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Novo Says Women Lost 25% on CagriSema in Trial Analysis, With Differences by Menopause Stage · 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.
• 0:06
  Visit glp1newspaper.com to see today's stories
• 0:09
  and sign up for email alerts. So imagine you
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  have two women, right? They're taking the exact
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  same dose of a brand new weight loss drug. Okay.
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  They follow the same diet, they have similar
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  lifestyles, a whole nine yards. But after a year,
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  one loses 25 pounds and the other loses almost
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  30. Oh, wow. Yeah. And the only real difference
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  between them is the precise year of their reproductive
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  life. Which, I mean, that sounds counterintuitive
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  if you're looking at it through a traditional
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  medical lens. Right. Because for the longest
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  time, clinical research just operated on this
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  assumption that if you give a group of people
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  the same dose, you should expect roughly the
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  same result. Exactly. Just totally ignoring the
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  massive hormonal shifts people actually experience.
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  Right. As they age. Human biology is just, it's
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  anything but standard. It really is. And I mean,
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  if you're one of the over 86 million women in
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  the U.S. who are navigating midlife, you know
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  this. You already know your metabolism feels
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  entirely different at 50 than it did at 35. Oh,
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  absolutely. But what's wild is that the clinical
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  data is actually finally catching up to what
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  you've known for years. Yeah. And today we're
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  looking at a brand new analysis of Novo Nordisk's
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  investigational drug, CagriSema. Right. which
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  shows just how drastically these weight loss
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  results can differ depending on, well, a patient's
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  stage of menopause. It really forces us to rethink
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  the whole approach to obesity care. But we also
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  have to view this data through a very specific
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  editorial lens. We do. So our mission for this
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  conversation is twofold. We're going to explore
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  the biology of why this new data on women is
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  so revealing, but we're also going to look at
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  why findings that are extracted after a trial
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  has already ended, what they call a post hoc
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  analysis, are really just a signal. Right. Just
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  a signal for future research. Exactly. Right.
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  They're a signpost, not a final medical conclusion,
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  especially since this is a drug the FDA hasn't
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  even approved yet. That distinction is paramount.
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  But before we get into how this drug affects
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  different women, let's just, you know, let's
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  talk about the drug itself. Yeah, let's back
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  up. I was looking at the top line numbers for
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  the full REDEFINE 1 trial earlier. Okay, the
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  big phase three trial. Right, huge trial, over
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  3 ,400 adults. And the overall average weight
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  loss was 22.7% at 68 weeks. Which is huge.
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  To a layperson, yeah, shedding nearly 23% of
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  your body weight sounds staggering. But from
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  a Wall Street perspective, analysts were actually
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  reportedly disappointed. Really? Yeah, they were
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  hoping to see it cross the 25% threshold to
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  justify it as, you know, the next massive leap
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  forward. Well, let's establish what makes CagriSema
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  biologically different from what's on the market
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  right now. Good point. It's a once-weekly injectable,
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  but it's a combination therapy. So it takes semaglutide,
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  that's the active GLP-1 ingredient in Wegovy,
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  and combines it with an investigational compound
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  called cagrelentide. Right, which is an amylin
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  analog. Exactly, a long-acting amylin analog.
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  I was trying to visualize how this dual action
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  thing actually works. And if we think about eating
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  a meal like flying a plane. Okay. I like this.
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  The pancreas is the cockpit, right? Insulin is
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  your main pilot managing blood sugar. Sure. But
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  it has co-pilots. So GLP-1 is the co-pilot
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  pulling the throttle back. It physically slows
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  down how fast the stomach empties. Right. Ameline,
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  on the other hand, is the co-pilot taking over
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  the radio. It actively signals the brain's reward
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  center, telling it, hey, we're completely satisfied.
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  No need to go looking for more fuel. That's a
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  great way to put it. So instead of just pulling
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  the throttle to slow digestion, you're killing
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  the psychological desire to keep flying. Exactly.
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  You're hitting multiple pathways in the brain
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  simultaneously, one for the physical pacing of
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  digestion and the other for the behavioral drive.
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  And that synergistic effect is why expectations
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  for CagriSema have been so incredibly high. Right.
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  And why that initial 22.7% overall average
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  left some of those analysts wanting more. But
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  then Novo sliced the data differently. They ran
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  a separate analysis just focusing on the 2 ,309
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  women in the REDEFINE-1 trial. And the number
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  jumped. It did. For the women, the drug was associated
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  with an average weight loss of exactly 25.0
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  % at 68 weeks. Compared to what, like 3% on
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  the placebo? Exactly, 3.0% for the placebo.
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  Now, it is worth clarifying here that this 25
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  % figure uses a statistical model. They call
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  it an efficacy estimate. Right, which sounds
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  very technical. Yeah, but in plain English, it's
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  just the estimated average weight loss in an
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  idealized scenario. Oh, meaning it assumes everybody
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  tolerated the drug perfectly and stayed on it
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  for the full 68 weeks. Right. And that they didn't
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  introduce any other weight loss therapies. So
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  it's basically the absolute best case scenario
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  for the drug. Still, hitting that 25 percent
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  top line number for women is a major milestone.
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  But it begs the question, if hitting that average
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  relies heavily on female participants, who is
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  pulling that average up and who's dragging it
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  down? Which is exactly what prompted researchers
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  to dig deeper. They took a subgroup of about
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  1 ,900 women from the trial and ran another analysis.
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  And this time they grouped them by menopausal
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  status. Yes. And the gradient they found is just
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  striking. I have the numbers right here. At 68
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  weeks, the premenopausal women, the youngest
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  cohort, lost an average of 26.7%. Wow. The perimenopausal
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  women lost 24.8%, and the postmenopausal women
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  lost 23.1%. It's a clear stair-step effect.
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  The further a woman progresses through menopause,
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  the lower the percentage of overall weight loss.
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  Yeah. And they also looked at waist circumference,
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  right? They did. The drug was linked to significant
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  reductions in waist circumference across all
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  three groups, which points to a decrease in visceral
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  fat. That's the dangerous fat around the organs.
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  Let's spend a minute on the biology here because
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  women made up roughly two-thirds of this trial.
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  Why does estrogen play such a huge, tyrannical
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  role in metabolism? Well, at a cellular level,
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  estrogen is not just a reproductive hormone.
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  It is a master metabolic regulator. Okay. You
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  have estrogen receptors located all over your
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  body, including directly on your fat cells. Oh,
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  wow. I didn't realize that. Yeah. And during
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  a woman's peak reproductive years, estrogen actively
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  promotes storing fat in the hips and thighs.
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  That's subcutaneous fat, which is relatively
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  benign from a metabolic standpoint. But then
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  perimenopause begins. Right. And as estrogen
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  levels begin to fluctuate and eventually plummet,
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  those receptors lose their primary signal. So
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  the body basically panics? Essentially, yeah.
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  It redirects where it stores energy. It shifts
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  fat storage away from the lower body and starts
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  hoarding it in the abdomen right around the internal
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  organs. And that's the visceral fat we were talking
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  about, which isn't just inert storage, right?
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  It acts almost like its own organ. Exactly. It's
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  highly biologically active. Visceral fat actually
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  releases inflammatory cytokines, which drive
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  up insulin resistance and cardiometabolic risk.
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  So the body is moving weight to a more dangerous
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  area, and the underlying resting metabolism is
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  slowing down. And to make matters worse, declining
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  estrogen makes it significantly harder to maintain
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  lean muscle mass. Which compounds the whole problem.
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  Right, because muscle burns more calories at
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  rest than fat does. Right, so if you lose muscle,
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  your basal metabolic rate drops even further.
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  It's a brutal biological cascade. It really is.
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  The loss of estrogen signaling, the increase
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  in inflammatory visceral fat, the decline in
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  muscle, it creates this formidable barrier. It
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  really highlights how this has nothing to do
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  with that outdated concept of willpower. Exactly.
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  So when you look at that CagriSema data, dropping
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  from almost 27% weight loss in premenopause
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  down to 23% in postmenopause, that gradient
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  is a mathematical reflection of estrogen decline.
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  It's incredible to see a lived experience validated
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  by the data like that. But I want to play devil's
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  advocate for a second. Go for it. We have to
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  look at the methodology here. Because measuring
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  menopausal impact was not the original plan for
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  the redefined one trial, was it? No, it wasn't.
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  The trial was designed to measure overall safety
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  and efficacy in a broad population. Which makes
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  this a post-hoc analysis. So if researchers
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  are just slicing up the data after the trial
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  has already ended, isn't that a bit like painting
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  the bullseye around the arrow after you've already
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  shot it? It's a vital skepticism to maintain,
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  honestly. The scientific community handles post
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  -hoc data very, very carefully. Because they
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  didn't proactively test hormone levels during
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  the trial? Right. They didn't draw blood to confirm
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  menopausal status biochemically. So how did they
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  even sort these women into the pre, peri, and
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  post buckets? They derived it retroactively using
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  demographic data. So the women's ages, their
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  medical histories, whatever symptoms happened
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  to be recorded. Oh, I see. Yeah. If a woman was
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  under 45 with no recorded indication of menopause,
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  she was assigned to the premenopausal group.
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  55 or older, postmenopausal group. So it was
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  an educated categorization, but it lacked rigorous
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  reproductive staging. Exactly. Let me translate
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  the statistics here for a second because there
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  is a known mathematical pitfall with this. When
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  researchers look at data after the fact, they
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  aren't forced to apply strict mathematical safeguards.
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  Right. Adjusting for multiplicity. Yeah. So without
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  those safeguards, you run the risk of basically
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  just rolling the statistical dice over and over.
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  You slice by age, then height, then symptoms
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  until you find a pattern that looks significant.
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  Even if it might just be random noise. Right.
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  And that is the inherent danger of post hoc data.
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  We cannot use this analysis to definitively claim
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  CagriSema is exactly 3.6% less effective for
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  a postmenopausal woman. We shouldn't totally
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  discard it either, right? I mean, Novo Nordisk
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  themselves said in their press release that these
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  analyses are, quote unquote, hypothesis generating.
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  Yes, they're essentially drawing a map for the
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  next scientific expedition. They're pointing
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  a massive spotlight at a phenomenon that demands
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  dedicated investigation. It tells researchers
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  they need future trials that specifically track
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  estrogen from day one. Exactly. But as our editorial
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  lens dictates, this is a signal, not a final
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  answer. And we have to remember, CagriSema is
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  investigational. Right. It's not approved in
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  the U.S. Novo filed a new drug application in
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  December 2025, and we're expecting an FDA decision
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  in the fourth quarter of 2026. And part of that
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  FDA review will look at tolerability. In this
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  trial, about 5.9% of participants on CagriSema
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  discontinued due to adverse events. Versus what,
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  3.5% on placebo? Right. And those events were
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  mostly gastrointestinal, nausea, constipation,
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  vomiting, which is fairly standard for incretin
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  therapies, but still a crucial piece of the regulatory
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  puzzle. So researchers will take these signals
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  and design better trials. But in the meantime,
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  the pharmaceutical industry is watching this
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  closely because the financial stakes are just
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  unfathomable. We really have to place this data
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  in the broader competitive landscape. Novo Nordisk
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  is under immense pressure to find a successor
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  to Wegovy. And people might wonder why they need
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  to replace a drug that's basically a household
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  name. But it all comes down to the patent cliff.
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  It does. Wegovy faces patent expiries after 2030.
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  When those expire, the door opens for cheaper
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  generic versions or biosimilars to flood the
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  market. Right. And even though manufacturing
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  complex peptides is hard, eventually competitors
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  will figure it out and undercut Novo's revenue.
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  So they need their next generational leap ready
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  before that cliff arrives. And analysts expect
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  Calgrissima to generate almost $12 billion in
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  obesity sales by 2028. That's $12 billion with
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  a B. But Novo isn't operating in a vacuum. Eli
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  Lilly is seeing the exact same hormonal signals
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  in their clinical data. This rivalry between
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  Novo and Lilly is the defining narrative of modern
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  obesity medicine. It really is. I pulled the
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  numbers on Lilly's drug Tezepatide, sold as Zepbound.
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  In one of their major SURMOUNT reports, women
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  lost up to 24.6% of their body weight, while
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  men only lost up to 18.1%. That's a massive
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  gap in efficacy between the sexes. Right. And
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  Lilly actually took it a step further. They ran
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  their own post hoc analyses based on menopausal
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  stage in their SURMOUNT-3 trial. And what did
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  they find? At 72 weeks, premenopausal women lost
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  25.5%, perimenopausal lost 24.4%, and postmenopausal
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  lost 21.5%. It's the exact same stair-step
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  gradient we just saw with CagriSema. Exactly.
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  Multiple drug makers using slightly different
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  molecular pathways are uncovering the undeniable
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  reality that a patient's reproductive life stage
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  dictates how well these meds perform. It just
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  solidifies this as a fundamental principle of
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  human biology, interacting with metabolic therapies.
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  And it brings us back to the race for the next
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  generation of drugs. Both companies are aggressively
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  targeting secondary pathways like amylin. Trying
• 13:02
  to push efficacy past that 25% mark. Right,
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  because if you can prove your compound works
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  significantly better for a specific demographic,
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  like those 86 million women over 40, you unlock
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  a massive competitive advantage. So understanding
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  these demographic nuances is no longer just a
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  scientific curiosity. It's the key to market
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  dominance. Absolutely. If a drug maker can prove
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  in a prospective trial that their medication
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  is uniquely optimized for post-menopause, that
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  becomes a multi-billion dollar differentiator.
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  It really highlights how rapidly our understanding
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  of obesity is evolving. A few years ago, we had...
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  Very few effective pharmaceutical interventions.
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  Now we're parsing the difference between 22 and
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  25 percent weight loss. And uncovering the profound
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  ways hormonal life stages dictate those outcomes.
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  It proves obesity is a deeply complex chronic
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  disease. Right. Influenced by genetics, environment
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  and reproductive aging, not just diet and exercise.
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  The data strips away the stigma and replaces
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  it with biological mechanics. And as this race
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  accelerates, it leaves us with a really compelling
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  question about the future of medicine. If the
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  data consistently proves these medications affect
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  people so differently based on their age and
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  hormonal status, will the future of obesity medicine
• 14:19
  shift entirely away from that old one size fits
• 14:23
  all prescription model? It's a great question.
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  Right. Like, could we be heading toward an era
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  of highly personalized obesity care where treatments
• 14:31
  and dosages are explicitly tailored to match
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  your precise reproductive life stage? Well, the
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  post hoc signals we explored today strongly suggest
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  that personalized metabolic care is exactly where
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  the science is heading next. Thanks for listening
• 14:45
  to the GLP-1 Newspaper. This show is for information
• 14:48
  only and is not medical advice. So always talk
• 14:51
  to your doctor before starting, stopping, or
• 14:52
  changing any medication. Visit glp1newspaper.com
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