Richard DiMarchi: The IU Researcher Behind the Ozempic Headlines

If you watch TV, you’ve surely seen the ads—the ones with the catchy “Oh, Oh, Oh, Ozempic!” line, a takeoff of the 1974 song “Magic” by the band Pilot. Careful, one listen and you might be humming it all day.

And you’ve likely come across countless news headlines over the past few years touting Ozempic and similar drugs:

• “5 Ways Ozempic and Other New Weight-Loss Drugs Have Changed Health”—Scientific American
• “How did Ozempic and Wegovy get so popular for weight loss, and why is there a shortage of the drugs?”—CBS News
• “Oprah and WeightWatchers are now embracing weight loss drugs. Here’s why”—National Public Radio
• “After weight loss, Alzheimer’s may be next frontier for drugs like Ozempic”—Reuters

Millions of people—as many as one in eight American adults—have taken one of these drugs at least once, enough to cause shortages. What started as diabetes medications caught fire as obesity drugs and, as the headlines above suggest, could end up easing many more conditions.

Much of the research and innovation of these pharmaceuticals—known as GLP-1 agonists—have ties to Indiana University, and a key player is IU Distinguished Professor Richard DiMarchi, PhD’79.

The scientific community has taken notice of his creative and revolutionary science. Earlier this year he was honored with the Mani L. Bhaumik Breakthrough of the Year Award, presented by the American Association for the Advancement of Science.

As the organization’s Science magazine points out, today’s headline-grabbing, game-changing obesity pharmaceuticals “may never have been delivered to patients if not for two problem-solvers”: IU’s DiMarchi and Danish co-honoree Lotte Bjerre Knudsen. Working separately but in the same direction, the two persevered with what the award’s namesake hails as the kind of outside-the-box thinking that’s critical to innovation.

For DiMarchi, it is one more accolade in a remarkable career that already has involved more than a hundred patents, the launch of several biotechnology companies, and the development of new drugs that have greatly impacted the lives of patients with diabetes and other conditions.

As with other examples of scientific progress, these breakthroughs haven’t happened overnight. DiMarchi compares the advances in biotechnology to that of flight over five decades in the last century: from the first trans-Atlantic flight, in 1919, to reaching and landing on the moon, in 1969.

Like the moon landing, GLP-1 agonists are a triumph of incredibly complex science, but the ultimate message is, in DiMarchi’s words, both simple and transformative: “The seemingly impossible, if not the impossible itself, is possible.”

Pondering Peptides

DiMarchi was raised in New York City and got his undergraduate degree at Florida Atlantic University. As he pondered where to do graduate studies in the chemistry of large molecules, he thought about the most prominent biochemistry textbook of the time. “It was written by two IU professors, Henry Mahler and Eugene Cordes,” he says. They were working in the company of many stellar faculty doing important work on proteins.

DiMarchi followed up his four years of study at IU with postdoctoral training at Rockefeller University. There, he studied with a biochemist, Bruce Merrifield, who specialized in creating peptides.

As our story delves into some science, it’s worth defining some key biological terms. At the building-block level are amino acids, which combine to create peptides. The human body produces thousands of peptides, and they play a role in many important functions in the body—supporting the immune system, assisting with digestion, aiding brain function and skin health, and speeding wound healing.

That makes peptides intriguing to breakthrough-minded researchers like DiMarchi. Not long after his time at Rockefeller, Merrifield was honored with a Nobel Prize in chemistry. DiMarchi, meanwhile, started to build a career in developing peptide-based drugs.

He established himself at Eli Lilly & Co.’s Lilly Research Labs in Indianapolis, where his work pioneered the field of biotechnology, which uses living organisms or biological systems to create new products. At the center of his attention was research into the endocrine system, the glands and organs that produce hormones that control many bodily functions. His discoveries involving peptides, for example, led to the Lilly drug Humalog, a form of insulin for treating diabetes.

“Humalog turned out to be the first chemically optimized molecule using biotechnology to create a medicine, and it went on to be Lilly’s largest-selling drug,” he says. Humalog was a revolution for diabetic patients because it’s fast-acting; can be administered closer to mealtime; and has fewer potential side effects, such as low blood sugar.

Coming up with a manufactured form of human insulin to improve its effects was a prime example of out-of-the-box thinking. But aspects of its synthetic nature made some experts uncomfortable.

“When it began, it was highly criticized—‘Isn’t that dangerous?’” DiMarchi recalls. Ultimately, this kind of insulin in a chemically modified form was much more precise than the natural hormone, and he was especially gratified when it eventually became recognized as a preferred drug for pregnancy-associated diabetes.

Tipping the Scales

DiMarchi’s work at Lilly improved the lives of countless patients and led him to the role of vice president of research and development. But over the years, DiMarchi’s aspirations were increasingly leaning in a different direction—one you might call ahead of its time.

“I very much wanted to focus on obesity,” he says. Back then, the percentage of adults considered to be obese was significantly lower than it is today, and the American Medical Association was still years away from declaring it to be a disease. (The AMA recognized obesity as a chronic disease in 2013.)

DiMarchi had noted how many conditions were associated with obesity and imagined the benefits that could come from tackling the condition. “It was very clear to me the adverse consequences of being overweight—increasing vascular disease, increasing diabetes, increasing oncological diseases—and now we have come to believe that it’s also compromising cognitive function.”

Key to the effort is GLP-1, short for glucagon-like peptide 1, a hormone produced in the small intestine that, among other things, lowers your blood sugar level (by triggering the pancreas to release insulin) and makes you feel full (by slowing digestion).

DiMarchi’s Lilly research collaboration with the late Suad Efendic, who was a diabetes expert at the Karolinska Institute in Sweden, found that the drug class known as GLP-1 agonists, which mimic the effects of natural GLP-1, could reduce body weight in adult-onset diabetes patients who were overweight.

At the time, though, the pharmaceutical industry was focusing its collective attention on diabetes and many other concerns. The industry didn’t see marketable potential in new obesity drugs, DiMarchi says, particularly ones that would likely require regular injections.

“I’ve often said that large companies are a bit like children playing soccer,” DiMarchi observes. “Ever watch young girls or boys playing soccer? The ball goes here, they go here, the ball goes there, they go there—and the kid who stands off in the corner looks to be [oblivious].”

DiMarchi, with his desire to find treatments for obesity, was like that kid away from the ball, gazing in a different direction. His diverging interests ultimately led him to an environment more suited to thinking differently—Indiana University.

“That’s the value of a university. A university is where you do real invention, not iteration on what other people have discovered,” he says. “But those initial exploratory ideas are best done in a university, where you don’t have the controls that come in a corporate enterprise.”

An IU Homecoming

Indeed, universities are exceptional places to step back and think about potentially life-improving concepts well before anyone has to consider how to market them. IU is certainly no stranger to that kind of innovation.

At IU in the 1940s, for example, dental and chemistry researchers made important discoveries about stannous fluoride. By the early 1950s, the IU researchers along with Procter & Gamble were conducting clinical toothpaste trials with Bloomington residents, and by the mid-1950s their concept hit the market as Crest toothpaste.

Similarly, the scientific appeal of Bloomington smiled upon DiMarchi following his 22 years at Lilly. He arrived in the academic world in 2003 as the Gill Chair at IU’s interdisciplinary Linda and Jack Gill Center for Neuroscience.

In his new role at IU, he found himself 120 miles down the road from another Lilly expatriate he had met years earlier: Matthias Tschöp, a physician who at the time was doing research at the University of Cincinnati College of Medicine.

They decided to explore new places chemistry and pharmacology could venture together.

“We got to take our chances and try to do something nobody has done before,” says Tschöp, who now serves in several prominent scientific roles, including CEO of Helmholtz Munich, a German governmental research organization.

Throughout his career in medicine, Tschöp says, he was “frustrated that obesity is a disease, but we have very little to offer other than tell people to be active and eat less.” He and DiMarchi decided to explore better ways to enlist the brain in the fight against obesity. “We said, ‘We want to use mother nature’s toolkit.’”

It’s All in the Mix

DiMarchi and Tschöp’s idea was to tap into the power of gut hormones that control the body’s metabolism. They began working to integrate multiple complementary hormones—including glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP)—into a single peptide-based medicine that would curb appetite and slow the digestion process so people would choose to eat less.

It’s not simple chemistry, and learning how the different components interact with one another isn’t just a matter of adding together the effects each has on its own. In fact, some of the components on their own don’t have much effect.

“What we were creating was this symphony of activities that replicates what happens physiologically,” he says. “We are not dependent on single molecules—it is the integration of multiple hormones that keeps us healthy.”

These new compounds were good at managing glucose, and were also proving themselves capable of triggering significant weight loss, too. With the significant weight-loss component, these compounds offered the potential to treat not just diabetes but such other conditions as cardiovascular and liver disease—and maybe even slow cognitive decline.

It was becoming clear that pharmaceuticals originally intended for diabetes had the potential to become breakthrough drugs with a far greater impact.

‘Strong in the Face of Critics’

Successfully traveling the path from lab to pharmacy requires plenty of innovative thinking. In celebrating the development of GLP-1 agonist medicines with its award earlier this year, the American Association for the Advancement of Science spotlighted the outside-the-box insights of both DiMarchi and co-winner Lotte Bjerre Knudsen, a chief scientific advisor for Novo Nordisk, the maker of Ozempic.

As the organization explains in its Science magazine, “DiMarchi transformed thinking about the hormones this class of therapies should mimic, a critical part of their efficacy.” A challenge of these kinds of substances is their tendency to be ephemeral, and Bjerre Knudsen’s work helped create a product that would last long enough in the body to be practical as a drug.

Just as vital, according to Science, was the persistence both scientists showed as they helped persuade the world to focus on the medical impacts of obesity: “Both stayed strong in the face of critics who doubted obesity was a disease at all.”

Fritz French, BS’81—who had a long career at Eli Lilly before working with DiMarchi launching biotech startup companies—similarly credits DiMarchi with helping medicine and health redirect their focus onto obesity. DiMarchi brings an unusual blend of passion and skills, French says.

“He has a special talent for peptide chemistry and knowing all about metabolic diseases and metabolism and how the biology interacts with the chemistry—those are very unique skills,” French says. “He has been admitted to the National Academy of Medicine, but he is not a medical doctor. He has a lot of savviness in business. He has that credibility, that knowledge, to get things done. And he knows how to manipulate these molecules.”

Just as important, French says, “His life’s mission and passion is to help patients. He’s almost like a priest who is called to the priesthood—it is genuine. When he gets messages out of the blue from patients who have been helped by what he has done, it is a huge reward for him, and it keeps him going.”

Moving Forward

In the eyes of the general public, drugs such as Ozempic (from Novo Nordisk) and Mounjaro (from Lilly) seemingly exploded suddenly onto the scene, but the truth is, their emergence as treatments for diabetes—and then obesity—is part of a long, ongoing evolution.

Novo Nordisk’s daily injection Victoza, for example, hit the market more than a decade ago as a GLP-1 agonist that can treat diabetes without insulin, with some potential for weight loss and a reduction in some adverse cardiovascular conditions. It’s known generically as liraglutide, and a few years later a version was approved to treat obesity under the brand name Saxenda.

Ozempic, known generically as semaglutide, arrived in 2017 as a once-a-week injection approved for diabetes. It was a much more potent GLP-1 agonist than Victoza. An even higher-dose version from Novo Nordisk came in 2021, and it got the green light to fight obesity under the name Wegovy.

In 2022, Lilly introduced Mounjaro, which was approved for diabetes. Known generically as tirzepatide, it is a dual-agonist that targets both the GLP-1 and GIP receptors. In 2023, it hit the market as Zepbound, approved as an obesity treatment.

“It’s built on the core technology we had discovered at Indiana University of integrating two hormones,” DiMarchi says.

And, as the headlines shared at the start of the story suggest, diabetes and obesity are just the beginning of the possibilities for these drugs.

As research has continued, “we see improvements in kidney function, and we are now seeing improvements in cognitive function,” DiMarchi says, noting that the findings regarding cognitive function involved the earlier Victoza, which leads one to wonder if today’s more potent drugs in this class might have even more impressive results.

“The ability to decrease body weight and improve kidney and liver function, and possibly even brain function, is an unbelievably attractive profile. What it’s telling us is: What seemed impossible is now becoming possible.”

That kind of thinking only leads further down the path of possibility. DiMarchi points out that all kinds of technologies and sciences—flight is a good example, he says—experience a breakthrough that feels revolutionary, only to see that followed up with another step that’s even more astonishing.

DiMarchi’s view is that biotechnology will continue to unfold in astonishing and increasingly fast ways. He asks: What’s the molecular basis of a memory? How is it that we store information and retrieve information? Why is it easier in youth? Why is it harder in adults? Why do we tend to lose that memory if it came in later life versus something that seemed to have been hotwired in our adolescence?

With answers to those compelling questions, DiMarchi says, we gain the ability to intervene, to reverse pathology with pharmacology.

“From health to disease, back to health,” he says. “And even longevity is not off the table.”

DiMarchi considers the 21st century to be the century of biology as much as the prior one was the century of physical sciences.

“Where we end up at the end of the century is not clear, but it will be a very different place than where we are today, and I think a far better place than where we are now.”