Could Ozempic microdosing boost brain health and fight cancer?

Commentary by  Dr. Donald Greig

The advent of GLP-1 (glucagon-like peptide-1) agonists, such as Ozempic (semaglutide) and Rybelsus (oral semaglutide), has revolutionized the treatment landscape for Type 2 diabetes and obesity. Growing interest in microdosing these medications—administering subtherapeutic doses—has prompted exploration into their broader health benefits, particularly in cardiovascular health, diabetes management, and cognitive function, including potential implications for Alzheimer’s disease.

Cardiovascular Health

One of the most significant benefits of GLP-1 agonists is their favorable impact on cardiovascular health. Clinical studies have demonstrated that these medications can reduce the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes. By promoting weight loss, improving glycemic control, and enhancing lipid profiles, GLP-1 agonists help mitigate key risk factors associated with cardiovascular disease.

Microdosing may amplify these effects by minimizing side effects commonly associated with full doses, such as gastrointestinal disturbances. This could lead to higher adherence rates among patients who might otherwise be deterred by more intense regimens. As cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, even modest improvements through microdosing could have substantial population-level benefits.

Improvement in Diabetes Management

Microdosing GLP-1 agonists could also provide tailored diabetes management. These medications enhance insulin secretion in response to meals while suppressing glucagon release, thereby improving overall glycemic control. By using lower doses, patients may experience a gradual adjustment period, potentially leading to fewer fluctuations in blood glucose levels.

Moreover, microdosing may optimize the weight loss benefits associated with GLP-1 agonists. Weight reduction is a critical factor in managing Type 2 diabetes, and even small reductions in body weight can lead to significant improvements in insulin sensitivity. This approach may appeal to patients seeking to minimize side effects while still benefiting from enhanced metabolic control.

Reducing Brain Fog and Investigating Alzheimer’s Disease

Cognitive function is a growing area of interest in the study of GLP-1 agonists. Preliminary evidence suggests that these medications may have neuroprotective properties, which could play a role in reducing symptoms of "brain fog" often reported by individuals with diabetes. The potential mechanisms include improved insulin signaling in the brain and reduction of inflammatory markers associated with cognitive decline.

The investigation into GLP-1 agonists for Alzheimer’s disease is particularly compelling. Research has indicated that GLP-1 receptors are present in brain regions associated with learning and memory. Studies are ongoing to determine whether these agonists can slow the progression of Alzheimer's or mitigate its symptoms. Microdosing could be a strategy to explore in this context, as it may minimize adverse effects while providing a novel therapeutic avenue for cognitive impairment.

Conclusion

While the microdosing of GLP-1 agonists like Ozempic and Rybelsus is still in the early stages of research, the potential benefits in cardiovascular health, diabetes management, and cognitive function are promising. As the medical community continues to explore these medications' diverse effects, personalized dosing strategies may emerge as a viable option to enhance patient outcomes, particularly for those seeking to balance efficacy with tolerability. Future studies will be crucial in elucidating the full spectrum of benefits and establishing guidelines for microdosing in various patient populations.

The Times article further explores these potential management pathways.

Source

Article by: Rhys Blakely

Dr Wendy Denning, who runs a private clinic off Harley Street in London, says many of her patients are delighted with the results they have seen from the weight-loss drugs Mounjaro and Wegovy. But as they shed the pounds, she has started asking herself: could their doses be slimmed down as well?

Increasingly, she’s being asked about “microdosing”, which involves taking a smaller amount of these medicines than the manufacturers recommend, by patients who have seen it discussed on social media. This might not be for weight loss, but to boost health in other ways. In America a legion of online influencers are promoting microdosing, but leading researchers are also intrigued. “I think it’s a very interesting idea,” Denning said.

The drugs, which mimic a naturally produced hormone known as glucagon-like peptide 1 (GLP-1), have been used to treat diabetes for more than a decade. More recently they have become a wildly popular way for people to lose weight, winning celebrity endorsements from the likes of Elon Musk and Oprah Winfrey.

But their effects are not limited to slimming, with patients reporting a host of unanticipated benefits, ranging from improvements to psoriasis to the clearing of brain fog.

Dr Wendy Denning has several patients who were prescribed Mounjaro and Wegovy for weight loss and then noticed that their desire for alcohol had evaporated

Semaglutide — the active ingredient in Ozempic, which is used to treat type 2 diabetes, and the weight-loss drug Wegovy — is being evaluated in two phase-two trials for people with Alzheimer’s. Other GLP-1 agonists are being tested as possible treatments for everything from liver disease to opioid addiction.

The health secretary, Wes Streeting, has said you should not use Ozempic unless you are obese. But trials have already suggested that semaglutide may improve cardiovascular health, even when people do not lose weight. There are signs that GLP-1 drugs reduce inflammation, a risk factor for some cancers, heart disease and dementia.

In rodents, they appear to improve memory and reduce the build-up of toxic proteins in the brain. They also seem to reduce oxidative stress, which damages cells. In one small trial, patients with mild Alzheimer’s experienced less shrinking of the brain and slower cognitive decline when they took liraglutide, another GLP-1 medication.

Elsewhere in the body, GLP-1 agonists bind to receptors on heart cells and blood vessels, helping to modulate blood pressure and fat levels. Little wonder, then, that researchers have begun to ask whether even slim patients might now benefit from small preventive doses.

“You need a low dose to control your blood sugar. You need a higher dose to get better weight loss,” said Dr Daniel Drucker of the Lunenfeld-Tanenbaum Research Institute in Toronto, who has developed treatments for diabetes and obesity. It is feasible, he added, that the doses required to reduce inflammation or to guard against heart disease will be lower than those used to treat obesity.

He cited a large trial of semaglutide involving 17,600 overweight and obese patients. “It didn’t seem to matter whether or not you lost weight, people still had a 20 per cent reduction in heart attack, strokes and death,” he said.

“We should be open to the possibility that people may experience different benefits at various doses.”

But he is not about to start writing microdose prescriptions. “As a scientist, I would say that’s a great hypothesis — now what we need is a clinical trial.”

Professor Tricia Tan, consultant in diabetes, endocrinology and metabolic medicine at Imperial College London, is also keen to see more data. She fears that many patients on GLP-1 drugs for obesity are racing towards a cliff edge: the evidence suggests that about two thirds of people regain weight when they stop having the injections.

Could microdosing help them stay at a healthy weight? “It would be fantastic if we could do the trial to learn whether we can put people on a lower, maintenance dose,” she said.

The drugs stimulate the pancreas to release insulin, which lowers blood-sugar levels, and suppress glucagon, which can increase them. They also prolong the feeling of being full, partly by slowing down how fast food moves through the gut.

But GLP-1 also acts on regions of the brain, including the hypothalamus, which controls hunger and on networks of neurons that modulate cravings.

Denning has several patients who were prescribed Mounjaro and Wegovy for weight loss and then noticed that their desire for alcohol had evaporated. A few were close to liver cirrhosis. “For some people these drugs are a game-changer in terms of alcohol addiction. I could see microdosing playing a role for them,” she said.

She also wonders whether it might benefit patients with elevated levels of glycated haemoglobin (HbA1c), a marker of insulin resistance. Higher levels are linked to cardiovascular disease, inflammation and a greater risk of dementia. “If you can effect a change and bring that down, which this drug does, then you do definitely change the parameters of cardiovascular and dementia risk,” Denning said.

“And when you’re dealing with women in the menopause, where weight loss is very difficult and where cardiovascular risk increases, then you might want to microdose them fairly long term.”

Dr Tamsin Lewis, a longevity specialist at Solice Health, a private clinic in London, will already consider microdosing GLP-1 agonists on a case-by-case basis. “Although it’s still relatively niche in the UK, we’re beginning to see more interest in microdosing,” she said. “We are seeing more interest from slim individuals, particularly women, who are exploring GLP-1 agonists for their broader health benefits.”

Mounjaro, another GLP-1 agonist, had dramatic effects on patients’ weight in clinical trials

The drugs can strip away muscle as well as fat, and she insists that patients watch their diets. “I caution these individuals about nutritional deficiencies which often occur on these medications,” she said.

“It’s important to note that I do not recommend purchasing these medications online. They are not risk-free, and without medical supervision there could be serious complications. All treatments, especially off-licence uses like microdosing, should be carefully considered and guided by a qualified doctor.

“Even at microdoses, GLP-1 agonists can cause side-effects such as nausea, digestive issues and in rare cases more serious complications like pancreatitis.”

Long-term use is another consideration. “While these medications may offer significant benefits, we don’t yet fully understand the effects of prolonged use in individuals without diabetes or obesity,” Lewis said.

In Toronto, Drucker says he is getting a steady stream of anecdotal reports. “I have patients writing to tell me that their brains are better, their long Covid is better, they can think more clearly. Their arthritis is better, their ulcerative colitis is better, their knee arthritis is better, their psoriasis is better. I literally get these emails all the time.”

Some of these people will, of course, be experiencing the corollary benefits of losing weight. But he is open to the idea that something else is going on.

“I believe every single person, but the broader question is: if I treat 100 people like that, what’s the response rate? If the response rate is 1 per cent then it’s not a particularly clinically useful observation. If the response rate is 30 or 40 per cent then maybe this is something that’s useful. And we just don’t have enough information for now.”

He repeats that when it comes to microdosing, what is needed are large high-quality trials. But he doubts that the big pharmaceutical companies will fund them while demand is still high for standard doses. “They can already sell all the drug they want for the next five years,” he said.

A spokesman for Novo Nordisk, which makes Ozempic and Wegovy, said: “Novo Nordisk does not condone, suggest, or encourage misuse of any of our medicines outside of their approved indications. For Ozempic (semaglutide injection), only the marked doses on the pens (0.25mg, 0.5mg, 1.0mg) are approved for use in the UK (with 0.25 mg only approved for initiation and not maintenance).

“It is important to note that the decision to prescribe Ozempic in any dosage should be made by a healthcare professional. The approved doses are the only dose strengths that have been studied as maintenance doses in our phase 3 clinical development programme.”