"Pericoloso Sporgersi" or Ask for Informed Consent prior to GLP1RA "weightloss drug" use.

(Response to "GLP1RA : going beyond traditional use" https://pmc.ncbi.nlm.nih.gov/articles/PMC8775408/ )

I have personally witnessed the widespread, and often casual, prescription of GLP-1 receptor agonists (GLP1RAs), such as Mounjaro and Ozempic, to people close to me—family, friends, and patients. What deeply concerns me is that these medications are being given without a full understanding or appreciation of their long-term risks, raising serious questions about the quality of informed consent in these cases.

?When I reflect on the devastating consequences of the opioid epidemic, I see alarming parallels. The opioid crisis was driven by loose prescription practices and heavy pharmaceutical marketing, which ultimately led to untold suffering. I feel that we are walking a similar path with GLP1RAs, where short-term benefits like weight loss are being promoted, but long-term metabolic and genetic risks are being overlooked or minimized.

?As someone who values non-maleficence, the ethical principle of "do no harm," I feel compelled to voice my concerns about these medications. I cannot, in good conscience, ignore consideration of longterm risks linked to longterm use of these medications, which I hope to carefully explain here.

?It deeply troubles me that some celebrity doctors—those with enormous influence—are endorsing these medications without fully considering the downstream effects on patients' health. I believe that with this level of influence comes a profound ethical responsibility to critically assess the long-term molecular and genetic impacts of any treatment, especially one that is being prescribed for short-term results like weight loss.

?In offering my own version of informed consent, I need to ensure that people understand that these drugs come with serious risks that go beyond the immediate benefits being marketed. I feel it is my duty to advocate for a more cautious approach, one that takes into account the potential harms that might arise from repeated interference with complex biological systems—especially when so much remains unknown about their long-term effects.

?What constitutes informed consent?

?Informed consent is fundamental to ethical and legal standards in healthcare. It requires that patients are fully informed about the risks, benefits, alternatives, and possible outcomes of any medical treatment before they agree to it. This process ensures that individuals can make educated and voluntary decisions about their care, based on adequate information and understanding.

There are several key components of informed consent:

• Disclosure: Healthcare providers must offer all relevant information about the proposed treatment, including potential risks and benefits.
• Comprehension: Patients must understand the information provided, which means using clear language and addressing any questions or concerns they may have. If patients have barriers to understanding, such as language or cognitive issues, additional steps should be taken to ensure clarity.
• Voluntariness: The patient’s decision must be made freely, without coercion or pressure from medical professionals, family members, or others. Patients should feel comfortable asking questions or seeking a second opinion if needed.
• Capacity: The patient must have the mental capacity to make the decision. If they are unable to do so (due to age, mental health conditions, etc.), a legal guardian or proxy may step in to provide consent on their behalf.
• Documentation: While informed consent is often a verbal process, it's usually accompanied by a written consent form that the patient signs to indicate their understanding. However, a signed form alone doesn’t constitute informed consent—it’s the discussion and understanding that truly matter.?

Informed consent respects patient autonomy, allowing individuals to have control over their medical choices. It ensures that medical interventions are done with the patient’s knowledge and agreement, not merely by medical authority. This principle is crucial for maintaining trust between patients and healthcare providers and ensuring ethical medical practices.

?In research settings, informed consent is particularly stringent, as participants must understand the experimental nature of the treatment or intervention.

Informed consent is not just a formality but a continuous dialogue between patients and providers to ensure that decisions about health are made with full knowledge and freedom.

The importance of POWER in study design, and why it matters?

?As I wish to focus on what informed consent should entail regarding GLP1RA, I want to highlight just one essential element related to all the studies included in the article "On Going Beyond Intended Use," which is crucial to understanding the risks posed by such publications: the importance of powering a study appropriately.

?In clinical research, study power refers to the ability of a study to detect a statistically significant effect if one exists for the hypothesis established at the onset. In the case of GLP1RAs, this was the effectiveness in reversing diabetes. This is largely determined by the sample size (N) and the effect size being studied. If a study is insufficiently powered, it may fail to identify meaningful effects, or worse, lead to false conclusions about the efficacy or safety of a treatment. This becomes particularly problematic when hypotheses change after initial studies are conducted, as the original study design may not be appropriate for the new hypothesis.

?When GLP-1 receptor agonists (GLP1RAs) were first approved by the FDA, the primary hypothesis centered around their ability to reverse diabetes and improve glycemic control. The expectation was that if these drugs were used for life, they could maintain blood sugar regulation and potentially reverse type 2 diabetes by improving insulin sensitivity and reducing blood glucose levels.

Initial studies were powered to prove this specific hypothesis—focusing on the effects on diabetes management—meaning the sample sizes and statistical models were tailored to detect outcomes directly related to glycemic control.

?As GLP1RAs were more widely used, researchers noticed unintended consequences, such as weight loss and appetite suppression, that went beyond the initial diabetes-focused outcomes. These effects were likely due to the wide distribution of GLP-1 receptors throughout the body, in areas involved in appetite control, gastric motility, and even brain signaling. While originally unexpected, these outcomes were rebranded as beneficial effects, leading to the drugs being marketed for weight loss and obesity management.

?The key issue is that the original studies were not designed or powered to detect these newly discovered "benefits" with statistical rigor. Consequently, many of the studies that now tout these secondary outcomes (e.g., weight loss or appetite regulation and others added in the study cited above) are using sample sizes and statistical models that were not tailored to evaluate these specific effects. This creates several problems:

• Underpowered Studies: A study that is underpowered to detect an effect might show statistical significance due to chance rather than a true effect. For example, weight loss observed in patients using GLP1RAs might be real, but without adequate sample size and correct powering for this new hypothesis, it’s impossible to confirm whether this effect is consistently reproducible across populations or simply an artifact.
• False Positives (Type I Errors): Studies that shift focus from the original hypothesis (diabetes management) to a new one (weight loss) may risk detecting false positives. A treatment may appear to lead to weight loss when, in fact, this could be a result of chance in a sample that was insufficiently powered to study this outcome.
• Misleading Clinical Guidelines: The reinterpretation of study data based on new hypotheses—such as weight loss or even appetite suppression as major outcomes—can mislead clinicians. Drugs originally approved for diabetes management are now being prescribed off-label for weight loss based on studies that lack sufficient power to make such recommendations. This leads to widespread use based on weak evidence.
• Exaggeration of Benefits: As new unintended effects are found, the benefits of GLP1RAs are often amplified in the literature, with claims being made based on small or insufficiently powered studies. These studies may not adequately account for confounding variables or may not represent diverse patient populations. This leads to an overestimation of the benefits in broader populations, creating a potential public health risk.
• Missed Harms and Long-Term Effects: While the initial studies were focused on diabetes, the shift toward weight loss and metabolic changes might overlook potential adverse effects because the original studies weren't powered to detect these outcomes. For example, muscle loss, long-term metabolic damage, or mental health issues may arise from GLP1RAs, but without properly powered studies focused on these outcomes, they may go undetected.?

When drugs like GLP1RAs are scaled from their original intended use (diabetes management) to a much broader application (such as obesity management or even general appetite suppression), underpowered studies create significant issues at scale:

• Misinformed Decision-Making: Physicians and healthcare systems may base treatment decisions on incomplete or weak evidence, leading to inappropriate or overly aggressive use of the drugs. In the study on the unintended use of GLP1RA, in which the authors gathered and analysed multiple papers they “had no conflict of interest”, as their study did nothing but summarize reports from 14 previously published papers. I am concerned that more than half of the studies included in this paper declared a "conflict of interest" due to receiving funds for their research directly from Novo Nordisk, the maker of Ozempic, or used available “repurposed” ?GLP1RA drugs by the same company. This raises serious concerns about the ability to interpret their results and makes the inferences questionable.
• Widespread Off-Label Use: Off-label uses of GLP1RAs for weight loss or cosmetic purposes are based on insufficient data, increasing the risk of unanticipated adverse effects in the general population.
• Cost and Resource Allocation: Large-scale deployment of drugs for new indications that aren't thoroughly validated can lead to wasted healthcare resources, as patients receive treatments that may not deliver the claimed benefits or may even cause harm.?

Inadequately powered studies, especially when hypotheses evolve post-hoc (such as from diabetes management to weight loss for GLP1RAs), can lead to misleading conclusions, exaggerated benefits, and significant public health risks. For claims of new benefits to be valid, studies must be properly powered and designed specifically to investigate these outcomes. This ensures the rigor of scientific evidence and safeguards the health and well-being of patients at scale.

?What short and longterm consequences of using GLP1RA should concern you?

?I will now turn my focus to explaining the key mode of action that has led to the widespread marketing of GLP-1 receptor agonists (GLP1RAs) as "weight loss drugs," an unintended consequence of their original use, and why this should raise concerns.

?GLP-1 Receptor Agonists Affect Digestion and Absorption GLP-1 receptor agonists (such as Mounjaro and Ozempic) work by slowing down gastric emptying, meaning food remains in the stomach longer before passing into the intestines. This delayed gastric emptying can influence digestion and nutrient absorption in several significant ways.

?Prolonged Exposure to Stomach Acid The stomach has a highly acidic environment (pH around 2), which helps break down food and activate digestive enzymes like pepsin, necessary for protein breakdown. When food stays in the stomach longer due to the slowed gastric emptying caused by GLP1RAs, it is exposed to this acidic environment for an extended period. This can lead to several effects:

• Protein Denaturation: Extended exposure to stomach acid may lead to over-denaturation of proteins, potentially affecting their digestion and absorption. This could reduce protein bioavailability, which is concerning for maintaining muscle mass, particularly in those at risk for conditions like sarcopenia (age-related muscle loss).
• Altered Nutrient Absorption: Fat-soluble vitamins (A, D, E, K) and certain minerals (iron and calcium) are absorbed in different regions of the gut. When food stays in the stomach too long, it can disrupt the timing of their absorption, potentially leading to deficiencies over time.?

Impact on Gut Function Delayed gastric emptying means that food takes longer to reach the duodenum and small intestine, where most nutrient absorption occurs. This slower process can affect digestion in several ways, leading to symptoms like bloating, discomfort, and dyspepsia (indigestion). Additionally, delayed gastric emptying can disrupt the timely release of pancreatic enzymes (like lipase and amylase), which are critical for the digestion of fats and carbohydrates. This can lead to malabsorption of these nutrients, potentially causing diarrhea or steatorrhea (fatty stools).

?Bacterial Fermentation Prolonged stagnation of food in the stomach can promote bacterial fermentation, which can increase gas production, leading to bloating and discomfort. Over time, this condition can contribute to small intestinal bacterial overgrowth (SIBO), where bacteria grow excessively in the small intestine, further disrupting digestion and nutrient absorption.

?Long-Term Nutrient Deficiencies When nutrient absorption is compromised over time, it can lead to deficiencies in essential vitamins and minerals. For example:

• Iron Deficiency: Stomach acid helps convert dietary iron into a form the body can absorb more easily. Delayed gastric emptying can interfere with this process, potentially leading to iron deficiency anemia.
• Vitamin B12 Deficiency: Prolonged exposure to stomach acid can affect the release of intrinsic factor, a protein essential for vitamin B12 absorption. Over time, this can lead to a B12 deficiency, which may result in fatigue, weakness, and cognitive problems.?

Muscle Loss and Sarcopenia Risk Slower gastric emptying can also negatively affect protein metabolism. When combined with reduced nutrient absorption, this can contribute to muscle loss, particularly in people at risk for sarcopenia. Maintaining muscle mass requires sufficient protein intake, but the appetite suppression caused by GLP1RAs can reduce caloric and protein intake, exacerbating muscle loss over time.

?Potential Long-Term Consequences Chronic use of GLP1RAs may lead to changes in gut motility, permanently altering nutrient absorption dynamics. This can result in a vicious cycle where the body becomes less efficient at processing nutrients, affecting metabolism and body composition (such as muscle loss and fat gain).

?Epigenetic Changes: Persistent changes in nutrient availability and metabolic stress can also trigger epigenetic modifications that influence gene expression related to digestion, nutrient metabolism, and muscle maintenance. These changes may further aggravate metabolic inefficiencies and reduce the body’s flexibility in switching between energy sources.

?How do GLP1RA’s impact your brain?

?Another major reason these drugs are effective as weight-loss agents involves their impact on the brain’s reward system, particularly the nucleus accumbens, which is linked to dopamine secretion. If dopamine release is externally influenced, it can trigger a complex cascade of effects in the brain-gut axis, affecting other neurotransmitters like serotonin and oxytocin, and possibly leading to long-term epigenetic changes.

?Delayed Gastric Emptying and Stretch Receptors : When gastric emptying is delayed, the stomach remains stretched for an extended period, which stimulates the stretch receptors that usually signal satiety via the release of cholecystokinin (CCK).

?Here’s how this plays out:

• Prolonged Stomach Stretching Without Satiety: The prolonged stretching can trigger continuous stimulation of stretch receptors, but because food remains in the stomach longer, the sensation of fullness may be prolonged and uncomfortable, potentially leading to nausea.
• CCK Response: Delayed emptying may sustain CCK release, which typically signals the brain to stop eating. However, due to blunted dopamine response, food no longer provides the usual pleasure. This disconnect between fullness and reward can, over time, alter the way the brain and body interpret food intake.

?Blunted Dopamine and Diminished Reward : Dopamine is critical for experiencing pleasure, particularly from activities like eating. When GLP1RAs interfere with dopamine release, it reduces the reward associated with food.

Food Becomes Less Rewarding: With dopamine release blunted, eating may no longer feel as satisfying, which can reduce the motivation to eat, even though hunger persists.

Craving Without Satisfaction: Dopamine plays a role in both the craving for and satisfaction from eating. When dopamine is disrupted, cravings may remain, but the act of eating may no longer bring the usual pleasure, creating a disconnect between the body’s need for food and the brain’s response to it.

?Serotonin Dysregulation

Role in Satiety: Serotonin helps suppress appetite and regulate gut motility. When delayed gastric emptying disrupts serotonin signaling, it can impair the body’s ability to signal fullness, leading to dysregulated appetite.

Mood Impact: Serotonin also regulates mood. When eating no longer brings pleasure, and satiety signals are disrupted, it can lead to depression or anxiety. Over time, this can deplete serotonin levels further, creating a feedback loop where mood worsens, and appetite continues to be dysregulated.

?Oxytocin’s Role in Eating and Social Bonding

Pleasure in Social Eating: Oxytocin is linked to social bonding and can enhance the reward of eating in a social setting. When dopamine signaling is impaired, the role of oxytocin in promoting food-related pleasure may be reduced, causing individuals to feel less connected to food and social eating experiences.

Interaction with Satiety: Oxytocin works with hormones like CCK to promote satiety. If delayed gastric emptying disrupts the release of CCK and oxytocin, the feeling of fullness may be further impaired, leading to disordered eating behaviors.

?Over time, chronic disruption of neurotransmitters like dopamine, serotonin, and oxytocin can lead to epigenetic changes—modifications in gene expression that don’t alter DNA sequences but can change how genes are expressed.

Persistent disruption of reward and hunger signals can lead to permanent alterations in the genes that regulate dopamine and serotonin. This could make it harder for the brain to recover normal signaling, even after discontinuing GLP1RAs.

Prolonged dysregulation may also increase stress hormone activity (CRH), further affecting appetite and emotional regulation. Chronic stress can lead to epigenetic modifications that predispose individuals to anxiety, depression, and eating disorders.

?Downstream Health Effects

Disordered Eating Patterns: The combined effect of blunted reward, dysregulated hunger signals, and impaired mood regulation can lead to disordered eating behaviors. Without the normal pleasure or satisfaction from food, people may overeat, undereat, or binge in an attempt to regain the lost sense of reward.

Metabolic Changes: Long-term disruption of appetite and hunger regulation can lead to metabolic changes, such as insulin resistance or malnutrition, which increase the risk of obesity or type 2 diabetes.

Mood Disorders: Chronic depletion of serotonin and dopamine can contribute to long-term mood disorders like depression or anxiety, worsening the disconnect between hunger and reward.

?Why does muscle loss matter for your health and how do GLP1RA directly lead to sarcopenia? ?

?I’ve previously discussed how delayed gastric emptying affects the stomach, stretches it out, and disrupts satiety hormones like cholecystokinin (CCK). This disruption reduces dopamine release, making eating less rewarding. As a result, the brain’s hunger signals and actual food intake become disconnected, leading to disordered eating patterns, which can negatively impact mood and metabolism through the dysregulation of serotonin, dopamine, and oxytocin.

?GLP-1 receptor agonists can also contribute to muscle loss, a condition known as sarcopenia. Sarcopenia is the gradual decline in muscle mass and function, often associated with aging, but it can be worsened by malnutrition, chronic illness, or prolonged inactivity. When sarcopenia occurs alongside delayed gastric emptying and impaired food-related reward systems, it creates a harmful cycle for both metabolism and mental health.

?Muscle is a highly metabolically active tissue, which means it has a major impact on your basal metabolic rate (BMR)—the number of calories your body burns at rest. When muscle mass is lost, the BMR decreases, which can lead to weight gain, insulin resistance, and other metabolic complications. Furthermore, reduced muscle mass means less energy expenditure during physical activity, contributing even further to metabolic decline.

?Muscles play a central role in absorbing glucose from the bloodstream. Loss of muscle tissue can lead to insulin resistance and poor blood sugar control, heightening the risk of type 2 diabetes and other metabolic diseases.

?If the substance reduces the pleasure of eating, individuals may consume fewer calories and nutrients (especially protein), which worsens muscle wasting. A lack of adequate protein intake is a key factor in accelerating sarcopenia.

?The aforementioned disruption of serotonin, dopamine, and oxytocin creates a feedback loop that exacerbates muscle loss, let’s examine that closer:

• Dopamine: Decreased dopamine release not only reduces the pleasure derived from food but also diminishes the motivation to be physically active. Without sufficient activity, muscle mass declines more rapidly due to disuse. This creates a vicious cycle where lower activity levels further decrease dopamine, worsening depression and anhedonia (the inability to feel pleasure).
• Serotonin: Low serotonin levels, worsened by reduced food intake and disrupted gut-brain signaling, heighten the risk of depression. Depression, in turn, reduces physical activity, which, when combined with insufficient nutrient intake, accelerates muscle loss. Serotonin also influences gut motility, and its dysregulation can worsen gastric emptying problems, leading to chronic digestive issues that make eating even less appealing.
• Oxytocin: This hormone supports emotional regulation and social bonding. When its activity is reduced, so are the social and emotional rewards of eating together or exercising with others. This lack of oxytocin may indirectly reduce muscle protein synthesis by worsening emotional well-being and encouraging a more sedentary lifestyle.?

What are Epigenetic Changes and Long-Term Consequences of these processes induced by GLP1RA use?

?Epigenetic changes—modifications in gene expression caused by environmental factors—occur as a result of the stress from metabolic imbalances, muscle loss, and neurotransmitter disruption. Over time, these changes can lead to irreversible damage to both mental and physical health:

• Epigenetic Impact on Muscle Maintenance: Chronic stress and malnutrition can trigger epigenetic alterations that downregulate the genes responsible for muscle growth and repair. For example, the mTOR pathway, essential for muscle synthesis, may become downregulated due to insufficient protein intake and ongoing inflammation, resulting in persistent muscle atrophy.
• Impact on Neurotransmitter Pathways: Prolonged dysregulation of serotonin, dopamine, and oxytocin can alter the expression of genes that regulate reward and mood pathways, making it more difficult for the brain to return to normal functioning, even after external conditions improve. This can lead to chronic anhedonia, ongoing depression, and anxiety.
• Metabolic Epigenetics: Over time, the suppression of physical activity and loss of muscle mass will likely result in epigenetic changes that reduce metabolic flexibility—meaning the body becomes less capable of efficiently burning fat or regulating blood sugar. These changes can lead to lifelong issues with obesity, insulin resistance, and metabolic syndrome.?

Downstream Health Effects

The combined impact of delayed gastric emptying, diminished pleasure from eating, muscle loss, and neurotransmitter imbalances leads to cascading health effects:

• Metabolic Disorders: The risk of type 2 diabetes, obesity, and metabolic syndrome increases due to insulin resistance and muscle loss.
• Mental Health Issues: Higher rates of depression, anxiety, and anhedonia develop as a result of imbalances in serotonin, dopamine, and oxytocin.
• Chronic Fatigue and Weakness: Muscle loss not only weakens the body but also contributes to chronic fatigue, making it harder to engage in daily activities. This leads to further physical and mental decline.
• Social Withdrawal: As oxytocin levels drop, the desire for social interaction diminishes, leading to isolation and exacerbating mental health issues.

?How does this all come together?

?As a patient, choosing to use GLP-1 receptor agonists ultimately places you as the N=1 in your own health journey. But at a minimum, you should be aware of and fully understand the potential long-term impact of these medications on a larger scale. The informed consent process for patients considering GLP1RAs should cover:

• The potential for delayed gastric emptying and subsequent nutrient malabsorption.
• The downregulation of appetite signals, leading to metabolic imbalances and mental health concerns.
• The potential for muscle loss, which may be irreversible or difficult to restore if not detected early.
• The risk of epigenetic changes that could permanently alter the body’s ability to regulate hunger, weight, and metabolism.?

By offering this personal informed consent statement, I hope to underscore the importance of transparency, responsibility, and foresight in how we approach the use of these widely prescribed medications.

?If you’ve reached this far in this article, I hope you can confidently say:

?"I acknowledge that the following risks are associated with the use of GLP1RA which can induce delayed gastric emptying, directly interfere with brain reward centers, and causes muscle loss:

• Induced delayed gastric emptying alters satiety signals, prolongs stomach stretching, and changes how the brain perceives fullness.
• Blunted dopamine release reduces the pleasure and reward associated with food, leading to disordered eating and dysregulated hunger signals.
• Muscle loss (sarcopenia) results from impaired nutrient absorption, reduced appetite, and lower caloric intake, which may weaken physical function and cause long-term metabolic and mental health complications.

By consenting to the use of this substance, I understand the potential short-term and long-term health consequences, including effects on my digestive system, brain reward system, and muscle mass. I have been fully informed of these risks and agree to proceed with full knowledge of the potential outcomes."

Lastly, before prescribing GLP-1 receptor agonists (GLP1RAs) such as Mounjaro or Ozempic, your physician should be able to confidently answer the following questions to ensure that you are receiving the necessary information and to prevent unintended consequences:

• What is the primary reason for prescribing GLP1RA to this patient?
• Is the patient fully informed about how GLP1RAs work and their possible effects?
• What are the potential long-term health risks associated with GLP1RA use for this specific patient?
• Are there sufficiently powered studies supporting the new claims, such as weight loss or appetite control?
• How will the patient be monitored for unintended side effects?

?These questions ensure that the decision to prescribe is rooted in evidence-based practice, prioritizing the patient’s long-term health and safety.

?I thank the reader for the patience and time spend. I appreciate thoughts, and comments so we can all learn together!