In this Nexus 🔗:
💉 What is Semaglutide?
🔬 Mechanism of Action
💊 Indications for Use
⚠️ Adverse Events
🧬 Ozempic, Obesity and Longevity
📈 Weight Regain
📉 Muscle Loss – The Most Unwanted Side Effect
👴 Ozempic Face
Can I call it Ozempic hysteria? Semaglutide, better known under the brand names Ozempic and Wegovy, has been in shortage since 2022 due to increased demand and only couple of days ago (3 years later) FDA has announced that this shortage has been resolved. Semaglutide is a groundbreaking medication initially developed to manage type 2 diabetes mellitus. Its effectiveness in improving glycemic control, combined with its significant impact on weight management, has put it into the spotlight among the general public. While an off-label use of this medication is skyrocketing, those overweight or obese but otherwise healthy individuals who have decided to use it as a shortcut in losing weight shall consider the pros and cons of doing so. In this Nexus I discuss semaglutide mechanism of action, it’s indications for use, adverse events, its’ potential in longevity, and also some concerns such as weight regain after discontinuation, muscle loss and “Ozempic face”.
What is Semaglutide?
Semaglutide (Ozempic) belongs to a class of medications called glucagon-like peptide-1 receptor agonists (GLP-1 RAs). GLP-1 is an incretin hormone (a type of hormone that helps regulate blood sugar levels) naturally produced in the intestines in response to food intake. It plays a vital role in glucose metabolism and appetite regulation. However, endogenous GLP-1 that is produced in our body has a short half-life due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) (1).
Semaglutide is a synthetic analogue of GLP-1 that is engineered to resist this degradation by DPP-4 enzyme, resulting in a significantly longer half-life (approximately one week). This allows for once-weekly dosing (2).
What Does Science Say?
Mechanism of Action
Semaglutide has a number mode of actions which makes it so effective in weight loss and related health benefits:
Increase of insulin secretion. Semaglutide stimulates the pancreas to release insulin in response to elevated blood glucose levels after a meal (3).
Suppression of glucagon secretion. Semaglutide reduces the release of glucagon (a hormone that raises blood sugar), preventing an excessive glucose production by the liver (1).
Delay and slowing of gastric emptying. Semaglutide slows down digestion by delaying first-hour gastric emptying, leading to a more gradual release of glucose into the bloodstream. The slowing of gastric emptying also helps control portion sizes and decreases overeating (4).
Reduction of appetite and promotion of satiety (feeling full). Semaglutide acts on the brain’s hypothalamus (a small brain region that regulates hormones, body temperature, hunger, thirst, sleep, and other vital functions to maintain homeostasis) to decrease hunger and food cravings (5). Semaglutide makes people feel full sooner and for longer, leading to reduced calorie intake.
Lower risk of major cardiovascular events. Clinical studies have shown that semaglutide can reduce the risk of heart attack, stroke, and cardiovascular events related death in people with diabetes and heart disease (6). It also reduces blood pressure likely due to weight loss and improved insulin sensitivity.
Decrease of inflammation and oxidative stress. Semaglutide has potential anti-inflammatory effects as studies suggest it can modulate inflammatory responses. However, the exact mechanisms of its anti-inflammatory effects are not yet fully understood (7).
May improve liver health. Semaglutide shows potential in reducing fat accumulation in the liver significantly improves liver enzymes, reduces liver stiffness, and improves metabolic parameters (8).
The key actions of semaglutide are summarized in the figure below (9):
Indications for Use
Currently there are 3 major approved indications for the use of Semaglutide (10):
- Type 2 diabetes mellitus. Ozempic is primarily indicated as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes. It is particularly beneficial for patients at high risk of cardiovascular events, as it has demonstrated a reduction in major adverse cardiovascular events in clinical trials.
- Chronic weight management. While marketed as Wegovy (a higher-dose formulation of semaglutide), Ozempic is also frequently used off-label for weight management. It is approved for individuals with a body mass index of ≥30 kg/m² or ≥27 kg/m² with comorbidities such as hypertension (high blood pressure) or dyslipidemia (abnormal levels of lipids, i.e. cholesterol and triglycerides, in the blood).
- Prevention of cardiovascular events. In patients with type 2 diabetes and established cardiovascular disease (CVD), Ozempic has shown efficacy in reducing the risk of stroke, myocardial infarction, and cardiovascular death.
Adverse Events
As with any medication, Ozempic is associated with potential side effects, though most are mild and transient. The most commonly reported adverse events include:
Gastrointestinal symptoms. Nausea, vomiting, diarrhea, constipation, and abdominal discomfort are the most frequently reported side effects. These typically occur early in treatment and diminish over time.
Hypoglycemia. While rare, hypoglycemia can occur, particularly when Ozempic is used in combination with other glucose-lowering medications like insulin or sulfonylureas.
Gallbladder-related disorders. Rapid weight loss may increase the risk of gallstones and cholecystitis.
Pancreatitis (inflammation of the pancreas). Though rare, there have been reports of acute pancreatitis in patients using GLP-1 receptor agonists. Patients should be monitored for symptoms such as severe abdominal pain.
Thyroid tumors. In rodent studies, semaglutide has been associated with an increased risk of medullary thyroid carcinoma. However, the incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk (11).
Ozempic, Obesity and Longevity
Obesity is a complex chronic condition characterized by excess adiposity, which increases the risk of numerous comorbidities such as diabetes, hypertension, and non-alcoholic fatty liver disease. Ozempic’s ability to promote significant weight loss makes it a game-changer in obesity management. The Semaglutide Treatment Effect in People with obesity – STEP clinical trial programme evaluated once‐weekly subcutaneous semaglutide 2.4 mg in people with overweight or obesity (12). Across STEP 1, 3, 4 and 8 clinical trials, semaglutide 2.4 mg was associated with mean weight losses of 14.9%‐17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68. In STEP 5, mean weight loss was −15.2% with semaglutide 2.4 mg versus −2.6% with placebo from baseline to week 104.
It is clear that obesity and longevity don’t go well together. The potential impact of Ozempic on longevity extends beyond its primary indications which I mentioned previously. Several pathways might link its effects to protential extension of healthspan and lifespan:
- Metabolic health. Improved glycemic control and weight loss reduce the risk of metabolic syndrome, type 2 diabetes, and cardiovascular disease, all of which are associated with premature mortality and are among the leading causes of death worldwide (13).
- Reduction of inflammation. GLP-1 receptor activation has been shown to reduce systemic inflammation, which is a driver of aging and age-related diseases (14).
- Neuroprotection. Preclinical studies suggested that GLP-1 receptor agonists may reduce the risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease by mitigating oxidative stress and inflammation in the brain. The neuroprotective effects were also demonstrated in clinical trials. Obese patients treated with semaglutide agonists showed significantly lower risks of developing Alzheimer’s disease, Lewy body dementia, vascular dementia and Parkinson’s disease. Additionally, a significant reduction in all-cause mortality was observed (15).
- Impact on fat composition. The reduction in visceral fat, which is a major contributor to chronic inflammation and insulin resistance, may enhance overall longevity. According to studies, semaglutide through GLP-1 enhances adipose tissue browning (a process when regular white fat which mainly stores energy)changes into brown-like fat, which helps burn calories and generate heat) and formation of new adipocytes and ameliorates dysfunctional adiposity in obesity (16).
While Ozempic is a promising candidate for improving both quality of life and lifespan, it’s impact on longevity requires further long-term research. Also it is important to note that Semaglutide has gained it marketing authorization only in 2021, which is less than 5 years on the market, thus, a number of post-authorization studies are still in progress researching not only the benefits, but also side effects. Therefore, before jumping into any miracle treatment, you need to understand that everything comes with a price, and there are some concerns which I discuss hereinafter.
Weight Regain
It is important to highlight, that if you are planning to use Ozempic off-label in order to lose weight and then discontinue after you reach the desired result, most probably – the lost kilos will come back to you.
This was shown in STEP 1 clinical trial (NCT03548935), which randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg or placebo, as an adjunct to lifestyle intervention. At week 68, treatments and lifestyle intervention were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. Extension analyses included 327 participants (17).
One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables.
These findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and cardiometabolic health.
Muscle Loss – The Most Unwanted Side Effect
Muscle loss (also known as sarcopenia when severe) is another potential concern during significant weight loss, including weight loss associated with the use of Ozempic. While Ozempic targets fat loss through appetite suppression and improved metabolic control, some lean muscle mass may also be lost. Of emerging concern is the loss of skeletal muscle mass and function that can accompany rapid substantial weight reduction. Such losses can lead to reduced functional and metabolic health, weight cycling, compromised quality of life, and other adverse outcomes (18).
Available evidence suggests that clinical trial participants receiving semaglutide for the treatment of obesity lost 10% or more of their muscle mass during the 68- to 72-week interventions, approximately equivalent to 20 years of age-related muscle loss.
This is particularly concerning for older adults, as muscle mass is critical for maintaining strength, mobility, and metabolic health. To mitigate muscle loss, individuals are advised to engage in regular resistance or strength-training exercises and ensure adequate protein intake during their weight loss.
Ozempic Face
“Ozempic face” is a term that has emerged to describe a phenomenon observed in some individuals who experience significant weight loss while using Ozempic. Rapid weight reduction, particularly in older adults, can lead to a noticeable loss of fat in the face, resulting in a gaunt or hollowed appearance.
This occurs because subcutaneous fat, which provides volume and a youthful contour to the face, diminishes as overall body fat decreases. While the term is not a medical diagnosis, it underscores the aesthetic changes that may follow significant weight loss. It is important to discuss your weight loss goals and potential side effects with your physician to ensure a balanced approach to treatment.
Ozempic is a significant advancement in the management of type 2 diabetes and obesity, offering not only improved glycemic control but also substantial weight loss benefits. Its mechanisms of action, which extend beyond glycemic regulation to appetite control and anti-inflammatory effects, position it as a potential agent for improving overall health and longevity. However, like all medications, it doesn’t come without risks. Hope you have enjoyed this Nexus edition. More on longevity, healthspan and health optimization coming soon! Subscribe, stay tuned and do not hesitate to engage!
