GLP-1 Not Working? Here’s Why and Alternatives That Can Help You Reach Your Weight-Loss Goals
New research suggests your genetics may play a role in how well your body responds
Key Takeaways
- A gene variant may explain why some people don’t respond to GLP-1 medications.
- Most differences in weight-loss results come down to dose, diet and lifestyle factors.
- There are proven alternatives and ways to boost results if GLP-1 progress stalls.
You finally took the plunge and started taking a GLP-1 drug to improve your health. You’re keeping up with your GLP-1 pill or injection schedule, and you can’t wait to see results in your blood sugar and weight loss. But the weeks have turned into months, and although the medication seems to be working well for everyone around you, your GLP-1 is not working. What gives?
While there are several reasons you may not be seeing your desired results from a GLP-1, new research points to a cause that might not be on your radar yet: your genes. We asked experts to explain everything you need to know about this research, including what this gene could mean for you and alternatives that may help you manage your health conditions or support weight loss.
What is a GLP-1?
“GLP-1 receptor agonists are medications that mimic a natural hormone in your body called glucagon-like peptide-1 [GLP-1],” explains Thomas Tsang, MD, MPH, Chief Medical Officer at Omada Health. “From my perspective, these medications have an effect both on your brain and your metabolism because they act on areas that regulate appetite and reward while also affecting how your pancreas releases insulin and how quickly your stomach empties.”
Woman's World Answers
“Many people think about GLP-1s as weight loss drugs, but their benefits can go far beyond that to include improved blood sugar control, better heart health and decreased appetite,” adds Dr. Tsang.
Common reasons your GLP-1 is not working
If you’ve been on a GLP-1 medication for months without seeing meaningful changes in your health or significant weight loss, you’re likely wondering what’s going on. Kardie Tobb, DO, MS, FASPC, FACC, a board‑certified preventive cardiologist and the medical director for the Cone Health HeartCare Women’s Heart Health and Cardio-Obstetrics Clinic, explains some of the most common reasons why GLP-1s may not deliver the results you’re hoping for, including:
- You need a higher dose and have not yet reached a therapeutic dose as determined by your doctor
- High intake of liquid calories, including alcohol and ultra-processed foods
- Not getting enough protein, which can leave you persistently hungry and makes it harder to feel full
- Advanced diabetes or insulin resistance
- Taking other medications such as sulfonylureas, which lower blood sugar but can lead to weight gain
- Not adhering to your dosing schedule, such as inconsistent weekly injections or missed doses
- Differences in gut hormones or genetics
And just because your GLP-1 isn’t working immediately doesn’t mean it won’t work for you. Dr. Tsang says using a GLP-1 requires practicing self-awareness and patience over time if you expect to lose weight and keep it off.
“You might notice that you have reduced appetite and food cravings and feel satisfied with smaller portions,” says Dr. Tsang. “You might also notice improved blood sugar readings, better energy or mood and gradual weight loss. All these factors indicate that you possibly just need time or dose adjustment and likely should continue.”
“However, if you have no reduction in appetite after eight to 12 weeks, no weight loss or blood sugar improvement after three to six months or persistent severe side effects that prevent you from going up in dosage, GLP-1s may not be for you,” adds Dr. Tsang.
Your genes can impact how you respond to a GLP-1
In a study published in Genome Medicine, researchers found that about 10 percent of people carry certain variants of what’s known as the PAM gene, and those individuals had a weaker blood sugar response to GLP-1–based drugs compared to non-carriers. This suggests the drugs may not work as well for them. And while the study focused on blood sugar control, experts say it may also help explain why some people don’t see the same weight loss results on GLP-1s.
Why? Dr. Tobb explains that the PAM gene helps activate hormones like GLP-1 so they can work properly in the body. If you carry certain variants, your body may not process or “turn on” those hormones as efficiently, leading to weaker GLP-1 signaling. That means even if you’re taking a GLP-1 medication for diabetes or weight management, the body’s response, like insulin release, may be blunted. So the drug is there, but its full effect isn’t.
How much does genetic testing cost?
If you’re hearing about this gene for the first time, you may be wondering how to get tested and what it might cost. Dr. Tobb says the only way to identify a PAM gene variant is through genetic testing, since there are no symptoms or routine lab tests that can detect it. She says this is usually done through broader genetic panels ordered by a doctor, rather than testing for the gene on its own.
“Many cases require prior authorization or are not covered, and out-of-pocket costs generally range from a few hundred dollars for targeted panels to $1,000 to $2,000 for broader panels and several thousand dollars for whole exome or genome sequencing,” says Dr. Tobb.
And while Dr. Tobb says the PAM gene is an interesting example of how genetics can influence weight loss and blood sugar control, she says that most differences in results come down to factors like sleep, medication adherence, diet quality, muscle mass and overall insulin resistance.
3 GLP-1 alternatives to consider
If you find you’re not responding to GLP-1s, or if you are seeing results and want to build on them, Dr. Tobb shares three GLP-1 alternatives that may help support blood sugar control and weight loss. Ask your doctor if one of these might be right for you.
Metformin
Metformin is a first-line oral medication for type 2 diabetes with a long history of data supporting its use. Dr. Tobb explains that it lowers glucose production in the liver and improves insulin sensitivity in the muscles, which can help stabilize blood sugar and helps reduce appetite in some people.
Empagliflozin (or another SGLT2 inhibitor)
This is a once-daily pill that works to support weight loss through the kidneys rather than gut hormones. It helps the body expel excess glucose through urine, Dr. Tobb explains, leading to mild calorie loss, modest weight reduction and improved blood sugar control.
Protein-rich diet
Dr. Tobb says this eating approach emphasizes protein, fiber and minimally processed carbs and can complement the results you might see on weight loss medications. Protein helps increase satiety hormones, reduces blood sugar spikes after meals and supports muscle mass, which plays a key role in improving insulin sensitivity, she adds.
The bottom line on GLP-1s not working
We get it. When a new health routine or medication seems to work beautifully for everyone else, it’s natural to feel frustrated, or even isolated, when you’re not seeing the same results. But here’s the truth: Your body is unique, and that’s not a flaw.
Understanding why your GLP-1 may not be working as expected is the first step toward finding what will work. Whether it’s adjusting your dosage, giving it more time, exploring alternatives or working with your doctor to try a different approach, you have options to reach your weight-loss goals.
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