Based on recent successful clinical trials, incretin mimetics (GLP1-RAs) show beneficial pleiotropic effects, such as immunomodulation, antiinflammation, and neuronal protection. These give hope for treating inflammatory and neurodegenerative conditions. I simplify and explain the mechanisms.

This story does not include health advice. It is for information, inspiration, and awareness purposes.

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Medications have their place, and regulatory bodies ensure their safety and efficacy. Scientists and clinicians leverage them to empower patients once they pass clinical trials. As a researcher and consultant, I find it valuable to reverse engineer the mechanisms of successful drugs for public health and use that knowledge to explore and articulate natural methods for addressing metabolic, immunological, digestive, and neurological conditions.

Lately, one of my articles on NewsBreak, titled Phentermine: An Old Drug That Brings New Hope for Obesity & Weight Management, was loved by thousands of readers who contacted me through my website to obtain more information about my research into diabetes and other metabolic/mental health conditions.

Some subscribers of my content dealing with type II diabetes and finding metformin ineffective have reached out to me. They shared that their doctors have recommended different GLP-1 receptor agonists, notably Tirzepatide or Semaglutide. Given my focus on metabolic and mental health research, they sought insights into the mechanisms behind these medications and were curious about my perspective.

Since the 1990s, as I intensely and passionately researched the evolving concept of type III diabetes in the brain, I have firmly believed in the interconnectedness of metabolic interventions with the brain and significant bodily components like the nervous, endocrine, cardiovascular, digestive, and immune systems.

The core mechanisms center on managing glucose and insulin. Recent clinical studies investigating pharmacological interventions like GLP1-RAs provide valuable insights and inspire optimism among scientists, clinicians, and the public. I focus on pleiotropic effects, which refer to the multiple and diverse impacts a single gene or drug may have on various physiological or biological processes.

When I transparently shared my journey of overcoming prediabetes, abdominal arthritis symptoms, leaky gut, and brain fog through improved glucose management and insulin sensitivity via lifestyle changes, skepticism persisted among some scientists and clinicians in my network.

The Purpose of This Important Piece About GLP1-RAs

In January 2024, a new clinical study was published in Nature’s Journal of Translational Medicine. It is titled “Tirzepatide prevents neurodegeneration through multiple molecular pathways”. Several pieces of evidence have demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment.

Likewise, in 2019, researchers in China and Taiwan published a study in the Journal of Parkinson's Disease investigating semaglutide and liraglutide in mice with conditions similar to Parkinson’s. They found that both drugs improved movement problems and protected brain cells. Semaglutide seemed to work better than liraglutide (GLP-1 receptor agonists). They decided to conduct a clinical study to investigate the neuroprotective effects of semaglutide.

Scientists and clinicians have recognized the intimate connection between metabolic and mental well-being for centuries, echoing ancient wisdom. Insights from drug repurposing, like the unexpected benefits of Viagra for treating impotence after heart disease patients, have spurred scientists to explore novel applications and different use cases for existing medications.

In this discussion, I aim to highlight two widely used glucagon-like peptide 1 receptor agonists, Tirzepatide and Semaglutide, to make my points. These drugs have the potential to affect the nervous, digestive, and immune systems positively.

Their neuroprotective and anti-inflammatory properties make them promising candidates for repurposing in these areas. To better understand their potential, I want to explain the functions and mechanisms of glucagon-like peptide-1 across the body, including its impact on the brain.

What is glucagon-like peptide-1?

As documented in this 2019 paper published in the Journal of Molecular Metabolism, glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential.

The paper states that GLP-1 has numerous metabolic effects, including glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation.

These researchers informed that GLP-1 also had cardio- and neuroprotective effects, decreased inflammation and apoptosis, and had implications for learning and memory, reward behavior, and palatability.

When studying metabolic hormones, I learned that glucagon-like peptide-1 (GLP-1) is a hormone produced in the intestines, specifically by specialized cells called L cells, in response to food intake. GLP-1 plays a specific role in regulating blood sugar levels. Let me summarize my knowledge of this unique and multifaceted hormone.

Firstly, GLP-1 stimulates insulin secretion from pancreatic beta cells in a glucose-dependent manner. This means that GLP-1 is released when blood sugar levels rise after a meal, and it helps lower blood sugar by promoting glucose uptake into cells.

Secondly, GLP-1 inhibits glucagon secretion, another hormone the pancreas produces. Glucagon typically raises blood sugar levels by promoting the release of glucose from the liver. By inhibiting glucagon secretion, GLP-1 helps to prevent excessive glucose production and release from the liver.

Thirdly, GLP-1 regulates appetite and food intake because it acts on the hypothalamus, a brain region involved in appetite control, to suppress appetite and reduce food intake. GLP-1 delays gastric emptying, contributing to feelings of fullness and satiety after meals.

Gastric emptying is the process by which food and liquids move from the stomach into the small intestine for further digestion and absorption before entering the bloodstream. I will cover gastric emptying in another story as it is a complex and comprehensive topic involving neural and hormonal signals and health conditions like gastroparesis, which is common in type II diabetes.

This NIH book chapter explains that Glucagon-like peptide-1 (GLP-1) agonists (also known as GLP-1 receptor agonists, incretin mimetics, or GLP-1 analogs) are a class of medications used to treat type 2 diabetes mellitus and in some cases, obesity. Examples of drugs in this class include exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, and semaglutide.

Researchers increasingly favor glucagon-like peptide-1 receptor agonists (GLP-1 RA) for treating type 2 diabetes because they effectively lower A1C and weight with minimal risk of hypoglycemia and potential cardiovascular benefits.

Various agents are available in the United States and Europe, each differing in efficacy, tolerability, dosing frequency, administration, and cost. These researchers in 2021, published in Therapeutic Advances in Endocrinology and Metabolism, reviewed phase III clinical trials and analyzed 14 head-to-head trials comparing agents like dulaglutide, exenatide, liraglutide, and semaglutide.

Results showed that while all GLP-1 RAs effectively reduce A1C, differences exist in their impact on A1C and weight and the frequency of adverse effects, providing insights into their unique advantages and disadvantages for type II diabetes management.

How do GLP1-RAs relate to the brain and dementia?

As I mentioned in my previous stories, the gut and the brain are tightly connected. In this case, GLP-1 receptors are located in various brain regions, including areas involved in appetite regulation, stress response, and cognitive function.

So, activation of GLP-1 receptors in the brain may have neuroprotective effects and contribute to improved cognitive function. Recent studies suggest that GLP-1 agonists may have potential therapeutic benefits in neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Our knowledge is limited, but GLP-1 is believed to interact with several other hormones and neurotransmitters. For example, it may interact with ghrelin, a hormone that stimulates appetite and regulates food intake.

GLP-1 may also modulate the activity of neurotransmitters such as dopamine, serotonin, and glutamate, which are involved in mood regulation, reward processing, and cognitive function.

GLP-1 plays a multifaceted role in glucose regulation, appetite control, and neurological function, making it a valuable target for treating conditions like type 2 diabetes, fatty liver disease, obesity, inflammatory conditions, and neurodegenerative diseases.

How do GLP1-RAs relate to osteoarthritis?

As documented in this 2022 review paper in the Journal of Orthopaedic Translation, osteoarthritis is a common joint disease affecting millions globally, where joint cells react to factors like stress, inflammation, or protein changes. Scientists have developed drugs similar to certain hormones called incretins, mainly for treating type 2 diabetes.

The paper stated that these drugs, called incretin mimetics, target a glucagon-like peptide-1 receptor (GLP-1R) receptor and have various positive effects, including reducing inflammation and protecting nerves. Because of these anti-inflammatory properties, GLP-1-based treatments could be helpful for osteoarthritis patients.

From my reviews, I noticed that the relationship between GLP-1 and osteoarthritis is new and still an area of ongoing research, but several potential mechanisms by which GLP-1 may influence osteoarthritis exist.

Inflammation plays a vital role in the development and progression of osteoarthritis. Recent studies found that GLP-1 has anti-inflammatory properties. By reducing inflammation in the joints, GLP-1 may alleviate symptoms and slow the progression of osteoarthritis.

Cartilage damage is a factor in osteoarthritis, and interventions that preserve cartilage integrity may help prevent or delay its onset. GLP-1 is believed to have protective effects on cartilage, the tissue that cushions the joints.

As documented in a 2022 review in Frontiers, some studies suggest that metabolic factors, like insulin resistance and obesity, may contribute to the development of osteoarthritis. As GLP-1 has metabolic effects, including the regulation of blood sugar levels and the promotion of weight loss, it may indirectly benefit joint health and reduce the risk of osteoarthritis.

As mentioned in the previous section, some studies have suggested that GLP-1 may have neuroprotective effects, which could be relevant to osteoarthritis, given the involvement of neurogenic inflammation in the pathogenesis of the disease.

What are Tirzepatide and Semaglutide, and how do they work?

Tirzepatide and semaglutide are both GLP-1 receptor agonists used to treat type 2 diabetes and fatty liver disease and consequently lower obesity in these patients, but they have some key similarities and differences.

Both tirzepatide and semaglutide are viable options for treating type 2 diabetes. However, their choice may depend on patient preference, dosing frequency, and individual response to treatment. They activate the GLP-1 receptors, leading to increased insulin secretion, decreased glucagon secretion, slowed gastric emptying, and reduced appetite.

In clinical studies, both drugs have shown efficacy in improving glycemic control, reducing HbA1c levels, and promoting weight loss in patients with type 2 diabetes. Both drugs are available in injectable forms, with tirzepatide typically administered once weekly and semaglutide available in both once-weekly injectable and once-daily oral formulations.

They differ in molecular structure, potency, and injection frequency. Let me summarize the key points. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a long-acting GLP-1 receptor agonist. Tirzepatide activates GIP (glucose-dependent insulinotropic polypeptide) receptors, which may further enhance its effects on glycemic control and weight loss.

Tirzepatide is a newer drug with a higher potency compared to semaglutide, leading to greater reductions in HbA1c levels and weight loss in clinical trials. Tirzepatide is typically administered once weekly, whereas semaglutide can be administered once weekly or once daily, depending on the formulation.

Insights from the Growing Literature on GLP1-RAs

I have been following the literature showing progress and noticed that accumulating data suggest that incretin mimetics binding to GLP-1R have beneficial pleiotropic effects like immunomodulation, anti-inflammation, and neuronal protection. There are many review papers and clinical studies. I will link and summarize the key points of a few outstanding ones.

This 2024 paper published in Nature’s Journal of Translational Medicine explored how Tirzepatide, a medication used in type 2 diabetes treatment, protects against memory and learning problems by investigating its effects on brain cells.

These researchers examined how Tirzepatide influenced various factors related to brain health, including cell growth, apoptosis (cell death), differentiation, and insulin resistance. The results suggest that Tirzepatide activates pathways that promote brain cell growth and protects against damage caused by high glucose levels and insulin resistance. This research sheds light on how TIR could potentially improve nerve damage linked to diabetes.

This 2023 study published in BMJ’s Annals of Rheumatic Diseases aimed to investigate whether glucagon-like peptide-1 receptor agonists (GLP-1RAs), commonly used for type 2 diabetes mellitus and obesity, could benefit knee osteoarthritis patients with diabetic patients over the long term.

Using data from the Shanghai Osteoarthritis Cohort study involving over 40,000 adults, the effects of GLP-1RA therapies were assessed by comparing participants receiving GLP-1RAs with those who did not and by before-and-after comparisons within the GLP-1RA group.

Results showed that the GLP-1RA group exhibited more weight loss, lower incidence of knee surgery, significant differences in pain scores, cartilage thickness, and cartilage-loss velocity compared to the non-GLP-1RA group. Within the GLP-1RA group, a decrease in medication consumption and cartilage loss velocity was observed after treatment.

Notably, weight loss, rather than improved blood sugar control, appeared to mediate the decreased risk of knee surgery associated with GLP-1RA therapy. These findings suggest that GLP-1RA therapies may have disease-modifying effects in osteoarthritis patients with type II diabetes, potentially through weight loss, warranting further investigation into their impact on osteoarthritis progression and patient-reported outcomes.

As GLP-1RAs, what makes Tirzepatide and Semaglutide valuable is their potential clinical use in treating type II diabetes, fatty liver disease, Parkinson’s, Alzheimer’s, and osteoarthritis.

This 2022 expert review in Springer informed that Semaglutide, a medication used to treat type 2 diabetes, has shown promising potential for addressing obesity, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders like Parkinson’s and Alzheimer’s disease. Clinical trials have demonstrated its effectiveness in reducing weight, leading to its recent approval by the FDA for obesity management.

Both animal and human studies suggest that semaglutide may offer protective effects for the liver in NASH and for the brain in neurodegenerative diseases. Given its existing clinical approval, further research and successful human trials could pave the way for semaglutide’s use in treating these conditions.

The approval of oral semaglutide in 2019 offered a new option for managing blood glucose levels in patients with type 2 diabetes, marking the first oral medication of its kind. Given the significant healthcare costs associated with diabetes in the US, it’s crucial to assess the cost-effectiveness of new interventions for inflammatory and neurodegenerative conditions, too.

To this end, this 2021 review on Springer compared the budget impact of using oral semaglutide 14 mg daily versus oral sitagliptin 100 mg daily over a 5-year period for patients not reaching their target glycated hemoglobin (HbA1c) levels despite treatment with metformin.

Using real-world data and simulation models, the analysis found that oral semaglutide 14 mg led to a substantial increase in direct medical and treatment costs compared to sitagliptin 100 mg, with a projected increase in spending for healthcare payers over the 5-year period. These findings emphasize the importance of considering both clinical effectiveness and cost implications when evaluating treatment options for type II diabetes.

Conclusions and Takeaways

Understanding GLP1-RAs, particularly Tirzepatide and Semaglutide, is a promising avenue for addressing not only diabetes but also inflammatory and neurodegenerative conditions like osteoarthritis and dementia.

Osteoarthritis is a degenerative joint disease characterized by the breakdown of joint cartilage and underlying bone, leading to pain, stiffness, and loss of function. Recent studies have suggested that GLP-1 RAs like Tirzepatide and Semaglutide may have protective effects on joint health and could potentially slow the progression of osteoarthritis.

Since Tirzepatide and Semaglutide have shown promise in improving metabolic parameters and reducing inflammation, researchers are exploring whether it could have neuroprotective effects and potentially lower the risk of dementia.

Dementia is a decline in cognitive function that interferes with daily life. While the exact mechanisms underlying dementia are complex and multifactorial, there is growing interest in the potential role of diabetes and metabolic dysfunction in its development.

While intriguing preliminary evidence suggests that Tirzepatide and Semaglutide may benefit beyond its primary indications, further research is needed to fully understand its potential role in preventing osteoarthritis and dementia.

Despite the focus on these medications, they represent just one facet of a multifaceted approach to health. By exploring the mechanisms behind these drugs, we can uncover insights that can guide us toward exploring natural methods for managing metabolic, digestive, immunological, and neurological health.

While medications play a vital role in treatment, they are part of a broader approach to health. Incorporating lifestyle changes, such as diet, exercise, and stress management, can complement medical interventions.

Exploring complementary therapies and natural interventions alongside conventional treatments can be helpful. Integrating approaches that address the root causes of health issues can lead to comprehensive and sustainable outcomes.

We need to connect with others who share similar health journeys. Support groups and online communities provide valuable resources, encouragement, and solidarity in navigating health challenges.

Healing is a journey marked by ups and downs. We must stay committed to our health goals, celebrate progress, and practice self-compassion. Remember that every step forward, no matter how small, contributes to our overall well-being.

When facing health challenges, we must seek information and engage with our healthcare providers. Open communication can facilitate collaboration and ensure that our treatment plan aligns with our goals and values.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.