David Shaywitz

While visiting my parents on Memorial Day weekend, I reflected on the wonder and joy of a life in medicine and science — theirs as well as mine. 

Incredible Progress in Medicine

My parents are academic physician-scientists at Yale Medical School, where they founded and continue to lead the Yale Center for Dyslexia and Creativity. Now in their early 80s, they are as active and engaged as ever, reading the literature, leading a research team, and giving talks. Just a year or so ago, their Coursera course, “Overcoming Dyslexia” went live, and has now enrolled over 40,000 learners.

David, Sally and Bennett Shaywitz

On the morning of Memorial Day, my dad and I, both early risers, were sipping coffees at the kitchen table when he began to reflect on how much medicine has changed over the course of his career in pediatric neurology.

He described clinical neurology before contemporary neuroimaging like CT and MRI scans.  Before their arrival, my dad said, neurologists had few tools beyond the classic neurological exam, an approach that is elegant, even charming in theory, but historically has been largely unfalsifiable in practice.  This changed, he said, when noninvasive neuroimaging arrived and gradually revealed the limitations and often specious conclusions of the beloved physical exam. 

Procedures were different as well. In the days before advanced noninvasive imaging, I was told, children with meningitis often received a subdural tap, meaning a needle was stuck into the skull to remove a potential effusion (fluid buildup). With the advent of CT imaging, neurologists quickly learned that effusions were common in these patients and would typically resolve on their own.  Bacterial meningitis itself has become far less common than it was decades ago, due to the introduction of vaccines that protect against the most common causes. 

My mom, who soon joined us at the table, reminded me that imaging also impacted other medical specialties, including obstetrics. When she was pregnant with twins, I learned, doctors struggled to make this determination; a plain X-ray film (with its associated radiation exposure) was ultimately required to be certain. Obstetrics was considerably riskier than today, and pediatricians (particularly pediatric neurologists) would often see infants with injuries from difficult deliveries.

It was also common, my mom recalled, for pediatricians to encounter children who suffered from viral conditions now preventable with vaccines. She saw many kids who were born deaf following maternal infection with rubella. There were also a number of children each year who she saw die from measles. In addition, it was not unusual to encounter adults (including my mom’s best friend) who were crippled because of a polio infection in childhood.

My parents also recall frequently seeing young patients with lead poisoning. Sometimes children would come in with seizures, or occasionally in a coma, because of lead-induced encephalopathy. Often, this happened when small children would pick up and eat bits of lead-containing paint. Since the late 1970s, when the manufacture of lead-based paint was banned and awareness of the health risks rose, fewer kids now suffer these symptoms.

(I would be remiss not to point out that our ability to identify and effectively support children and adults with dyslexia is also far better than it was years ago, reflecting the work of researchers like my parents and others.)

The progress my parents have seen across their careers – largely attributable to improved imaging technology, the development of highly effective vaccines, and impactful public health measures likes universal childhood vaccinations and the mandated removal of lead — is extraordinary. The capabilities we have today to diagnose and treat illness are so much more powerful than when they started.  To me, this reinforces why, if asked the question “If you could pick any time to live, when would you choose?” the response must be today — unless tomorrow is an option. 

Things are getting better – as neuroscientist Steven Pinker, among others, reminds us.

To be sure, while improved technology and medicines offer the possibility of better health, this promise will only be realized through access, and this remains a profound concern. A recent Wall Street Journal headline announced, “Cancer is Capsizing Americans’ Finances,” while a recent South Park lampooned the byzantine process required in the U.S. healthcare system to access GLP-1 medicines for diabetes and weight loss. 

Our challenge here is finding a way to address the urgent need to ensure access to the best care available today while simultaneously continuing to incentivize the development of even better diagnostics and therapeutics (including those like vaccines aimed at preventing rather than treating disease) for future generations.

Craig Garthwaite, professor of strategy, Northwestern University’s Kellogg School of Management

As Craig Garthwaite, a health economist at Northwestern University, nicely frames it, the need for better treatments can be seen as another category of access challenge. 

“I’ve lost close family members to cancer that didn’t yet have treatments available,” he writes. “The hardest part for them wasn’t affording it. A lack of innovation is the access problem we often overlook because it isn’t as salient — but it is a far larger barrier than price (emphasis added).”

Today, no one can access desperately needed transformative medicines for conditions like glioblastoma, pancreatic cancer, and Alzheimer’s Disease; they haven’t been invented yet.

Diversity of Global Science

While home, I also came across mementos I saved from lab experiences over the years. One example: a 24-well plate signed and gifted to me nearly four decades ago by a colleague (now a professor at UCSF) in tribute to the weeks we spent one summer in the Janeway lab at Yale doing an assay using these plates over and over (and over).

Reflecting on my experiences in science, both in academia and industry, I was struck by the incredible diversity of people I’ve worked with, reflecting so many different paths and life experiences and even politics. 

For instance, while most researchers tend to shade to the left, I vividly remember a phenomenal technician from the Janeway lab who proudly wore a belt buckle proclaiming “God, Guns, and Guts Made America Great.” I also recall a postdoc from my PhD lab who was emphatically pro-life, and who has gone on to a highly successful career in science, now leading drug discovery at a prominent AI company.

Science is intrinsically international. Difficult and compelling problems attract passionate researchers from across the world. An incredible privilege of a life in and around science is how second nature it becomes to collaborate with colleagues from everywhere. 

In college, I learned molecular biology next to brilliant colleagues who had grown up in places like India and Iran and are now accomplished biomedical scientists and entrepreneurs. In the labs I’ve worked in, it was routine to see a postdoc from South America next to a postdoc from Eastern Europe next to a graduate student from Michigan. 

Scientists at the companies where I’ve worked also came from around the globe; in my last role, at a company headquartered in Japan, the Chief Data and Technology Officer hailed (very, very proudly) from Ireland; innovation in pharmaceutical sciences was driven by a brilliant colleague from Austria; and the physician-scientist leading the gastroenterology, immunology, and inflammation therapeutic area had emigrated from Nigeria when he was eighteen.

Diversity in science includes religion as well. 

In the Tonegawa lab, at MIT, a Mormon graduate student helped me better understand the purpose and fulfillment of missions. At Takeda, a talented epidemiologist and officemate shared his experience fasting for Ramadan, and the joy of Eid al-Fitr as the month-long observance concludes.

That’s not to say, of course, that science is as representative as it needs to be if it is to truly capture the full potential of the most capable minds in the world. In my last role, an exceptionally effective African-American vice president and science technology leader would poignantly lament how few African-American colleagues there were at senior levels in the organization, a disparity he worked passionately to address.

Compared to the perfect state, science clearly has a distance to go. 

But there is so much about the community of science that is encouraging, including its ability to attract global talent with diverse viewpoints to pursue collaboratively the shared goal of better understanding nature, and if we’re lucky, translating this understanding into more effective treatments for patients wherever they live, and whatever their politics and beliefs.

Good Listens

My drive from Massachusetts to Connecticut also afforded me the opportunity to catch up on some podcasts; here are a few episodes that might be of interest.

• Acquired episode, discussing Microsoft’s early days. Fun fact: Windows was Plan B. 
• WSJ – The Future of Everything episode featuring the always interesting “Science of Success” columnist Ben Cohen discussing how Birkenstock’s became such a big deal.
• Invest Like The Best episode, discussing how Mitch Rales built Danaher into the life science tools colossus it is today.
• Running Through Walls episode – Venrock’s Bob Kocher sits down with Mark McKenna, the former CEO of Prometheus, which was acquired last year by Merck for $10.8B.
• Honestly podcast: for readers looking for a fresh perspective on journalism-related topics, two recent episodes may be of interest:
  • Here, host (and former New York Times reporter) Bari Weiss interviews (former) NPR senior reporter Uri Berliner about how the media business is changing;
  • Here, Weiss interviews (former) New York Times reporter Nellie Bowles about Bowles’s recently published Morning After the Revolution – one of my favorite recent reads.

David Shaywitz

The two broad categories of medical discovery that command the most attention are insights resulting from rare, informative genetic conditions (see here) and advances resulting from fortuitous observations.  

A canonical example of the value of extreme genetic phenotypes is the patient with familial hypercholesterolemia who inspired Brown and Goldstein’s scientific pursuit of cholesterol metabolism and led to the statins. Similarly, Vertex’s promising pain medicine was directly inspired by rare genetic conditions associated with pain hypersensitivity and hyposensitivity.   

Meanwhile, as we’ve discussed frequently in this column, many medicines, particularly in neuroscience, have been discovered by “happy accidents” – tricyclic antidepressants are one example.

Decades of Painstaking Science

But GLP-1 medicines like semaglutide (Wegovy) and tirzepatide (Zepbound) do not fall into either of these categories. Their development reflects decades of meticulous biology and physiology, of researchers working slowly and painstakingly through the complicated science.

Daniel Drucker, professor of medicine, Lunenfeld Tanenbaum Research Institute of Mt. Sinai Hospital and the University of Toronto.

As pioneering researcher Daniel Drucker and colleagues wrote in a comprehensive review in 2017, “the field was built slowly with a series of non flashy yet solid studies examining the physiology, pharmacology, and pleiotropic actions of native GLP-1 and multiple GLP-1R agonists.”

Drucker notes that most papers in the GLP-1 field (at least until recently, one imagines) “were published in traditional physiology or endocrinology subspecialty journals and might be described as ‘descriptive’ or ‘incremental’ by many colleagues.”

His summary:

“Taken together, the story of discovery and characterization of the GLP’s highlights how old-fashioned biochemistry, physiology, molecular biology, and traditional analyses of hormone action provides a firm scientific foundation for the development of multiple novel therapeutics for the treatment of obesity, diabetes, and intestinal disorders.”

To put a finer point on it: genetics were not a key component of the GLP-1 story.  Drucker explicitly pointed this out in his interview with Eric Topol (discussed in previous column), noting that physiologically, removal of GLP-1 or GLP-1 receptor doesn’t seem to have profound consequences. In contrast, molecules identified through genetic analysis, like leptin, have not proven to be of great therapeutic utility.

Similarly, the potential of GLP-1 medicines to cause weight loss was also not a happy accident – rather, it was seen from some of the earliest rodent studies of GLP-1, and a key thesis of the Novo GLP-1 program from the earliest days. 

Key Enablers and Challenges

There were some lucky breaks, to be sure. 

For one, as discussed in my last column, the adverse effects associated with GLP-1 initiation – nausea and vomiting in particular – generally wane over time, while the therapeutic effect (suppression of appetite) endures. 

The biology could easily have gone the opposite way. 

Also helpful: encouraging results from large cardiovascular outcome studies for long-acting GLP-1 medicines used for the treatment of diabetes (high-risk patients were found to have a significantly lower rate of adverse cardiovascular events – here, here). 

These results, together with a decade of reassuring experience using GLP-1. The first, exenatide (Byetta), was approved by the FDA for use in diabetes in 2005. That molecule, originally a twice-daily injection and then formulated into a LAR version allowing once-weekly injection, helped provide confidence in the safety of this class.

Weight loss was consistently observed in patients with type 2 diabetes. The clean safety profile over time, combined with the long-term cardiovascular benefit, helped encourage companies to take a shot at a much larger patient population – people who are overweight or obese but don’t have diabetes.

Drucker acknowledges that translation of promising GLP-1 science into approved therapeutics was a particularly challenging task that required decades. 

He cites several hurdles, including:

• Need for a longer-acting peptide (endogenous GLP-1 has an incredibly short half-life in the blood – only about two minutes); legendary Novo researcher Lotte Bjerre Knudsen famously spent years focused on figuring out how to create a longer-lasting therapeutic version this before finally developing a solution that become liraglutide (Victoza), a once-daily injection.
• Need to figure out dosing to address GI side effects; Drucker points out that in every clinical study, GLP-1 medicines cause GI discomfort including nausea and vomiting; eventually, Drucker says, researchers recognized that these side effects can be significantly mitigated through slow titration.
• Need for better assay reagents to detect levels of key molecules like GLP-1, GLP-2, and their receptors. Some large pharmas have analytic lab groups specifically focused on developing such tests for R&D; I recall a particularly capable team at Merck Research Labs in Rahway, NJ when I was there nearly 20 years ago.

New diabetes medicines – as well as potential obesity medicines – also require large cardiovascular outcome trials, to prove that the benefit delivered by these medicines outweigh any risk.

These concerns were motivated on the diabetes side by the experience of GSK’s rosiglitazone (Avandia), an insulin sensitizer which seemed to have a positive effect on diabetes parameters but, unexpectedly, a negative effect on cardiovascular outcomes. The high-profile safety controversy led the FDA to mandate cardiovascular outcome trials for future diabetes medicines – a move that added considerable time and cost to type 2 diabetes R&D programs. 

Obesity medicines have long concerned regulators both because of the perception that they might be widely utilized as so-called lifestyle medicines, and more specifically because of the experience with the combined use of two drugs individually approved by the FDA, fenfluramine and phentermine. Used together (“fen-phen”), the combo caused some patients to develop valvular heart disease and pulmonary hypertension.

The key point here is that in many ways, GLP-1 drugs were ideally suited for large pharmas, given the time, resources, and range of expertise required to address all of these drug development challenges. 

Lessons for Drug Developers

I asked Drucker what he saw as the key lessons for drug development. He cited three.

• “We should embrace multiple lines of evidence, and not just pursue human genetics-based leads”
• “Nice to use human genetics to screen out for worrisome oppositional signals or for supportive directional biology but not exclusively as a must-have criteria (or we would not have SGLT2i in heart and kidney disease, or GLP-1RAs etc)”
• “The solid reproducible non-flashy tortoise (careful papers in solid mid-tier journals) often beats the spectacular Nature/Science/Cell”

There may be an addition lesson as well.

In reviewing Drucker’s many publications, I was struck by the insight and brilliance that seemed to be required to drive the science in this complicated area. Yet when I put this to Drucker, he suggested instead that the most important attributes he’s brought to the field were his tendency to be “careful, persistent, and tenacious.” 

I suspect these characteristics apply to the vast majority of successful drug developers.

We’re often attracted to the idea of science and drug development advancing through a series of brilliant ideas, eureka moments, and incandescent insights. Without question, narratives with these features make compelling stories.

Yet in the case of the GLP-1s, a category of medicine that is poised to transform everything in our world, these blockbuster medicines seem to have resulted from something quite different: decades of slow, determined science, both on the part of academics like Drucker, and companies like Novo and Lilly, patiently and deliberately nudging the work relentlessly forward.

Prediction is Hard

Finally, just to emphasize how difficult the future is to predict in medicine and science, even by the most informed experts, I feel obliged to call out a particularly revealing sentence from Drucker’s 2017 review.

Drucker writes, “market penetration for many GLP-1R agonists remains disappointing, raising questions about the potential clinical appeal, expense, and commercial success of newer formulations.” 

In other words, as recently as 2017 — twelve years after the first FDA-approved GLP-1 medicine, exenatide (Byetta) for diabetes, and three years after the approval of liraglutide for obesity (marketed as Saxenda), after previous approval for diabetes (as Victoza) — it was clearly not a foregone conclusion that GLP-1 molecules were tracking to be the blockbuster obesity drugs they are today.

Michael Moritz

As legendary Sequoia VC Michael Moritz said (and as I recently discussed here), even great successes aren’t obvious early on: “I have never been involved in an investment that became a very successful business without fearing earlier that the business was going to fail, not even once.”

The problem, as Judah Folkman observed, is that to succeed, you have to proceed with conviction, but you don’t know until the end (in the case of the GLP-1 drugs, the randomized controlled trials demonstrating profound weight loss) whether you’re persistent or obstinate.

So where does this leave R&D leaders? 

One thought: we should be humbled by the challenges of forecasting, cognizant of the limitations of genetics (useful as it often can be) or of any single approach to drug discovery, inspired by accomplishments of determined academic researchers and pharmaceutical scientists, awed by the intriguing complexity of human biology, and deeply grateful for our collective opportunity, as contemporary drug developers with an unprecedented set of tools and capabilities, to fashion transformative new medicines for patients. 

David Shaywitz

GLP-1 medicines are obviously having a real moment – medically and culturally. 

These once-weekly injectables, which reduce appetite and result in significant, long-lasting (so long as you’re taking them…) weight loss, have been demonstrated to have a number of important health benefits beyond simply shedding pounds. 

In March, Novo Nordisk’s semaglutide (Wegovy) was approved by the FDA for its ability to reduce the risk of heart attack, stroke, and death from cardiovascular disease in patients who are obese or overweight.  

This new wave of effective weight loss drugs has elevated the pharma companies that make them, Novo Nordisk and Eli Lilly. Novo Nordisk reported $1.3 billion in Wegovy sales in the first quarter of 2024 – about double the amount from the same period a year earlier. Eli Lilly’s rival GLP-1 and GIP receptor agonist, tirzepatide (Zepbound), recorded an extraordinary $517 million in US sales in the first quarter of 2024, in the first full quarter after being approved by the FDA in November.

The progress and momentum has also generated significant interest from other pharmas suddenly seeking to enter a therapeutic area that they have long been avoiding.

The availability of an apparently safe category of medicines that address a key societal preoccupation – obesity – has reverberations that have been felt everywhere from the Oscars to the diet industry – and, potentially, many other sectors of the economy.

Many companies focused on weight management, for example, have decided that instead of competing directly with GLP-1 medicines, it makes more sense to incorporate these medicines into their offerings (eg Weight Watchers) or to position themselves as an off-ramp (Virta).   

On a personal level, I appreciate their motivation. After significant success on Virta (discussed here, here), I’ve found it increasingly difficult to sustain (a common experience, it seems). As my weight, sadly, starts to creep back up despite regular exercise, I find myself actively contemplating a switch to GLP-1s, especially as I encounter more and more physician colleagues experiencing success with these powerful medicines.

Keeping up with the GLP-1 story can be difficult; fortunately, several recently-released podcasts, each with a slightly different focus, can help get you up to speed quickly – ideally while you’re exercising.

Ground Truths: Eric Topol interviews Daniel Drucker

Let’s start with the science. Here, the one person you’d most want to speak with is endocrinologist and physician-scientist Daniel Drucker, who has spent his career focused on incretins – molecules such as GIP-1 (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) that potentiate the secretion of insulin after meals.

Eric Topol (left) and Daniel Drucker (right) on the Ground Truths podcast.

His website, glucagon.com, has for years served as a central repository of information in this field, including the many foundational studies and integrative reviews authored by Drucker and his colleagues.

In the latest episode of famed cardiologist Eric Topol’s invariably interesting podcast Ground Truths, he asks Drucker key questions about the underlying science.  What I found particularly striking was how much is still unknown.  (This seems like another example of a phenomenon I’ve frequently encountered, where real experts are comfortable enough to recognize and acknowledge the vast extent of our collective ignorance; in contrast, many with a more tenuous grasp of the material tend to present it with more certitude and bluster.)

The entire, relatively short (36-minute) podcast is an obvious must for anyone interested in a data-driven, grounded, sophisticated perspective on GLP-1s, but several points of particular relevance for readers of TR and this column include:

• Subtle biology of GLP-1: Drucker say, “if we take GLP-1 away or we take the receptor away, you don’t really develop diabetes without GLP-1. You don’t really gain a lot of weight without GLP-1. So physiologically it’s not that important.”  In other words, for all our interest in leveraging genetics to find new drugs, GLP-1 is an example of how this approach can be limiting – the pharmacological effects of GLP-1 might not have been predicted by extrapolating from observed physiology and pathophysiology.  Moreover, Drucker notes, molecules that were associated with more informative genetics, like leptin, have not translated thus far into broadly effective medicines for the treatment of obesity.
• GLP-1 seems to “talk to the brain,” but indirectly; the mechanism seems unclear:  Drucker explains that GLP-1 “doesn’t directly get into the brain to a meaningful extent,” and how it communicates with the brain is “is not well understood … in the magic that we see.”  Given the impact of GLP-1 on appetite control, this seems like a glaring gap in understanding – or rather, an important opportunity for future study.
• Role of serendipity: GLP-1 medicines emerged from decades of meticulous research (including foundational and continuing work by Drucker).  In other words, the discovery of GLP-1 and the elucidation of their biological and pharmacological effects weren’t simply a happy accident.  But what was unbelievably lucky, it seems, is that the medicines work as well as they do with an apparent paucity of serious side effects.  Drucker notes that while there are some side effects when patients start taking GLP-1 medicines, these tend to dissipate, while the positive effects on appetite suppression persist. (The most common side effects are nausea, vomiting, and diarrhea).

Acquired: Novo Nordisk

The Acquired podcast – recently described by the Wall Street Journal as what “the smartest people in the room are all listening to” – is a monthly, in-depth discussion of a leading company, hosted by former-VCs Ben Gilbert and David Rosenthal. 

In January, Gilbert and Rosenthal took on their first life science company, Novo Nordisk, reviewing its fascinating history, and contextualizing its strategy in the context of other businesses.  Listening to two smart, enthusiastic business analysts, who aren’t pharma insiders, wrap their heads around the complexities of healthcare and drug development was engaging and illuminating. The episode, as usual for Acquired, is long (this one runs over three and half hours!) but captivating and worth your time.

Key points for TR readers:

• Importance of a champion: Drug development requires champions (see here, here, here).  In this case, the champion is Novo Nordisk’s Lotte Bjerre Knudsen, who led the effort to develop a long-acting GLP-1, and then to guide it towards obesity.  The magnitude of this achievement is especially remarkable since the CEO at the time, Lars Rebien Sorensen, was initially skeptical about developing GLP-1 for obesity.  “Obesity is primarily a social and cultural problem,” he once said. “It should be solved by means of a radical restructuring of society. There is no business for Novo Nordisk in that area.”
  

  Lotte Bjerre Knudsen

• Focus on obesity from the beginning (this is actually from ACQ2, a second podcast hosted by Gilbert and Rosenthal, in an episode focused on Knudsen): “The target market was also obesity from the beginning,” Knudsen says about GLP-1 molecules, pushing back on idea that they somehow stumbled into obesity.  “We did have a strategic intent to go after obesity early on.
• Recognition of the risk of drug development: Perhaps my favorite part of the episode was when Gilbert and Rosenthal discuss the remarkable challenges and exceptional risks of drug development, in the context of other businesses.  Their recognition and articulation of the difficulty and urgency of coming up with new medicines represents a level of insight that seems to have eluded many others.

As strong as this episode is, the hosts may overstate their case when they suggest Novo’s exceptional business performance may be attributable to their concentration in, and singular focus on diabetes and metabolism. While Novo’s deep experience in diabetes and metabolism unquestionably facilitated their development of GLP-1 medicines, they are also incredibly lucky that these medicines turned out to be such a breakout hit, and not (as discussed above) saddled with all sorts of side-effects or other challenges. 

Concentrating efforts in any one area is like putting all your chips on a particular Roulette number – if you’re lucky, you can win big, but if not (for example, if you went all-in on Alzheimer’s Disease, an incredibly urgent medical need that hasn’t yet seen great therapeutic success), you might fare poorly. 

If you are going to bet big, however, it makes sense to do it in an area where you are expert, and can both choose as wisely as possible, and also be prepared to take advantage of a win if you get one. Gilead’s acquisition of Pharmasset for $11.4B in 2011 – derided by many analysts at the time, just before they started applauding Gilead’s subsequent success in curing hepatitis C – seems like a similar example.

Honestly: Bari Weiss interviews Johann Hari

Bari Weiss and the Honestly podcast offer independent-minded takes on a range of issues, including topics related to health. Here, she interviews author Johann Hari about his latest book, Magic Pill (I discussed his previous effort, Stolen Focus, for TR readers here).

Hari’s new work features reporting on GLP-1 medicines including in particular their social context, a perspective he succinctly summarizes in a recent New York Times op-ed.

It was especially interesting to listen to Hari’s distillation after hearing Drucker’s, because Drucker’s presentation emphasized the limitations of science and the many areas of ambiguity and uncertainty, while Hari offered a tidy narrative that at times felt scientifically dubious.

Key highlights for TR readers:

• View that the American diet is responsible for altered satiety setpoint:  Hari tells us about a neuroscientist, Paul Kenny, who early in his career was struck by the differences between the United States and his native Ireland, and his sense that American food was affecting his mind as well as his body.  Kenney later discovered that rats who were raised on a normal diet and then offered American food “went crazy for the American diet…within a couple of days, they were different animals. And they very rapidly all became obese.”
• Examples of healthier food in other countries like Japan, where the obesity rate is 4%, compared to a rate of 42% in the United States:  Hari describes visiting a “typical” school in Japan, and discovering processed food is banned, kids are served “unbelievably healthy” freshly-prepared meals, and children express preferences for healthy vegetables like broccoli.  (Like Hari, I found this unimaginable, and wasn’t surprised to hear his first thought was that he was being trolled by the kids; he wasn’t.)
• Examples of approaches to obesity management in the work setting that seem unimaginably over the top.  Hari tells us about a law in Japan mandating that “every company in Japan has to weigh its entire staff on a particular day. And if your weight has gone up, you have to make a plan with your employer to bring it down. And if as a company overall your staff’s weight has gone up, you are fined by the government.”

The Journal: Trillion Dollar Shot

One of my favorite podcasts is The Journal, co-produced by Gimlet and the Wall Street Journal.  Most days, they look in depth at a topic in the news, but occasionally they put together a series taking an even deeper look at an important topic, seeking and sharing multiple perspectives across several episodes. I recent highlighted another Journal series (With Great Power) that focused on the birth of Marvel studios.

The current series (as of this writing only the first episode has dropped) promises an examination of GLP-1 medicines – how they were developed, and the effects they are having on “bodies, fortunes, and industries.”

Key highlights for TR readers:

• A recurrent theme of innovation has been the need for persistence and conviction, along with the uncomfortable fact that, as Judah Folkman said, “If your idea succeeds, everybody says you’re persistent. If it doesn’t, you’re obstinate.”  The problem is you can’t figure out until later the category in which you belong. It’s clear from this podcast that Lotte Bjerre Knudsen, the champion we met earlier, was persistent. The former CEO of Novo, Lars Rebien Sorensen, describes Knudsen as “a person that’s very, very difficult to say ‘No’ to,” someone whose team succeeded “because of their stubbornness and their skills and their professionalism.”
• Industry view of obesity drugs: Sorensen also highlights the initial concerns of pursuing GLP-1 medicines for obesity, noting that “at the time, almost all without exception, weight-lowering drugs had failed, some even so badly that companies were sued. So I knew that if we started talking too much about the obesity effect of GLP-1, we might taint a very good diabetes drug.” (As noted earlier, Sorensen also viewed obesity as a social rather than a medical challenge.)
  

  Dr. Fatima Cody Stanford, obesity medicine expert, MGH

• Unexpected high discontinuation rate: Perhaps the most striking fact I learned from all of these podcasts was the exceptionally high discontinuation rate from GLP-1 medicines.  The Acquired podcast that noted “one out of six patients have side effects that are so severe that they discontinue the drug,” and “as many as 68% of people roll off it after a year.” This is especially surprising since most of the weight lost due to GLP-1 medicines returns if the drug is discontinued. The Journal podcast offered the most compelling insight into the potential reasons for the high rate of discontinuations; one of the journalists reporting the story actually stopped taking the medicine himself although it seemed to be working well for him.  The key reasons for discontinuation seem to be (a) cost (a huge factor and the reason the reporter stopped); (b) side effects; (c) the inconvenience of needing to hunt for supplies of a medicine where manufacturing can’t keep with the demand. Dr. Fatima Cody Stanford, of the MGH Weight Center, tells me that the most significant issue in her experience has been serious ongoing challenges with the supply.

Collectively, these podcasts offer different but overlapping perspectives on GLP-1 medicines, and provide insight into the history, science, and strategy around these medicines. They also remind us of the complex interplay between transformative medicines and broader society, and the need for life science companies to engage with it – ideally with authentic curiosity, humility, and empathy.