They called 2023 the “year of Ozempic,” but it now seems GLP-1 drugs might define an entire decade — or an even longer era. The game-changing drugs, which mimic the hormone GLP-1, offer large benefits for not just diabetes management and especially weight loss but also, apparently, heart and kidney and liver disease, Alzheimer’s and dementia, Parkinson’s and addiction of all kinds. And perhaps because of widespread use of the drugs, the obesity epidemic in America may finally and mercifully be reversing.
But of all the things we learned this year about GLP-1s, the most astonishing could be that the revolution might have started decades earlier. Researchers identified the key breakthrough for GLP-1 drugs nearly 40 years ago, it turns out, long before most Americans had even heard the phrase “obesity epidemic.”
This summer, a former dean of Harvard Medical School, Jeffrey Flier, published a long personal reflection that doubled as an alternate history of what may well be the most spectacular and impactful medical breakthrough of the century so far. In 1987, Flier co-founded a biotech start-up that pursued GLP-1 as a potential treatment for diabetes, not long after it had first been identified by researchers who’d also found that the hormone enhanced insulin secretion in the presence of glucose.
The startup obtained worldwide rights to develop GLP-1 as a metabolic therapy from a group of those researchers, based at Massachusetts General Hospital. They even generated clinical results that suggested it might have promise as a weight-loss drug as well — only to have Pfizer, which had agreed to fund the research, withdraw its support, without providing the researchers with an especially satisfying explanation. Instead, Pfizer told Flier and his partners that the company didn’t believe there would be a market for another injectable diabetes treatment after insulin. Well, Flier tells me, “they were wrong.”
In 1987, nearly seven million Americans had diabetes, and about 40,000 Americans were dying of the disease each year. By 2021, more than 35 million had diabetes, and 100,000 were dying of it each year.
In 1987, fewer than one in five American adults were obese, and by 1999, obesity was responsible for more than 300,000 excess American deaths each year. By 2023, it was more than 40 percent of American adults, and as early as 2016, estimates were already showing as many as 500,000 excess deaths annually as a result.
The scale of the problem is why Flier says that GLP-1s “might turn out to be the most important class of drugs discovered over the last 50 years.” And then there are all the other unexpected benefits, which he calls “pretty well unprecedented.” Almost every month, it seems, we’re learning about a new therapeutic use for the drugs, many arriving without a clear understanding of the biological mechanism behind them. “At the deepest level,” Flier says, that astonishing diversity of surprising applications is a reminder of “how little we really do understand about a lot of human diseases.” We may know more than we did 20 years ago, he says, “But what we don’t know still greatly exceeds what we know.”
And yet what is perhaps most remarkable about Flier’s drug-development memoir is not what is or was mysterious, but what was known, quite a long time ago, at least by those researchers and their backers at Pfizer. Early studies in people with diabetes had shown not only that GLP-1 infusions could be an effective treatment for the disease, but also that such therapy also kept food in people’s stomachs for longer and reduced hunger — findings and implications that Flier and his team discussed extensively. This made GLP-1s look like a potentially promising treatment for obesity, too.
The fact of these conversations, so long ago they precede Bill Clinton’s famous jogs to McDonald’s, conjures up an almost magical-seeming alternate reality. In fact, they invite you to fantasize about the possibility that Pfizer might have rushed GLP-1 drugs to market decades ago and that in addition to improving the health and well-being of tens of millions of Americans, the new class of drugs might have become available by now as ubiquitous cheap generics. All of our present-day concerns about price-gouging and affordability could be entirely behind us.
Of course, this isn’t how drug development works, at least outside of pandemic pressure. Even the most promising biomedical research tends to proceed in fits and starts, with disappointments and setbacks marking the path from insight to therapeutic use. In 1990, reviewing Flier’s team’s results, Pfizer gave the researchers one year to develop a non-injectable delivery system that might justify the expense of developing an alternative to insulin — a quixotically short timeline that effectively doomed the project, forestalling work on some of the obvious next research steps.
From that point, Flier guesses that the next major breakthrough, identifying the enzyme that naturally degrades GLP-1 in minutes in order to develop a mechanism to counteract or stall that effect, would have taken only a few months. But “it wasn’t a sure thing,” he acknowledges, and “it’s almost always longer than you would imagine.” It took 15 years for Exendin-4, which was isolated from Gila monster venom in 1990, to make it to market as the first GLP-1 therapy, Exenatide. The original patent Flier and his colleagues licensed from Massachusetts General, which eventually passed to Novo Nordisk, didn’t yield an F.D.A.-approved drug until 2010.
“I wasn’t trying to tell a story that the whole drug development industry is idiots — not at all,” Flier says of his history, which he called “Drug Development Failure.” “Despite our early promising data, it’s far from certain that Pfizer and CalBio” — a biotechnology firm — “would have brought GLP-1s to market much earlier,” he wrote in STAT News. “And yet, it’s hard for me to understand, for either scientific or commercial reasons, Pfizer’s decision in 1990 to walk away.”
But Flier’s memoir is not just a lament for what might have been. In the aftermath of the pandemic emergency, as citizens and officials alike have embraced a more libertarian attribute toward public health, there’s been a similar drift in the public conversation about drug discovery and development. Operation Warp Speed is often held up as a new model — calls for a “Warp Speed 2.0” have been followed by those for an “OWS for everything” — typically by advocates focused on the way that pandemic vaccine development streamlined some aspects of regulatory bureaucracy rather than on the impact of the enormous and unprecedented federal commitment to buy hundreds of millions of Covid vaccine doses whatever the results in the clinical trials (which were still completed). Many of these same reformers will complain about all the red tape at the F.D.A. and C.D.C., tallying up huge mortality costs imposed by slow-moving government, arguing for human challenge trials in which individuals volunteer to take untested drugs and be deliberately infected, and even talking about the “invisible graveyard” of unnecessary regulation and delay.
This is all fine and good — there are surely lots of things those agencies can speed up. And in recent years, reformers of various stripes have lobbied some worthy additional proposals into the biomedical zeitgeist — for a system based not on patents but on huge and direct cash prizes for medical breakthroughs, for instance, or one helped along by “advance market commitments” or “benevolent patent extensions.” Just last week, the researchers Willy Chertman and Ruxandra Tesloianu published “The Case for Clinical Trial Abundance,” an invigorating manifesto for drug development reform.
But the alternate history of Ozempic is also a reminder that there is another invisible graveyard — the one presided over, somewhat capriciously, by Big Pharma. And in focusing on government bureaucracy as the major biomedical bottleneck, we are seeing just one piece of the picture and overlooking what is perhaps the central challenge of research and development — that it is, at present, so complicated that difficulties or bad decisions at any stage can stifle the whole decades-long process, distorting the actual medical and public-health functions of drug development in countless ways.
Now, it’s not like the United States is exactly a drug-development backwater, at present, and there are good reasons to think we are not in a fallow period for medical breakthroughs but at the beginning of a new golden age. And Flier himself isn’t a drug-development radical proposing we rethink the profit-based system root and branch. “If you spend your time around biopharmaceutical companies, they’re always making decisions about what to move forward with and what to kill, because you can’t pursue all of them,” he says.
“Those are business decisions, but they’re conditioned by scientific intuition,” Flier goes on. And with GLP-1s, he says, “if there had been a business leader who had the scientific intuition that this is too interesting to pass up on for a major disease, they would’ve moved ahead. That’s the way it works.”
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