GLP-1 Drugs: Research Insights Even When They Don’t Work
- Injectable GLP-1 drugs have been a game-changer for many people with obesity.
- Obesity shaped Anna Olson's earliest notions of herself, when she saw a photo and thought, "Oh, I look different than the other kids."
- Olson's obesity began in toddlerhood, ran in her family, and left her with a chronic hunger hard to satiate.
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Injectable GLP-1 drugs have been a game-changer for many people with obesity. But as researchers discover why the medicines fail for others,they are gaining insights about the complexity of the condition.
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Obesity shaped Anna Olson’s earliest notions of herself, when she saw a photo and thought, “Oh, I look different than the other kids.”
Olson’s obesity began in toddlerhood, ran in her family, and left her with a chronic hunger hard to satiate. Dozens of diet, drug and exercise regimens didn’t work, and advice from doctors was always the same: Eat less. “And I’m kind of like,’well,it’s what I’m doing now.What else can I do?'” she says, and the response, again, was: “Well, you just got to eat less.”
Actually,science now shows obesity is far more complex – with numerous genetic,biological,neurological,lifestyle,metabolic and behavioral factors contributing to it.
Root causes vary
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Doctors,patients and drug companies have learned a lot more in recent years about obesity and what works – or doesn’t – since the new class of obesity treatments known as GLP-1 drugs have come to market. although obesity manifests one way – excess weight - doctors say there are perhaps dozens of different forms of it. For treatment to work, thus, root causes must be identified, then addressed, for each person. Obesity doctors and researchers say within several years, they expect treatment will be more customized to meet the needs of each patient.
For Olson, genetic testing indicated she likely has several genetic and hormonal factors setting her hunger and satiety sensors out of whack. One of the GLP-1 drugs – Ozempic – worked briefly, but it turned out another, Zepbound, better recalibrated Olson’s hormone imbalance. It was only when she started tackling her specific obesity drivers that Olson began losing lots of weight – 65 pounds to date, as she remains on the medicine. “I’ve been able to keep it off,” she says.
Popular drugs a precursor to precision medicine?
Use of GLP-1 drugs is already huge and is set to become even more common, as the medicines become cheaper, with more variations, including the recently launched, easier-to-use Wegovy pill from Novo Nordisk.
Ozempic and Wegovy are the brand names for a drug called semaglutide. Zepbound and Mounjaro are the brands of a drug called tirzepatide. Both are GLP-1 agonists, and tirzepatide blocks an additional hormone, known as GIP.
Within a few years, doctors say, there also will be more ways to determine an individual’s specific obesity factors, which will enable a more precise targeting of the root causes of their obesity, similar to how chemotherapies can target specific cancer subtypes.
The complex makeup of obesity might also explain why GLP-1s don’t work for many people. A sizable minority experience side effects like nausea; studies have shown a important portion of patients lose less than 5% of their body weight on the drug, though they may experience other metabolic improvements.
Obesity subtypes
“There are many types of obesity, and each type of obesity has a unique genetic predisposition,” says Andres acosta, a gastroenterologist and hepatologist at the mayo Clinic. Acosta says early research indicates genetic markers might be measured to predict, for example, whether a person might not respond well to GLP-1 medicines.
Acosta is also co-founder of Phenomix Sciences, a company selling genetic testing through some doctors’ offices; the testing is not covered by insurance.
The cheek-swab genetic test groups people into four basic obesity phenotypes (meaning observable traits): Hungry gut, Hungry Brain, Emotional Hunger, and slow Burn. (A person might belong to more than one of these groups.) Each category has different hormonal or lifestyle factors that drive obesity.For example, someone with emotionally driven eating habits might not benefit as much from GLP-1 drugs.
Acosta says also, those with abnormalities in their gut hormones tend to lose more weight on GLP-1 medicines, while some people with “Hungry Brain” genetic markers may have a broken neural pathway that prevents the drug from being as effective for that group. For those people, Acosta says, often earlier generations of weight-loss medicines – or a combination of new and old drugs - work best.
A workable treatment plan
Anna Olson says this kind of personalization was key. Through genetic testing, she found out her phenotype is “Hungry Brain.” She also found out she has Bardet-Biedl syndrome, a genetic disorder that predisposes her to eat too much.Knowing that,she says,reduced her sense of stigma and helped her find the most fitting combination of medications for her.
Now 36, she says her cholesterol and blood sugar levels have improved, and she’s closer to her dream of traveling further afield from her native Minneapolis. “When I was more overweight than now, there was absolutely no way that I could do that.”
More precise diagnosis of s
The Inflation Reduction Act and prescription Drug Pricing
The Inflation Reduction Act of 2022 allows Medicare to negotiate the prices of certain high-cost prescription drugs, marking a significant shift in federal policy regarding pharmaceutical costs. This negotiation process began in 2023, with the first negotiated prices taking effect in 2026.
For decades, Medicare was prohibited from directly negotiating drug prices with manufacturers. This prohibition contributed to the United States having considerably higher prescription drug costs compared to other developed nations.The Inflation Reduction Act changed this by authorizing the Centers for Medicare & Medicaid Services (CMS) to select drugs for negotiation based on factors like high Medicare spending and lack of generic or biosimilar competition. The initial ten drugs selected for negotiation in 2023 represent a ample portion of Medicare’s total drug spending.
On August 29, 2023, CMS announced the first 10 drugs selected for Medicare price negotiation, potentially saving Medicare and beneficiaries billions of dollars. CMS Press Release
how Medicare Drug Price Negotiation Works
Medicare drug price negotiation under the Inflation Reduction Act is a phased-in process. It initially focuses on a limited number of high-expenditure drugs without generic or biosimilar alternatives. The CMS identifies eligible drugs and then engages in negotiations with manufacturers to secure lower prices.
The negotiation process involves submitting offers and counteroffers, with the goal of reaching an agreement on a maximum fair price. Manufacturers can face penalties, including excise taxes and withdrawal from Medicare and Medicaid, if they refuse to participate in negotiations or fail to comply with the agreed-upon prices.The negotiated prices are then made available to all Medicare beneficiaries, nonetheless of their specific plan.
The Congressional Budget Office (CBO) estimated that the Inflation Reduction Act would reduce federal deficits by $264 billion over ten years, with $101.4 billion of those savings coming from lower drug costs. CBO Report
Drugs Selected for Initial Negotiation (2026)
The first ten drugs selected for price negotiation, with prices taking effect in 2026, address a range of conditions, including diabetes, heart disease, and blood clots. these drugs were chosen based on their high Medicare spending and the absence of generic or biosimilar competition.
The selected drugs include Eliquis (apixaban) for preventing blood clots, Jardiance (empagliflozin) for diabetes and heart failure, xarelto (rivaroxaban) for preventing blood clots, Januvia (sitagliptin) for diabetes, Farxiga (dapagliflozin) for diabetes and heart failure, Entresto (sacubitril/valsartan) for heart failure, Imbruvica (ibrutinib) for blood cancers, Stelara (ustekinumab) for autoimmune disorders, Fiasp and NovoLog (insulin aspart) for diabetes.
A detailed list of the selected drugs and their corresponding manufacturers can be found on the CMS website: CMS Medicare Drug Price Negotiation Program
Impact on Pharmaceutical Companies
The inflation reduction Act’s drug price negotiation provisions have drawn criticism from the pharmaceutical industry, which argues that they will stifle innovation and reduce investment in research and development.Industry groups, such as the Pharmaceutical Research and Manufacturers of America (PhRMA), have filed lawsuits challenging the law’s constitutionality.
PhRMA argues that the law violates the Fifth Amendment’s Takings clause by effectively forcing companies to give up their intellectual property rights without just compensation. The Biden administration maintains that the law is constitutional and will benefit millions of Americans by lowering prescription drug costs. Several lawsuits have been filed, and the legal challenges are ongoing as of january 27, 2026.
On December 14, 2023, a federal judge ruled against PhRMA’s challenge, finding that the Inflation Reduction Act does not violate the Fifth Amendment. Reuters Report on Court Ruling