Time Stamps

  • 02:08 Framework for thinking about obesity
  • 03:42 History of obesity treatment
  • 06:29 Gila monsters and GLP and GIP mechanisms
  • 08:29 Story of how medications for diabetes were found to have a weight loss benefit
  • 12:50 SURMOUNT-1 trial

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Show Notes

  • Obesity is an increasingly prevalent epidemic associated with many adverse health outcomes
    • Prevalence rate of ~40% per the CDC
    • Associated conditions include heart disease, stroke, diabetes, cancers
    • Lifestyle interventions such as exercise and diet modifications 
  • History of treatments for obesity
    • Medications & their side effects:
      • Fenfluramine (MOA: SSRI): 
      • Phentermine-Topiramate (MOA: Stimulant-GABA modulator):
        • Phentermine cannot be prescribed long-term
        • Topiramate associated with cognitive dulling, metabolic acidosis, kidney stones, and other side effects
        • Combination therapy can be prescribed long-term but requires REMS (risk mitigation prescription program through the FDA)
      • Lorcaserin (MOA: Serotonergic agonist): 
      • Orlistat (MOA: Pancreatic lipase inhibitor)
    • Bariatric surgery: 
      • Includes banding, sleeve gastrectomy, roux-en-y bypass, duodenal switch etc. 
      • Invasive, vastly underutilized, and patients can have bias towards procedures 
      • Often associated with development of GERD, malabsorption, and nutritional deficiencies in the long-term 
    • Access to the Rotation Prep Endocrinology guide on NEJM Resident 360 is free for October 2023. View the relevant section on Obesity.
  • Incretin system:
    • Complex pathway of multiple hormones that regulates hunger and the response to eating (See infographic)
      • Main hormones:
        • GLP-1 (glucagon-like peptide 1)
        • GIP (glucose-dependent insulinotropic peptide)
      • Major effects are decrease in appetite, regulation of insulin, delayed gastric emptying
    • Discovery of exendin-4, a molecule with GLP-1-like effects, in Gila monsters allowed scientists to create GLP-1 mimickers for humans
    • Many drugs mimic one molecule in the pathway (e.g. GLP-1 agonist or DPP-4 inhibitor)
      • DPP-4 is responsible for degradation of GLP-1
        • Thus inhibition of DPP-4 leads to more biologically active GLP-1
      • Tirzepatide is a dual agonist, mimicking both GLP-1 and GIP
  • History of trials for diabetes mellitus
    • Trial designs:
    • Landmark trials in Obesity Management Meds: 
      • LEADER trial: Liraglutide (GLP-1 agonist) reduced rate of death from CV causes, nonfatal MI, and nonfatal stroke in T2DM
        • In prespecified exploratory analysis, all-cause mortality was also reduced with liraglutide
      • SUSTAIN trials: Semaglutide (GLP-1 agonist) vs various agents for A1C reduction
        • SUSTAIN-6: semaglutide reduced composite outcome of death from CV causes, nonfatal MI, and nonfatal stroke compared to placebo
        • SUSTAIN-6 also showed weight loss of 2.9-4.3 kg compared to placebo, though this was not a primary endpoint
      • SURPASS trials: Tirzepatide (dual GLP-1 and GIP agonist) vs. various agents for A1C reduction
        • SURPASS-2: Tirzepatide reduced A1C compared to semaglutide
          • Caveats: low doses of semaglutide used, no CV outcomes measured, unblinded trial
      • STEP trials: Semaglutide vs. placebo in various populations for weight loss
        • STEP-1: Semaglutide reduced weight compared to placebo in those without diabetes (-15.3 kg vs. -2.6 kg)
          • Gastrointestinal side effects occurred in the treatment group more often, 4.5% vs. 0.8%
    • SURMOUNT-1 trial:
      • Main question: does tirzepatide reduce a coprimary endpoint of percent weight loss and weight loss of 5% or more in those with obesity without diabetes mellitus?
      • Population:
        • Mean age 44.9 years, 67.5% were female, 70.6% white
        • Average A1C was 5.6%, and 40.6% had prediabetes at enrollment
        • Enrollment required BMI ≥30 or ≥27 and one weight-related complication (HTN, OSA, dyslipidemia, cardiovascular disease)
        • Fasting insulin levels were elevated, suggesting insulin resistance
      • Trial design:
        • Randomized 1:1:1:1 to 5mg, 10mg, 15 mg of tirzepatide or placebo
        • Follow-up was 72 weeks
        • Primary outcome: coprimary endpoint of percent weight loss and weight loss of 5% or more
        • Secondary outcomes:
          • Weight loss of 10% or more, 15% or more, and 20% or more; change in weight at week 20
          • Change in waist circumference, systolic BP, fasting insulin, lipid levels, and physical function score
      • Outcomes:
        • % weight loss at week 72 was -15%, -19.5, and -20.9% with 5mg, 10mg, and 15 mg tirzepatide respectively vs. -3.1% with placebo
          • The dose response observed supports a true effect of the drug
        • Weight loss curves seems most steep initially and plateaus with time:

        • A prespecified exploratory endpoint of >25% weight loss was impressive
          • 15%, 32%, and 36% of participants in the 5mg, 10mg, and 15 mg tirzepatide groups lost >25% of weight
          • Vs. 1.5% in placebo group
        • Secondary endpoints also all improved:
          • 95% of patients in the tirzepatide groups with prediabetes reverted back to normoglycemia, vs. 62% in the placebo group
          • Waist circumference was reduced 10.1-14.5 cm compared to placebo
          • Systolic blood pressure decreased 6.2 mmHg compared to placebo
          • Triglycerides, non-HDL cholesterol, and fasting insulin all were reduced compared to placebo
          • Total body fat mass was reduced 33.9% with tirzepatide vs. 8.2% with placebo
        • Serious adverse events (primary GI side effects of nausea, vomiting, diarrhea, etc) were reported by 6.3% of patients overall
      • Implications:
        • Perhaps a mechanism that involves multiple portions of the incretin system (e.g. tirzepatide) is more effect than just involving one portion (e.g. semaglutide)
        • Long-term side effects and efficacy are unknown

Transcript

Dr. Shreya Trivedi: Welcome to the second installment of Beyond Journal Club, a collaboration between Core IM and NEJM Group.

Dr. Clem Lee: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context. Telling the story of how we got to where we are, what it means for our patients, and how we take care of them.

Dr. Shreya Trivedi: So today we are gonna talk about a pretty hot topic in medicine, which has been a revolution in safe and effective obesity drugs. I’m Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center.

Dr. Greg Katz: I am Dr. Greg Katz, cardiologist at NYU.

Dr. Clem Lee: And I’m Dr. Clem Lee, former fellow and current guest editor at the New England Journal of Medicine. Today we are talking about the SURMOUNT-1 trial, which was published in the July 22nd issue of the journal in 2022.

Dr. Shreya Trivedi: SURMOUNT-1 asked the question, does Tirzepatide, a once weekly injectable drug used for diabetes, help patients lose weight compared to placebo?

Dr. Greg Katz: This is such an important question because when you think about it, almost all of contemporary medicine revolves around treating the complications of obesity and its frequent travel partner metabolic syndrome. I’m don’t really think its an exaggeration to say that. Things like heart disease, even cancer, and Alzheimer’s are all diseases that are patients with obesity are at increased risk for developing.

Dr. Shreya Trivedi: Exactly. We know the two diagnoses, obesity and metabolic syndrome go hand in hand. And when one gets better, the other one usually does too. But unfortunately, we haven’t had great treatments for either, at least until recently.

Dr. Clem Lee: That’s right, Shreya. Until we develop drugs that mimic the incretin system, we basically haven’t had effective medicines for weight loss.

Dr. Shreya Trivedi: And we will get into just that today. First we will look at a new framework for thinking about obesity. Then we’ll get into the failed history of medical efforts to date.

Dr. Clem Lee: Next, we’re gonna simplify the incretin system by taking a detour through the world of gila monsters, and then we’ll discuss how studying diabetic drugs through the lens of cardiac risk led us to a revolution in medical weight loss.

Dr. Greg Katz: And finally we’ll discuss the SURMOUNT-1 trial, which honestly, if I had a crystal ball, I think we may look back on in 20 years as one of the most impactful trials in all of medicine over the early 21st century.

Framework for thinking about obesity

Dr. Greg Katz: The rising numbers on obesity are less of an epidemic than they are a crisis. Almost 40% of Americans are obese, which is totally staggering because in the year 2000, no state had an obesity rate over 25%.

Dr. Clem Lee: And the problem isn’t just about weight cause people with obesity have higher healthcare costs, lower self-perception of health, and they often experience tons of discrimination from the healthcare system.

Dr. Shreya Trivedi: Yeah and even though we’ve all heard stories of how diet and exercise helped that single person lose weight, it’s pretty disappointing when you look at the literature, study after study, diet and exercise fail in the long term.

Dr. Clem Lee: And the reason that diet and exercise fail in those studies is recidivism. A lifestyle intervention really only works if it’s used forever, and prior studies have shown us that long-term adherence is pretty poor.

Dr. Greg Katz: The disappointing data on long-term weight loss is the single best arguments why I think the correct way to think about obesity is that it’s actually an environmental disease. The contemporary environment, the way we eat, move, and live is obesogenic. 

Dr. Shreya Trivedi: Ugh, Greg. I love that idea of thinking about obesity as an environmental disease, and all the things in our society are obesogenic, just I think that’s a very powerful to think of as a framework.

Dr. Greg Katz: It’s the best way that I found to think about it. You can remove yourself from the blame game of individual responsibility, food companies, and farm subsidies, and focus on what matters. What can we do to help our patients dealing with obesity?

Dr. Shreya Trivedi: And let’s get into just that, the history of obesity treatment. 

History of obesity treatment

Dr. Clem Lee: Unfortunately, the history of drugs to treat obesity is a sad story. It’s filled with side effects, ineffectiveness and really not making a dent in the problem.

Dr. Shreya Trivedi: Yep. Lots of drugs that were proposed to help people lose weight, turned out to actually be unsafe. Amphetamines, exogenous thyroid hormones, fenfluramine, ephedra, locaserin. The trade-off for weight loss in exchange for unanticipated, disastrous side effects like pulmonary hypertension, increased cancer risk, and cardiac arrhythmias was just not worth it.

Dr. Clem Lee: And one of the main reasons to treat obesity is to prevent cardiovascular complications. So most of these drugs being cardiotoxic means that they were non-starters to begin with.

Dr. Greg Katz: Let’s then transition to the safe medical options, which unfortunately just haven’t been that effective. And just as a reference, you usually need to lose about 5% of your body weight to have an impact on metabolic parameters. So the first drug we’re gonna look at is Orlistat. Orlistat decreases intestinal fat absorption and leads to a weight loss of about 3% of body weight. But in exchange for that pretty unimpressive weight loss, you get nasty GI side effects like steatorrhea, bloating and potentially even fecal incontinence.

Dr. Clem Lee: I don’t think anyone wants that. At least I don’t.

Dr. Shreya Trivedi: Very, most relatable thing ever said.

Dr. Clem Lee: There are some other options on the market. Phentermine is an amphetamine and Topiramate is a sodium channel blocker with many other mechanisms. But the data for them wasn’t all that impressive. And topiramate was associated with cognitive dulling and phentermine you can’t use it long term.

Dr. Shreya Trivedi: And then there was metformin, which sensitizes insulin through many different mechanisms. It had a reputation for assisting with weight loss, but most of us have probably taken care of thousands of patients on metformin, and it’s pretty obvious. Metformin isn’t really a wonder drug when it comes to weight loss.

Dr. Greg Katz: And so until a few years ago, the only truly effective option that we’ve had for obesity has been bariatric surgery. Which is effective, but it’s really underutilized, partly because surgery for obesity is scary for patients, and that partly because of the potential long-term complications in the form of nutrient deficiencies and other negative side effects.

Dr. Clem Lee: And because we don’t have effective medical treatments, in addition to our worsening obesogenic environment, the problem of obesity continues to just grow and grow. It’s not that we don’t recognize a problem, it’s that the treatments to date have been quite ineffective.

Dr. Shreya Trivedi: And that’s where Gila monsters and the Incretin system comes in.

Dr. Greg Katz: The story of the drugs that everyone in medicine is talking about. Semaglutide with trade names like Ozempic and Wegovy, or Tirzepatide with a trade name of Mounjaro. So the story starts in kind of an odd place, the southwestern United States in Northern Mexico where the Gila monster lives.

Gila monsters and GLP and GIP mechanisms

Dr. Shreya Trivedi: I’ll be honest, before researching this stuff, I had no idea what Gila monsters were. Turns out it’s a venomous lizard that only eats a couple times a year.

Dr. Clem Lee: Wow, that is shocking and I could never do that. But also that lizard will be great at residency. And the fact that Gila monsters eat so infrequently lets some investigators to think that they might have a unique way of modulating their blood sugar. Turns out they have a substance in their saliva called Exendin-4, that is an agonist for glucagon-like peptide one, also known as GLP-1. 

Dr. Greg Katz: You may have previously heard of Exenatide, which goes by the trade name of Byetta. It’s the synthetic version of Exendin-4 that’s been approved for diabetes treatment since 2005.

Dr. Clem Lee: Luckily for us, Exenatide isnt the end of the road for GLP-1. In order to understand this stuff well, you need to understand something called the incretin effect.

Dr. Greg Katz: Yeah, you can get very deep into the weeds with a physiology, but the way I remember this stuff is that the incretin system is what tells our body that we’ve eaten. The two major hormones at play here are GLP-1, which is glucagon-like peptide-1 and GIP, which is glucose-dependent insulinotropic polypeptide. These hormones act all over our bodies, but I think that most experts in the field are converging around the idea that the reason these drugs lead to weight loss is because the central effect that helps to regulate appetite. And that fits with talking to patients about these drugs who say that they’re just less hungry. And I’ve even had some patients tell me that they didn’t realize how much of their eating was emotional because they were just feeling so damn hungry all the time.

Dr. Clem Lee: Yep, everything that Greg just described is known as the incretin effect. So, it’s a sum of all the hormones that are released when a person has eaten.

Dr. Shreya Trivedi: And the drugs that we’re gonna talk about for the rest of the episode mimic these hormones.

Dr. Clem Lee: We’ll link to some graphics explaining this in more detail in the show notes, but let’s finish the story of how these incretin mimics went from gila monsters to blockbusters.

Story of how medications for diabetes were found to have a weight loss benefit

Dr. Clem Lee: So before we get into weight loss, I think it’s important to dial back and understand that the incretin mimetics were developed as anti-diabetic agents. The weight loss that we’ve seen from them really was just a happy accident.

Dr. Shreya Trivedi: Oh, I love me a happy accident story. Like when Alexander Fleming contaminated his staff culture and then found penicillin, or when scientists were looking at sildenafil as an anti-anginal agent, and then discovered its use for erectile dysfunction. Love, love, love!

Dr. Clem Lee: Me too! I love these underdog stories. So for a long time, the bar to get a diabetes drug approved was based on the glucose centric model of diabetes control. Meaning if we get the sugar down, we’ll make the disease better.

Dr. Greg Katz: But that glucose centric approach to diabetes management has really been falling out of favor. And the reason that it is because of trials like ACCORD, which have showed that lower glucose doesn’t reduce cardiovascular risk.

Dr. Clem Lee: Or the big plot twist. That was the tragedy of rosiglitazone a thiazolidinedione that actually ended up increasing the risk of heart failure. Unfortunately, this was only publicized after it was FDA approved and widely prescribed.

Dr. Shreya Trivedi: That rosiglitazone scandal led the FDA to decide in 2008 that diabetes drugs needed to demonstrate cardiovascular safety in addition to glucose lowering effect. And this then really brought in that cardiocentric model in the diabetes management era.

Dr. Greg Katz: And this shift to demonstrating cardiovascular safety in addition to A1c reduction has been a boon to us all. As the two new classes of drugs passing muster in the cardio centric model of diabetes care are the SGLT-2 inhibitors and the incretin-memetics.

Dr. Shreya Trivedi: The SGLT-2 story is interesting in its own right, but let’s see how the story of GLP-1 and GIP agonist played out.

Dr. Clem Lee: And just to lay the groundwork, there are a handful of GLP-1 and GIP agonists that you should know, and they all end with -tide. The three most famous ones are semaglutide, also known by the brand names of Ozempic, Wegovy, or Rybelsus. Liraglutide, which is also known as Victoza. And Tirzepatide, as we mentioned earlier, also known as Mounjaro.

Dr. Shreya Trivedi: And adding to that groundwork, something to keep in mind about the incretin mimetics, is that the first two, semaglutide and liraglutide are only GLP agonists, but tirzepatide takes it up a notch and a both a GLP-1 and GIP agonist. And then the trials you are going hear about on semaglutide, liraglutide, and tirzepatide are trials like LEADER, or a series of TRIALS under like SUSTAIN or SURPASS umbrellas. 

Dr. Greg Katz: And so let’s start with SUSTAIN-6 and LEADER, which were both published in the Journal in 2016. These were game changing trials that put the GLP-1 agonists on our cardiovascular map. Semaglutide reduced heart attacks by 25%, and liraglutide even reduced all cause mortality, which honestly seemed impossible for those of us that trained in the ACCORD era. That a diabetes drug would actually have a cardiovascular benefit.

Dr. Shreya Trivedi: Yeah, totally. And then it was SUSTAIN-6 where we started to see the potential of semaglutide as a weight loss drug. I will mention that it wasn’t a primary endpoint of any of the proceeding trials.

Dr. Greg Katz: And then the SURPASS trials introduced Tirzepatide, a once weekly injectable dual agonist of GLP-1 and GIP, which hits the two major hormones in the incretin system.

Dr. Shreya Trivedi: And then SURPASS-2 published in the journal in 2021 was really interesting. It compared then head-to-head, Tirzepatide and Semaglutide and found that Tirzepatide was superior at controlling diabetes than semaglutide.

Dr. Clem Lee: Some caveats with SURPASS-2 was that they use low doses of semaglutide, one milligram to be exact, so maybe it wasn’t an exact apples to apples comparison. And the treatment groups were unblinded and they didn’t really measure cardiovascular outcomes. 

Dr. Greg Katz: But caveats aside, LEADER, SURPASS and SUSTAIN were all really exciting trials. And to recap, these trials showed us that the incretin mimicers, like Semaglutide and Tirzepatide, are not only safe, but actually improve cardiovascular outcomes for patients with diabetes. 

Dr. Shreya Trivedi: And the weight loss signal suggested that we might have a new class of diabetes drugs designed from a biologic system to naturally help regulate glucose and appetite.

Dr. Clem Lee: That signal for weight loss was a sign of big things to come.

SURMOUNT-1 trial

Dr. Clem Lee: As the trial name suggests, the STEP I trial was a last, well, step we need to go up before we get to the trial of today’s SURMOUNT-1. Thanks for the weak laugh, guys. 

Dr. Greg Katz: I’m not sure I love that pun, but I think we’ll let it slide since we are trekking up to SURMOUNT-1.

Dr. Clem Lee: Oh, no.

Dr. Shreya Trivedi: Ah!  You know what? As bad as they are a good way to remember all these trials. So I think it’s a win. Let’s start with STEP-1. It looked at Semaglutide 2.4 milligrams weekly injection compared to placebo, and found that patients lost a whopping 15% of their body weight over the course of a year compared to a humble 2% with a placebo.

Dr. Clem Lee: Yeah, and this is particularly exciting because patients in the STEP I trial didn’t have diabetes and they weren’t all that sick, but they lost a lot of weight. And the cardiovascular outcomes from SUSTAIN-6 that we mentioned make us feel comfortable with their short-term safety.

Dr. Greg Katz: STEP I was a big deal for the treatment of obesity. But in my clinical practice, patients on semaglutide often report almost every single GI side effect that you can think of. Nausea, vomiting, diarrhea, constipation. So there’s definitely room here for a better tolerated drug.

Dr. Shreya Trivedi: Okay. That is very fair. And I love that clinical point about the semaglutide side effects. And we just mentioned the last section in the SURPASS-2 data that Tirzepatide was better than Semaglutide for diabetes. So it’s not so crazy to think that Tirzepatide may even be better than semaglutide in terms of weight loss. And that is what brings us to the SURMOUNT-1 trial.

Dr. Clem Lee: So SURMOUNT-1 looked at the types of patients we see in primary care, basically all the time. Middle aged people with a mean age of 45 who aren’t all that chronically ill, but who are overweight and have at least one weight related complication. These include things like hypertension, OSA, dyslipidemia or cardiovascular disease.

Dr. Shreya Trivedi: And this was a pretty diverse patient group. Almost two thirds of the patients were women with a mix of different races and ethnic groups.

Dr. Greg Katz: I think another really important thing to note about these patients is that they had elevated fasting insulin levels, but they didn’t have diabetes. That means that even if they didn’t meet strict criteria for metabolic syndrome, they were insulin resistant or as I like to think about it, even if they weren’t pre-diabetic, they were pre pre-diabetic.

Dr. Shreya Trivedi: Let’s sit with that preferred bit. Greg, why do they include patients with just elevated fasting insulin?

Dr. Greg Katz: One of the early signs of insulin resistance before you develop diabetes is fasting hyperinsulinemia. And so seeing high fasting insulin levels is an important sign in the metabolic health of these patients. And it tells me that a lot of these patients are on the road to diabetes. 

Dr. Clem Lee: Greg, that’s such an interesting point. I really hadn’t thought about the fact that a high fasting insulin was informative about metabolic health.

Dr. Shreya Trivedi: Yeah, same. So SURMOUNT-1 took patients with this elevated fasting insulin, randomized them to escalating doses of Tirzepatide versus placebo. And all these patients did receive some type of lifestyle counseling.

Dr. Clem Lee: And then they followed the patients for over a year, and what they found was pretty astounding.

Dr. Greg Katz: Patients on a 10 milligram or 15 milligram dose of weekly Tirzepatide lost 20% of their body weight, and the patients on the five milligram dose lost 15%. And this is all compared to a 3% body weight loss with placebo. 

Dr. Clem Lee: And if you look at the weight loss curves for SURMOUNT-1 and STEP-1, they look similar. There’s rapid weight loss at first step plateaus after a few months on the drug and then persist over a year. But the numbers in SURMOUNT-1 were more impressive than they were in STEP-1.

Dr. Shreya Trivedi: Yeah, there was a striking dose response to Tirzepatide, which really confirmed that the drug works. About a third of the patients on 15 milligrams Tirzepatide lost over 25% of weight, which is pretty astounding. Think of a 200 pound person that’s 50 pounds of weight loss. It wasn’t just weight that improved. These patients also got healthier. Waist circumference went down 10 to 15 centimeters. Systolic blood pressure dropped six points compared to placebo. LDL, cholesterol, non-HDL cholesterol, triglycerides, fasting insulin, they all went down. Even body composition, also known as body fat that improved considerably in these patients.

Dr. Clem Lee: Yeah. And more than a third of patients had pre-diabetes at enrollment. Of those who had pre-diabetes, 95% of those reverted back to normal glycemic control on the drug and although we can’t compared directly to the semaglutide in the STEP-1 trial. SURMOUNT-1 had similar rates of drug discontinuation around 7%. And Tirzepatide had less nausea, diarrhea, and vomiting than with Semaglutide.

Dr. Shreya Trivedi: Yeah, that tolerability is a pretty big deal. This is often the reasons why people are stopping their drug. So important to keep in mind.

Dr. Greg Katz: And so to summarize, compared to the results from the STEP-1 semaglutide trial patients in the SURMOUNT-1 trial on Tirzepatide lost more weight on average, and more people lost a significant amount of weight with a similar number of side effects. And even though it’s not a full apples to apples comparison, the trial data here certainly matches my anecdotal experience with these drugs, where I’ve seen fewer GI side effects with Tirzepatide compared to semaglutide.

Dr. Shreya Trivedi: That makes me wonder why is it that Tirzepatide is both more effective and better tolerated than semaglutide it almost seems too good to be true, to have both more effectiveness and better toleration.

Dr. Clem Lee: Yeah. I agree. One possible explanation is that Tirzepatide hits multiple places in the incretin system, so it’s going to be more effective than just an agonist for GLP-1, such as semaglutide.

Dr. Greg Katz: I think of this similar to the way that I think about neurohormonal blockade and heart failure or antiretroviral therapy in HIV. Attacking multiple mechanisms at once is often more effective than just hitting one mechanism particularly hard. It’s almost like biology is just a bit too smart for a single-minded approach to work.

Dr. Shreya Trivedi: Yeah, I like that analogy a lot. Hitting multiple pathways at once, better than just one. It makes me wonder, though, with the next generation of incretin mimicers, I hear that there’s ones that hit GLP-1, GIP, and glucagon. A triple agonist! I’m curious if that’s gonna be even more effective than Tirzepatide.

Dr. Clem Lee: Yeah! It’s really exciting to think about what’s coming down the road, especially looking at the way that Tirzepatide seems to work across the board. It emphasizes that the drug might help our patients in ways that have nothing to do with their body fat percentage.

Dr. Greg Katz: Yeah, I just keep staring at that remarkable secondary endpoints table that looks at all the improvements that the Tirzepatide group had in essentially every marker of health that we focus on when thinking about chronic disease risk. Their lipids, blood pressure, and physical function all looked way better at the end of the trial than at the beginning, and they were all way better than the placebo group.

Dr. Clem Lee: Yeah, it makes sense given what you said in the beginning of the episode on how obesity and metabolic syndrome are so tightly linked. But it can’t be all that good. Right? Are we just gonna put Tirzepatide in the water supply now?

Dr. Shreya Trivedi: Yeah. I think there’s still a few unanswered questions, right, before we wrap up. First, I’m curious how durable is the weight loss here?

Dr. Greg Katz: So we don’t know. We can’t really draw definitive conclusions on long-term effect of Tirzepatide. And so we don’t know what’s gonna happen five years or 10 years down the road. We do have a sense that when you come off of these drugs, you regain the weight pretty rapidly. And that’s from extrapolating the semaglutide withdrawal studies to, to suggest that a similar thing happens with Tirzepatide.

Dr. Shreya Trivedi: Okay. That’s really good to know when counseling our patients. What about the other thing that I feel like a lot of patients will ask, which is, “Hey, what are the side effects?” And then also in terms of long term, are there any unknown side effects?

Dr. Greg Katz: We don’t know what we don’t know! SURMOUNT-1 followed these patients for a little over a year, but what does that look like a decade down the road? I really don’t think anybody can answer that question for us. But in all the data that we have now, the results of SURMOUNT-1 are really promising to me as a way to help our patients who are struggling to lose weight.

Dr. Clem Lee: Yeah, and so I guess its just one more step forward in how we treat obesity. Pardon that bad pun. It’s all about the steps. 10,000 steps. Studies on steps forward in obesity. I hope you are taking steps while listening!

Dr. Shreya Trivedi: It’s probably getting late while we’re recording! I am sure there are people getting steps while they’re listening, but I’m not sure another bad step pun is the best way to conclude our second Beyond Journal Club episode. But maybe we should end with some optimism about the way these drugs may really positively change our patients’ lives. I like get kudos to all these authors. It all makes sense in the whole world of these diabetes drugs ended up being effective in weight loss, we had to first figure out how to SUSTAIN ourselves to SURPASS and then STEP into the real game changer, which was SURMOUNT!

Dr. Greg Katz: And that is a wrap for today. If you found this episode helpful, please share with your team and colleagues and give us a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us!

Dr. Clem Lee: Yeah, and if you have any feedback, please email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

References

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