The Food and Drug Administration approved Novo Nordisk’s Victoza (liraglutide) in January 2010. While it wasn’t the first GLP-1 receptor agonist to pass regulatory muster, it was the first to offer people with Type 2 diabetes glycemic control in a once-daily shot.

Nevertheless, Novo scientist Lotte Bjerre Knudsen, who discovered the drug, is often frustrated when she reads the news these days. Her lament: ‘“It looks like we’ve now just jumped onto obesity, and just found that GLP-1s can help with this,’” recalled her colleague, Novo global chief medical officer and SVP of global medical affairs Stephen Gough, at a recent forum.

But it’s not for nothing that Novo and Eli Lilly, whose GLP-1 drug Byetta was approved nearly five years before Victoza, are now frontrunners in a market set to exceed $100 billion in revenue. The companies’ roots in the drug class run more than three decades deep.

Novo’s semaglutide (sold under brand names Ozempic and Wegovy) and Lilly’s tirzepatide (marketed as Mounjaro and Zepbound) have since become transformational treatment options for Type 2 diabetes and obesity, respectively. With a potency in rapid weight loss replacing the need for gastric surgery and with a favorable safety profile, they’ve earned copious use in appropriate patients.

The quest for superior weight-loss treatments is far from over, and that doesn’t just mean efficacy. Here are several ways these companies envision the incretin field evolving — from more tolerable, convenient and durable therapies to better education for prescribers and some of the new entrants clamoring for a slice of the market.

Not just ‘more and more weight loss’

“The current generation of weight loss drugs, and drugs in clinical trials, are achieving life-changing levels of efficacy,” said Lilly Research Labs EVP, chief scientific and medical officer and president Dr. Daniel Skovronsky. “In our last tirzepatide obesity trial, we had 26% weight loss.”

He was referring to two trials, SURMOUNT-3 and SURMOUNT-4, in which subjects were on tirzepatide for 72 weeks (following a 12-week intensive lifestyle intervention) or treatment alone for 88 weeks. Skovronsky said he envisions “one more generation of drugs” from Lilly (and others) that can exceed that. 

Analysts hailed Phase 2 results for LIlly’s investigational drug retatrutide, a GLP-1/GIP/Glucagon triagonist, as perhaps the best ever by an incretin candidate. According to data shared at a recent medical meeting, non-diabetic obese and overweight patients lost an average of 24.2% of their body weight in just 16 weeks.

“But after that, it’s probably not about more and more weight loss — for most people at least,” Skovronsky said.

His counterpart at Novo didn’t disagree: “Forgive me for saying this, but we’ve reached a stage where the magnitude of weight loss is pretty good,” Gough said. “We’re in the realms of bariatric surgery.”

The execs said their focus will begin to shift toward looking at how weight loss may affect preservation of muscle mass. In clinical trials, subjects don’t only lose fat mass but also lean body mass and muscle mass.

“That’s not really what you would like,” said Boehringer Ingelheim SVP and global head of cardio-metabolic disease research Søren Tullin. “It’s a very heterogeneous population. When you get to the really high BMIs, it’s desirable to induce an even bigger weight loss.” 

Added Gough, “The question we’re asking ourselves is, ‘What is the quality of that weight loss? What are the impacts on other outcomes? What is tolerability?’”

Quality, not quantity

Novo’s SELECT trial, for instance, showed that semaglutide led to a 20% reduction in cardiovascular events. But people taking GLP-1 drugs experience varying degrees of weight loss and varying side effects, like nausea, vomiting and diarrhea. 

“The GLP-1 medications may not be for everyone,” Tullin acknowledged. He said the German pharma’s primary research focus is going “beyond the GLP-1-based medicines and appetite suppression, trying to find new modes of action that could help with solving some of these problems.” 

It’s not clear whether oral GLP-1s alone can solve them all, however. “Because these are small molecules that will have a relatively short half life, I wouldn’t be surprised if that led to even worse tolerability issues,” Tullin cautioned.

Convenience and durability

Nevertheless, calls are building for a more convenient and widely available formulation than the weekly shot. The World Obesity Federation predicts that half the world’s population will be obese or overweight by 2035. If, by 2030, a billion people need these kinds of drugs, that would entail 52 billion injections a year. 

“I don’t think anyone can conceive of humanity making 52 billion doses of injectables,” said Skovronsky. “So we need orals to meet the global needs of obesity.” 

Novo currently sells an oral form of semaglutide, dubbed Rybelsus, and is testing a high-dose version. Efficacy results have been on par with injectables, although many patients experience gastrointestinal side effects. Lilly is developing its own GLP-1 pill, orforlipron.

Another question is how the medications will be used in the long term. Discontinuation rates can be high, due in part to tolerability issues.

To wit: Pfizer said it won’t advance its twice-daily oral GLP-1, dubbed danuglipron, into Phase 3 studies. That’s due to the drug’s tolerability profile, which led to an over 50% discontinuation rate, per topline results of a Phase 2b trial announced Friday morning. Although a once-daily formulation will move forward, analyst expectations are low.

“Now we see the first hint that people stay on these medications for less than a year,” said Tullin. “We know what will happen: If they go off the medications, they will quickly catch up, and that may negate the health benefits.” 

This underscores the need for drugs that patients can stop taking and still maintain the weight loss. 

“We don’t have that for any other chronic disease, like high blood pressure or cholesterol,” said Gough. “I want that for every disease. That’ll be a big breakthrough.”

‘We’ve been stigmatized’

While physicians used to recommend lifestyle changes to patients battling weight problems, scientists now understand that multiple genetic and environmental factors can make that battle nearly impossible to win without medical intervention. Yet patients may not be viewed by medical professionals as having a treatable disease, such as a heart or psychiatric illness. That stigma makes it hard for patients to step forward and seek help, said patient advocate Joe Nadglowski, president and CEO of the Obesity Action Coalition. 

With every news story about another celebrity who’s using Ozempic for occasional slimming, the notion that obesity is more of a cosmetic issue may be reinforced in the eyes of HCPs, Nadglowski said.

“We’re living in this world of remarkable innovation that really could help people, but we’ve actually made it not OK to seek help for your obesity,” he explained. “You’re told you should just be able to push away from the table and go exercise.”

Largely due to that prevailing mindset, healthcare providers aren’t typically trained in prescribing the medicines. Insurance coverage thus remains low. 

Dr. Lee Kaplan, professor of medicine and chief of obesity medicine at Dartmouth’s Geisel School of Medicine, agreed. “Stigma is a critical problem. It sits behind everything.” 

And it’s not only among patients. “The problem with us physicians in obesity is we’re defensive about the treatment of obesity, because we’ve been stigmatized,” Kaplan noted.

Institutional policies used to require clinicians to secure patient consent before prescribing medicine off-label for obesity, or even to discuss the topic with a patient. That has compounded their defensiveness and prevented an approach that emphasizes relief of suffering for these patients.

“Obesity is the only disease that you’re allowed to talk about at a cocktail party but you’re not allowed to talk about in the office, and that’s crazy,” Kaplan said.

Obesity’s Prozac moment

Lilly and Novo’s first-mover advantage will make it cost-prohibitive for smaller biotechs that are angling for a slice of the market to run the large and lengthy trials needed to generate cardiovascular outcomes data, a la Novo’s SELECT trial. Rivals would also need to work their way through clinical development, delivering data at least as strong as the established benchmarks, as well as invest in manufacturing at the scale required to supply indications as large as obesity.

That hasn’t deterred drugmakers from exploring the white space in this developing sector. “Even though we’ve come a long way, it’s very clear there are some gaps we need to fill,” Tullin said.

Whether non-GLP modes of action or just better orals are the ultimate answer, there will be new molecules coming along, Gough predicted.

“How do we use incretin biology and beyond it in combinations so we can address the heterogeneity of people living with obesity?” Gough asked. “How we do combinations is exciting. It may be important how you combine these therapies — is it two separate injections or something you can co-formulate? These medicines behave differently even though they seem similar on the surface.”

Considering the advances in obesity treatment, we’re living through one of those “pivotal moments in medicine” that happen from time to time, Skovronsky said.

“Lilly was part of this with psychiatry,” he recalled. “When we came out a few decades ago with Prozac, depression wasn’t really seen as a disease and was viewed as something you can just ‘get over.’ Now, doctors can talk about it and treat it. We’re on the verge of seeing that kind of progress for patients in obesity.”

To read about a December 2023 Senate HELP hearing on high prices of diabetes drugs, click here.