tracked dysesthesia,
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  and the incidence was 4.8% for retatrutide
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  9 mg and 6.5% for retatrutide 12 mg. Compared
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  to? Versus 2.7% for a Zempik. And for the urinary
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  tract infections? Urinary tract infections were
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  recorded at a rate of 5.8% for retatrutide
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  9 mg, 4.2% for retatrutide 12 mg, versus 5.8
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  % for a Zempik. Okay, so when you look closely
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  at those exact side effect percentages, particularly
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  the gastrointestinal events and the dysesthesia,
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  you see a higher incidence in some categories
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  for the investigational drug compared to the
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  established comparator. You do, yeah. But the
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  crucial question for a clinical trial is how
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  those side effects actually translated into participants
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  leaving the study. Exactly, the discontinuation
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  rate. Right. What were the exact treatment discontinuation
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  rates due to adverse events? The treatment discontinuation
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  rates due to adverse events give us that specific
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  data. The rates were 4.8% for participants
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  on retatrutide 9 mg, 7.9% for participants
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  on retatrutide 12 mg, and 2.7% for participants
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  on Ozempic. So, while the 12 mg dose of retatrutide
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  showed the highest treatment discontinuation
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  rate at 7.9%, compared to 2.7% for Ozempic,
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  we now have the full top-line picture. We do.
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  We have the A1c reductions, the weight reduction
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  data showing more than double the weight loss
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  from the 225.8-pound average baseline, the
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  improvements in cardiovascular markers, and the
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  full adverse event profile and discontinuation
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  rates. That's a lot of data. It is. So what happens
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  next with all of this data? Well, according to
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  Eli Lilly, the detailed results from the TRANSCEND-T2D-2
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  trial will be presented at a future medical
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  meeting and published in a peer-reviewed journal.
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  And it is important to emphasize that the top
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  line data we are discussing today has not yet
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  been peer reviewed. Absolutely. And we also need
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  to explicitly state that the trial doses we discussed
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  today describe study arms only, not how anyone
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  should take any medicine. Right. These numbers
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  reflect a strictly controlled clinical trial
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  environment, testing an unapproved investigational
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  drug against an approved medication. Thanks for
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  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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  stopping, or changing any medication. Visit glp1newspaper.com
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