The Gene Behind GLP-1 Medication Failure

Why aren't GLP-1 medications working for everyone?

You may be frustrated that semaglutide or tirzepatide isn't helping you lose weight like it has for others. The problem might not be your diet or willpower - it could be genetic.

Discover how a single gene called TCF7L2 may be sabotaging your weight loss efforts with GLP-1 medications, and what you can do about it.

BY THE TIME YOU FINISH LISTENING, YOU'LL DISCOVER:

• Why 10-15% of people may be "non-responders" to GLP-1 agonists for weight loss
• The gene that could impact the effectiveness of  GLP-1 
• Strategies to overcome genetic resistance to GLP-1 medications

This episode could be a game-changer if you've been struggling with weight loss despite using GLP-1 agonists.

RESEARCH ARTICLES:

1. Efficacy And Safety Of Semaglutide For Weight Loss In Adults With Overweight Or Obesity
2. A review of receptor interactions and co-stimulation, Peptides
3. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

Transcript

Dr. Tamar: 0:00

Why do some people struggle to lose weight on GLP-1 medications?

Dr. Tamar: 0:05

It's not always about diet, you guys.

Dr. Tamar: 0:07

It's not always about exercise or even adherence to the medication regimen. If you want to break the mold of traditional pharmacy and healthcare, you are in the right place. Welcome to the Pivoting Pharmacy with Nutrigenomics podcast, part of the Pharmacy Podcast Network. Here's a little truth bomb. We're all unique, down to our DNA, so it's no wonder we react differently to the same medications, foods and environment. Here's a million dollar question how can you discover exactly what your body needs, which medication, what foods or supplements and which exercises are right for you? How can you manage chronic conditions like diabetes without more medications? How can you lose weight and keep it off? How do you tap into your genetic blueprints so you can stop surviving and start thriving in health and life? That is the question, and this podcast will give you the answer. I'm your host, dr Tamar, lawful doctor of pharmacy. Let's pivot into genomics and bring healthcare to higher levels. Hello, welcome back. I'm your host, Dr. Tamar, lawful doctor of pharmacy and certified nutritional genomics specialist. Today we're talking about an important and often overlooked you know what I can't even say? It's overlooked because, the fact is, not many people even are aware of this, but we're going to look into a reason why some people struggle to lose weight with GLP-1 receptor agonists like semaglutide and terzepatide. Ever since these medications were approved for weight loss, there's increasing talk about weight loss resistance or people being non-responders to these medications. Research has actually shown that about 10 to 15 percent of patients lose less than 5 percent of their body weight while on GLP-1 agonist. Why is that? Today I want to explore one possibility genetics, of course, specifically the role of one gene, one culprit, called TCF7L2. We're going to dive into some key studies that help explain this variability. If you've ever wondered why GLP-1 medications work wonders for some, but not others, this episode is for you, so listen in.

Dr. Tamar: 2:34

First, let's take a quick look at how these medications work. Glp-1 receptor agonist they mimic the effects of a naturally occurring hormone called GLP-1, which stands for glucagon-like peptide 1. This is produced in the intestines, in our guts, after eating, but it doesn't last very long once our guts make it. Glp-1 plays a vital role in regulating blood sugar. It enhances insulin secretion when blood sugar levels are high. So we have high blood sugar levels. Glp-1 will increase the release of insulin. Also, it reduces a hormone called glucagon. This is a hormone that raises the blood sugar when glucose levels are low.

Dr. Tamar: 3:23

These medications Also slow down gastric emptying, meaning that food moves through the stomach more slowly, which can prevent a fast rise in blood sugar. Additionally, glp-1 agonists help promote satiety, making you feel fuller sooner and possibly reducing your overall food intake, an effect that can support weight loss, of course. Now, in the STEP trial, s-t-e-p trials, semaglutide led to an average weight loss of 14.9% when combined with lifestyle changes. In the SURPASS trials, that's S-U-R-P-A-S-S trials terzepatide demonstrated even higher weight loss results, with reductions of 21 to 26% weight loss depending on a dose and the patient's history. However, it's important to remember that while these medications offer promising results, they can also cause side effects, including gastrointestinal discomfort like nausea, vomiting, diarrhea. They can also make you tired, feel very fatigued shortly after you take that injection and potentially you might have issues with low blood sugar, also dehydration, pancreatitis, gallbladder issues and kidney problems. Now the risk of thyroid tumors, such as medullary thyroid carcinoma, is a concern, primarily with certain GLP-1 agonists like liraglutide and semaglutide. So it's very important that your doctor does comprehensive medical history and family history with you before starting these medications.

Dr. Tamar: 4:57

So why do some people struggle to lose weight on GLP-1 medications? It's not always about diet, you guys. It's not always about exercise or even adherence to the medication regimen. You guys, it's not always about exercise or even adherence to the medication regimen. Here are a few reasons why weight loss results might be less than expected. And then I'm going to dive into the nitty gritty about the genetics. First, there's hormonal adaptation. Over time, your body can adapt to the hormonal effects of GLP-1 agonist. Your hormone levels might change in a way that reduces the medication's effectiveness for weight loss. Second, there may be underlying health conditions like thyroid disorders, insulin resistance or metabolic dysfunctions. These can interfere with how the body responds to these medications. These underlying issues might actually complicate the way the medication helps regulate blood sugar and your hunger.

Dr. Tamar: 5:52

Third, we have to consider your dietary and lifestyle factors. Glp-1 agonists work best when combined with a healthy diet and regular exercise. It's very important. I think a lot of people miss this part. You still have to eat healthy and exercise for it to work best. Without these lifestyle changes, the weight loss benefits may not be fully realized, right? So maybe you can lose 20 pounds, but if you're not eating healthy and having regular exercise, you may only lose 10. So why not boost the effects of these medications with your lifestyle right and diet? And fourth, there's a medication dosage and duration that has to be considered. Sometimes people may need adjustments's a medication dosage and duration that has to be considered. Sometimes people may need adjustments to the medication dosage or a longer treatment period to see optimal results. So let's keep those four points in mind as to reasons why these medications may not be working and a quick recap hormonal adaptation, underlying health conditions, dietary and lifestyle factors, and medication dosage and duration.

Dr. Tamar: 6:52

Now let's turn to genetics, my favorite part, specifically the TCF7L2 gene. This gene has emerged as a major player in how our bodies process glucose and how we respond to certain weight loss interventions, including these GLP-1 agonists. Tcf7-l2 stands for transcription factor 7-like-2, and it plays a significant role in insulin secretion and glucose metabolism. Variants of this gene have been identified as strong risk factors for type 2 diabetes, particularly in a variation known as RS7903146. People who carry this variant may struggle to release enough insulin in response to glucose, which can lead to insulin resistance and higher blood sugar levels over time. So how does this connect to GLP-1 agonists?

Dr. Tamar: 7:44

Research suggests that individuals with the TCF7L2 risk variant might not respond as well to GLP-1 medications, and here's why I'm going to give you three reasons why. One, impaired insulin secretion. Glp-1 agonists work by boosting insulin release when blood sugar levels rise, but if the TCF7L2 variant impairs insulin secretion, this effect may not be as pronounced, even with the added boost from the GLP-1 agonist. Second, there's altered GLP-1 production. Altered GLP-1 production the TCF7L2 gene is also expressed in the intestines, in the gut, where GLP-1 is produced. As I mentioned earlier, variants of this gene may result in a lower baseline level of GLP-1, which can reduce the drug's effectiveness.

Dr. Tamar: 8:36

And last, changes in appetite and regulation. This is still an emerging area of research when it comes to how this genetic variant affects appetite, but some studies have found that TCF7L2 variants could affect brain-gut signaling, which is responsible for how well GLP-1 suppresses appetite. This may lead to a diminished appetite suppressant effect of these medications. If you're curious about the science behind these findings, I've included links to the studies in the show notes so you can explore them further. So what does this mean for weight loss?

Dr. Tamar: 9:14

If you've been on a GLP-1 agonist and you haven't seen the results you're hoping for, it might not be about your diet, exercise or commitment. It may not be any result of anything you're doing or not doing. It could just be genetic. Understanding your TCF7L2 status through genetic testing, like nutrigenomic testing, could provide valuable insights into why your response differs from others. For those with the variant, that can reduce the effectiveness of these weight loss medications. It's not the end of the road, so don't worry. In fact, there are strategies that can help us, and definitely these strategies I'm talking about. These are things you want to talk about with your doctor or a trained healthcare professional, so you can combine GLP-1 medications with other treatments that increase your sensitivity to insulin. You can tailor your diet to support insulin regulation through personalized nutrition plans, and nutrigenomic testing is a great way to really hone in on the type of foods that you need to support insulin regulation. And you can incorporate resistance training, which has been shown to improve insulin regulation, and you can incorporate resistance training, which has been shown to improve insulin sensitivity. Pretty much, you're looking at external factors some medication related, some non-drug related to help boost how your body regulates insulin so that you can lose weight.

Dr. Tamar: 10:37

Now at Life Balance, we take a holistic approach to health. We understand that weight loss isn't just about one medication or one gene. It's about looking at the whole picture and finding strategies that work for you. That's why our Inner Glow program focuses on a variety of lifestyle changes Nutrition, exercise, sleep, stress management. All these help you achieve lasting results. If you or someone you know is struggling with weight loss despite being on GLP-1 agonists like semaglutide or terzapatide, this episode might be the game changer they need. Please share it with them and invite them to schedule a private consultation with me to discuss their specific goals and challenges. That's all for today's episode. If you found this information helpful, don't forget to subscribe, leave a five-star review and share this podcast with someone who might benefit, and if you have questions or topics you'd like me to cover in future episodes, reach out at pivotingpharmacycom or find me on social media at Dr Tamar Lawful. I'll talk to you next Friday. Until then, always remember to raise the script on health, because together we can bring healthcare to higher levels.