Drug manufacturers are developing a dizzying number of experimental drugs in the race to design the next blockbuster medication for obesity and diabetes.
In the coming years, experts anticipate the approval of a variety of newer GLP-1 drugs that will boast real improvements over semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) — including greater weight loss, easier administration, and additional health benefits.
“The future? It’s insane,” says Tina Vilsbøll, MD, a professor and the leader of the Steno Diabetes Center in Copenhagen, Denmark. “There are more than 200 different compounds in development … and I would say that probably more than 100 compounds are now [being tested] in humans.”
The research is moving quickly, and at the recent annual American Diabetes Association scientific conference, investigators released a flurry of new reports on the next generation of GLP-1 medications.
“It is incredible for a clinician to get these in the toolbox,” says Dr. Vilsbøll. But, she adds, “There’s so much more to learn before we can prescribe them.”
New Weight Loss Drugs May Be GLP-1 Pills
GLP-1 drugs may soon come in pill form rather than injections.
Most of today’s GLP-1 therapies are administered with a shot. It’s not easy to put semaglutide or tirzepatide into a pill because the active ingredients are largely dissolved in the stomach.
While the need to use injections has not apparently slowed the runaway success of GLP-1 drugs, experts are still eager to see a pill approved. Most people prefer a daily pill to a weekly injection.
Soon, however, a new generation of user-friendly “small molecule” GLP-1 pills could gain regulatory approval. These drugs use active ingredients that are thousands of times smaller than the protein chains that make up today’s GLP-1s. Small molecules move easily from the gut to the bloodstream, where they penetrate cells and attach directly to the hormone receptors that they target. The new GLP-1 pills, then, may offer benefits similar to existing drugs without the need for special eating, drinking, or timing instructions.
“There are also quite a few things that we do not know with these small molecules,” says Vilsbøll. “They could have off-target negative health effects, and it will be years before we know if they have the same kind of positive effects on long-term heart and kidney health as semaglutide and tirzepatide.”
But there may also be unanticipated benefits beyond easier use. For example, small-molecule GLP-1 pills appear to lower blood pressure even more than semaglutide and tirzepatide, says Vilsbøll. “Do we have a new antihypertensive agent here? I don’t know … we’ll have to see in the trials to come.”
Orforglipron Could Be the Next GLP-1 Pill to Win Approval
The small-molecule weight loss and diabetes drug that is closest to approval by the U.S. Food and Drug Adminstration is called orforglipron.
Data from a new trial in people with diabetes showed that orforglipron appears to offer blood sugar improvement (at the highest dose, A1C levels dropped by 1.5 percentage points) and weight loss results (16 pounds on average, or about 7.9 percent body weight) that are competitive with injectable GLP-1s like Ozempic. Up to two-thirds of participants saw their blood sugar level decline below the cutoff point for diabetes.
Lilly, the developer of orforglipron, will release data on weight loss in people without diabetes later this year.
Though the health benefits don’t exceed those of currently available drugs, experts anticipate that many patients will strongly prefer to take a daily pill than a weekly injection.
Orforglipron “doesn’t have any restrictions in terms of food intake or the time you take it,” says Julio Rosenstock, MD, the lead author of the new study, the director of Velocity Clinical Research, and a professor at the University of Texas Southwestern Medical Center in Dallas.
The rate of adverse events, particularly gastrointestinal side effects, “is not much different from what you see” with other GLP-1 drugs, he says. “I would venture to say that you perhaps may see a little bit less than with others,” Dr. Rosenstock says.
Orforglipron could become available for both diabetes and weight loss as soon as next year. “Lilly hopes to get this compound on the market by 2026,” says Vilsbøll.
Dr. Rosenstock predicts that orforglipron and other similar small-molecule pills will eventually form the backbone of mainstream diabetes treatment, a role played today by the older glucose-lowering drug metformin: “I can see these molecules as a first-line therapy,” he says, prescribed to patients “from day one.”
New Treatment Targets
Drug developers are also racing to devise medications that drive even greater weight loss and offer more comprehensive overall health benefits, primarily by testing new agents that affect more than just the GLP-1 hormone receptor.
GLP-1 receptor agonist drugs mimic the activity of a natural hormone, glucagon-like peptide-1 (GLP-1), that helps regulate blood sugar and promotes feelings of fullness after eating. But there are multiple gastrointestinal hormones that help regulate hunger and metabolism in similar ways, and drugmakers are working hard to learn which ones can be tweaked or mimicked to enhance the benefits.
Tirzepatide is the first GLP-1 receptor agonist on the market to target a second hormone, gastric inhibitory polypeptide (GIP). This may help explain its remarkable efficacy: Among approved drugs in this family, tirzepatide has the most potent weight loss effects. But tirzepatide may be only the beginning.
Drugmakers aren’t stopping at just three hormones: There are quadruple receptor agonists in development, and “rumor has it that scientists are working on compounds that will target five different receptors,” says Vilsbøll.
Improving on Current-Generation GLP-1s
In an effort to drive even more weight loss, Novo Nordisk, the maker of Ozempic and Wegovy, is testing two other GLP-1 medications that also mimic amylin, a hormone secreted by the pancreas that helps make you feel full after eating.
Other drugs in development could improve the GLP-1 experience in new ways. MariTide is a GLP-1 drug that also inhibits a different hormone receptor in the pancreas and requires only one injection per month, though its maker has said it could potentially be given even less frequently.
A drug that combines semaglutide and bimagrumab, developed to treat age-related muscle loss, has shown potential to allow users to retain significantly more lean muscle mass during weight loss.
Looking Forward
With the treatment landscape in such upheaval, experts are hesitant to predict what the future of obesity and diabetes treatment will look like.
As the number of approved GLP-1 medications grows, clinicians will increasingly be able to choose from a menu of options, some of which may be especially appropriate for individual patients. “Having a range of therapies targeting different pathways offers us the opportunity to move obesity and type 2 diabetes care into more personalized medicine,” says Dr. Papamargaritis.
There is also hope that the new generation of GLP-1 medications will bring down prices and enhance accessibility. The weight loss treatment market is currently dominated by two drugmakers, but as more pharmaceutical companies enter the field, increased competition could lead to lower costs for consumers.
The new small-molecule GLP-1 pills should cost less to make and distribute than today’s injectables, which require refrigeration and a more complex manufacturing process.
But Vilsbøll warns that the economics of weight loss therapies will not change overnight. Though experts hope that lower manufacturing costs for pills will increase the global availability of game-changing diabetes and obesity drugs, the pharmaceutical giants who spend billions developing and testing them may still choose to price them out of the reach of most customers.
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