Obesity, a chronic condition characterized by excessive fat accumulation, has become a global health concern. Defined as excessive fat accumulation, obesity is a concerning health issue that can lead to serious clinical complications, including cardiovascular disease, diabetes mellitus, musculoskeletal disorders, and malignancy. The condition has tripled worldwide since 1975, prompting the search for effective and safe treatments. While lifestyle interventions remain crucial, pharmacological options like semaglutide have emerged as promising tools in the fight against obesity.
The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has gained attention for its potential to aid weight loss, even in individuals without type 2 diabetes. This article delves into the efficacy, safety, and practical considerations of oral semaglutide for weight loss in non-diabetic individuals.
Understanding Semaglutide
Semaglutide belongs to a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 RAs were developed for the treatment of diabetes since the incretin GLP-1 was shown to decrease blood glucose by stimulating insulin secretion and decreasing glucagon release. It also promotes weight loss by inducing satiety, leading to decreased caloric intake by delaying gastric emptying. In the brain, it decreases appetite through the stimulation of satiety centers indirectly through neural afferents and directly by crossing the blood brain barrier. GLP-1, a hormone naturally produced in the small intestines, plays a crucial role in regulating appetite and blood sugar levels. Semaglutide mimics the action of GLP-1, leading to several beneficial effects:
- Slows Digestion: Semaglutide delays gastric emptying, promoting a feeling of fullness and reducing overall food intake.
- Reduces Hunger: By acting on the satiety centers in the brain, semaglutide decreases appetite and food cravings.
- Increases Feelings of Fullness: Semaglutide enhances satiety, helping individuals feel satisfied with smaller portions.
- Enhances Insulin Sensitivity: Semaglutide improves the body's response to insulin, aiding in blood sugar control.
- Manages Blood Sugar Levels: Although primarily used for diabetes management, semaglutide can help regulate blood sugar levels in non-diabetic individuals as well.
- Decreases Food Chatter and Food Noise: Many users report a reduction in constant thoughts about food, making it easier to adhere to a healthy eating plan.
Oral vs. Injectable Semaglutide: Key Differences
When GLP-1 medications first hit the market, they were only offered as injectables. For the needle averse among us, that may have been a complete non-starter. Now, you’ve got options. While early oral versions were less effective, largely due to poor absorption from the gut, we now have new oral formulations with improved absorption and adjusted dosing so you can see greater results without needing injections.
Semaglutide is available in both oral and injectable forms, each with its own advantages and disadvantages. The main differences between oral and injectable semaglutide hinges on how their delivery methods affect the body's absorption of the drug, impacting efficacy and results.
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Oral Semaglutide:
- Administration: Taken daily as a tablet (Rybelsus) or as sublingual drops that are placed under the tongue.
- Convenience: Offers a non-invasive option for those who prefer to avoid injections, and can be taken on the go without refrigeration.
- Absorption: Oral semaglutide needs to be taken once daily on an empty stomach, ideally early in the day for best efficacy. If that’s not possible, wait at least 30 minutes after eating. Sublingual drops bypass much of the digestive system, potentially improving absorption compared to tablets.
- Bioavailability: The different forms of semaglutide have different percentages of bioavailability. Oral Tablets: Because oral tablets have to be metabolized in the stomach, their bioavailability goes way down during digestion and exposure to stomach acids. After they're fully absorbed, you’re looking at a bioavailability range of only 0.4% to 1%.Oral Drops: Because the drug is absorbed through the tissues under your tongue, it bypasses much of the digestive system. This is believed to improve how much of the drug actually makes it into your bloodstream compared to standard oral tablets, with bioavailability potentially as high as 40%.
- Efficacy: The research, so far, suggests that all forms of semaglutide can aid in weight loss, but by how much will vary.
Injectable Semaglutide:
- Administration: Administered weekly as a subcutaneous injection.
- Convenience: Requires less frequent dosing, but necessitates injections and refrigeration.
- Absorption: High bioavailability, hovering around 89%.
- Efficacy: Has been shown to offer more consistent absorption and long-term efficacy, with studies demonstrating significant weight loss.
Efficacy of Semaglutide for Weight Loss in Non-Diabetics
The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Recent clinical trials have demonstrated the effectiveness of semaglutide for weight loss in individuals without diabetes. The search yielded 1208 articles, of which 263 were duplicates. After removal of duplicates and 895 articles based on title and abstract alone, 50 full text articles were assessed for eligibility, of which 46 were excluded since the studies were either done in patients with diabetes or non-obese population, used an intervention other than semaglutide, or had an outcome that was not compatible with the goals of this review. After careful evaluation, 4 RTCs were included in the review (Figure 1). These trials measured the percent change in body weight after treatment with semaglutide versus placebo and reported the most common adverse effects associated with treatment. Across 4 trials, 3,613 individuals were included in the study (2,350 in the semaglutide group and 1,263 in the placebo group). Baseline characteristics were similar between both groups in the 4 individual trials. The mean weight, BMI, age and sex of the participants included in the trials are shown in Table 2. All were adults ≥18 years old with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with at least 1 treated or untreated weight-related comorbidity without diabetes. The most common comorbidities were hypertension and dyslipidemia.
- Significant Weight Reduction: Combining the results of the trials showed that semaglutide is indeed associated with weight loss with a mean difference of 11.85% compared with placebo. Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity.
- Clinical Trial Results: In a study published in the New England Journal of Medicine, adults who were overweight or obese lost nearly 15% of their body weight after 68 weeks of weekly semaglutide injections.
- Oral Tablet Studies: One study found that the average weight loss with oral semaglutide tablets was roughly 9 pounds after 26 weeks.
- Emerging Research on Oral Drops: Research on the efficacy of oral drops is still emerging, but one recent animal study suggests it may be more effective than tablets, but this is highly dependent on how much time the drug has to be absorbed under the tongue before it's swallowed.
How to Take Oral Semaglutide Drops
Oral semaglutide needs to be taken once daily on an empty stomach, ideally early in the day for best efficacy. If that’s not possible, wait at least 30 minutes after eating. Here’s how to properly administer oral semaglutide drops:
- Roll the bottle between your hands or shake lightly before each use.
- Measure the prescribed amount in the oral syringe.
- Place the liquid under your tongue (the solution has a peppermint flavor to make it more pleasant).
- While keeping your mouth closed and relaxed, hold it there for at least 1-2 minutes (longer is better for absorption). Then swish it around your mouth before swallowing.
- Avoid eating, drinking, or brushing your teeth for about 30 minutes after. This gives the medication time to absorb fully.
Potential Benefits Beyond Weight Loss
Beyond weight loss, GLP-1s can have other long-term health benefits, including:
- Improving cholesterol levels
- Improving fatty liver disease
- Reducing your risk of heart disease and kidney disease
- Reducing alcohol intake and smoking
Who Should Consider Oral Semaglutide?
Oral semaglutide can be a suitable option for individuals who:
- Are obese or overweight with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with at least one weight-related comorbidity without diabetes.
- Have struggled to lose weight through diet and exercise alone.
- Prefer a non-invasive treatment option over injections.
- Are looking for additional health benefits beyond weight loss.
- Want to lose a smaller amount of weight, or for those who want to explore the other benefits of GLP-1s beyond diabetes control and major weight loss.
Potential Side Effects and Risks
Like all medications, oral semaglutide can cause side effects. It is therefore necessary to have an overall efficacy and safety evaluation of semaglutide as a promising option for the pharmacologic treatment of obesity. The safety profile was “generally in line with subcutaneous semaglutide,” the authors note, as well as with the GLP-1 receptor agonist class as a whole.
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The most frequently reported side effects are gastrointestinal, including:
- Nausea
- Diarrhea
- Constipation
- Vomiting
These were reported to be uncommon. The risk for developing serious adverse events was 1.6 times more likely for semaglutide than placebo (RR1.60, 95%CI [1.24, 2.07], p=0.0003, I2 0%) (Figure 5B). O’Neil, Wilding and Rubino et al.’s studies each mentioned that death was reported during the trial period, but was not considered to be related to semaglutide or placebo treatment. No death was reported in Wadden et al.’s study.
Serious risks to watch for include:
- Pancreatitis (severe abdominal pain)
- Thyroid tumors
- Hypoglycemia
- Gallstones or acute cholecystitis
Managing Side Effects
Many patients also find relief from mild nausea by sipping ginger tea or taking ginger capsules. At Midi, when we prescribe personalized GLP-1 medications we also supply patients with Ondansetron tablets, a medication that’s used to treat nausea and vomiting and can be used if significant symptoms occur.
The Role of Lifestyle Modifications
We observed that aside from the administration of semaglutide, reduced calorie diet and increased physical activity were also part of the intervention. Hence, semaglutide alone probably will not be able to achieve an 11.85% weight loss. To get the max benefits out of weight-loss meds, you have to put in the work to reshape your diet and exercise routines to support your goals. To help you reach your goals, a Midi clinician will support you with advice on the lifestyle changes that are best for you.
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- Dietary Changes: Focus on high-protein, fiber-rich foods to enhance satiety. Limit ultra-processed and high-sugar meals to optimize results.
- Exercise: Strength training and cardiovascular exercise improve fat loss and preserve muscle mass.
- Lifestyle Adjustments: Prioritize sleep, hydration, and stress management to maximize medication efficacy.
Oral Semaglutide and Menopause
When estrogen fluctuates and declines during perimenopause as you inch towards the end of your reproductive years, the effects are felt throughout the entire body. You have estrogen receptors everywhere, from your brain to your gut to your ovaries. Estrogen plays an important role in weight control, helping to curb appetite. So when levels start dropping during perimenopause, you may feel hungrier, making it harder to maintain your weight or drop pounds easily. On top of that, other menopause symptoms, including poor sleep and mood changes, can leave you craving sugary, comfort foods. It’s no wonder, then, that 87% of Midi patients complain of struggling with weight and body changes. The combination of dropping estrogen, the decline in physical activity that tends to happen as you age, and side effects of menopause like trouble sleeping all combine for a slow-and-steady weight gain. To make matters worse, due to the change in hormone levels, your basal metabolism may burn 250-300 fewer calories per day than before. That’s why semaglutide during menopause can help. It can quiet food cravings and how much time you spend thinking about food.
Semaglutide for Anti-Aging and Longevity
The more we learn about GLP-1s, the more we realize that they can do far more than just help us shed pounds. And research shows they can have a profound impact on our long-term health, counteracting the effects of depleted estrogen, in a number of ways.
- Fewer heart issues: By improving glucose metabolism, reducing inflammation, and aiding in the maintenance of lean body mass, semaglutide could potentially lower the risk of age-related diseases such as cardiovascular conditions, like heart disease, high blood pressure, and stroke.
- Lower risk of memory loss and dementia: Emerging research suggests that GLP-1 receptor agonists like semaglutide may have neuroprotective effects, potentially reducing the risk of neurodegenerative diseases such as Alzheimer's.
- Longer, healthier life: Early studies indicate that semaglutide may contribute to longevity by mitigating factors like oxidative stress and chronic inflammation, both of which are linked to aging.
Practical Considerations
- Cost: The cost of oral semaglutide may vary depending on dosage and insurance coverage. The manufacturer offers a savings card for eligible patients, which can significantly reduce the cost.
- Consultation with a Healthcare Provider: It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects. If you’re considering semaglutide for weight loss, your first step should be consulting your primary care physician (PCP). They know your personal and family medical history and can guide you in the best treatment for your condition. Working with a healthcare professional, like a Midi clinician, can help you decide if a personalized GLP-1 prescription is right for you and which one may be best for your goals, preferences, and health history.