The quest for effective and safe weight loss treatments is ongoing. Obesity, defined as excessive fat accumulation, has tripled worldwide since 1975 and is a chronic relapsing condition. It is associated with serious clinical complications such as diabetes mellitus, cardiovascular disease, musculoskeletal disorders, and malignancy.
Introduction to Semaglutide
Semaglutide belongs to a class of medications known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It mimics the GLP-1 hormone, which is released in the gut in response to eating. One role of GLP-1 is to prompt the body to produce more insulin, which reduces blood sugar (glucose). For that reason, health care providers have used semaglutide for more than 15 years to treat Type 2 diabetes. The injectable drug, initially used only as diabetes medication, is the first drug since Saxenda (2014) approved to treat chronic weight management in the 70% of American adults who are obese or overweight.
How Semaglutide Works
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.
In higher amounts, GLP-1 also interacts with the parts of the brain that suppress your appetite and signal you to feel full. When used in conjunction with diet and exercise, it can cause significant weight loss - and a reduced risk of cancer, diabetes, and heart disease - in people who are obese or overweight.
Semaglutide Brands and Administration
Currently, semaglutide is only approved for weight loss under the brand name Wegovy. The typical dose for weight loss is 2.4 milligrams, administered weekly as subcutaneous (under the skin) self-injections. Semaglutide is injected subcutaneously without regard to meals. Administration sites include the abdomen, thigh, and upper arm.
Read also: Transformations with Ozempic
As interest in semaglutide for weight loss continues to grow, health care professionals are finding ways to manage the demand. Many prescribe other brands of semaglutide, such as Ozempic and Rybelsus, off-label (using a drug that is FDA-approved for a different reason).
Efficacy of Semaglutide for Weight Loss in Non-Diabetics
There have been several anti-obesity medications that help suppress appetite and achieve weight loss. But semaglutide performs on a new level. An early study of 2,000 obese adults compared people using semaglutide plus a diet and exercise program with people who made the same lifestyle changes without semaglutide. After 68 weeks, half of the participants using semaglutide lost 15% of their body weight, and nearly a third lost 20%. Participants who incorporated only lifestyle changes lost about 2.4% of their weight. Since then, additional studies have shown similar results. But they’ve also revealed that participants tend to regain the weight lost when they stop taking semaglutide.
A meta-analysis of randomized controlled trials (RCT) of subcutaneous semaglutide on patients who are obese without T2DM aimed to determine the percent weight reduction from baseline after treatment with semaglutide. 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].
Another outcome of this review is the risk for gastrointestinal adverse events (typically nausea, vomiting, diarrhea, constipation). The review showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide treatment (RR 1.59, 95%CI [1.34, 1.88], p< 0.00001, I2 81%). However, between-trial heterogeneity was high I2 81%, which prompted a sensitivity analysis that decreased the heterogeneity to 68%. The major source of heterogeneity was with the dose of semaglutide.
Who Should (and Should Not) Take Semaglutide for Weight Loss?
The FDA recommends Wegovy for weight loss if you meet one of the following criteria:
Read also: Comprehensive guide: Tirzepatide and Semaglutide for weight management
- Have a body mass index (BMI) of 27kg/m2 or greater and at least one weight-related condition, such as high blood pressure, Type 2 diabetes, or high cholesterol
- Have a BMI of 30kg/m2 or greater
Avoid semaglutide if you have:
- History of medullary thyroid cancer
- History of gallbladder disease
- History of pancreatitis
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
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.
Side Effects of Semaglutide Injections
The side effects of semaglutide are typically mild - especially when compared to the complications associated with overweight and obesity. People taking semaglutide for weight loss may experience:
- Dizziness
- Fatigue
- Gastrointestinal issues, such as diarrhea, constipation, and gassiness
- Headache
- Stomach issues, including nausea, vomiting, pain, or distension (bloat)
Gastrointestinal issues are the most common complaint among people just starting semaglutide. But you may be able to reduce the side effects by beginning on a lower dose and then slowly increasing the amount you take.
Consolidating the trials showed nausea, vomiting, constipation and diarrhea to be the most common adverse events. The trials have reported that these were of mild to moderate severity and short duration that resolved without treatment. Moreover, adverse events leading to discontinuation and serious adverse events were uncommon.
Read also: Semaglutide Without Diet Changes
Important Precautions and Monitoring
It is crucial for your doctor to check your progress at regular visits to ensure that semaglutide is working properly. Blood and urine tests may be needed to check for unwanted effects.
Pregnancy: Tell your doctor if you are pregnant or planning to become pregnant. Do not use this medicine for at least 2 months before you plan to become pregnant.
Alcohol: Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team.
Other Medicines: Do not take other medicines during the time you are using semaglutide unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
This medicine may increase the risk of having thyroid tumors. Tell your doctor right away if you have a lump or swelling in your neck or throat, trouble swallowing or breathing, or if your voice gets hoarse.
Pancreatitis (swelling of the pancreas) may occur while you are using this medicine. Check with your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.
Check with your doctor right away if you have gaseous stomach pain, indigestion, recurrent fever, severe nausea or vomiting, stomach fullness, or yellow eyes or skin. These may be symptoms of gallbladder problems (e.g., cholelithiasis, cholecystitis).
This medicine may cause diabetic retinopathy. Check with your doctor if you have blurred vision or any other changes in vision.
This medicine does not cause hypoglycemia (low blood sugar). However, low blood sugar can occur when you use semaglutide with other medicines, including insulin or sulfonylureas, that can lower blood sugar. Low blood sugar also can occur if you delay or miss a meal or snack, exercise more than usual, drink alcohol, or cannot eat because of nausea or vomiting.
This medicine may cause serious allergic reactions, including anaphylaxis and angioedema, which can be life-threatening and require immediate medical attention. Check with your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, mouth, or throat while you are using this medicine.
Check with your doctor right away if you have bloody urine, decreased amount of urine, increased blood pressure, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, trouble breathing, weight gain, or vomiting. These may be symptoms of dehydration which can lead to serious kidney problem.
This medicine may cause severe stomach or bowel problems. Check with your doctor right away if you have belching, bloated or full feeling, blood in stools, constipation, diarrhea, excess air or gas in the stomach, hiccups, nausea, stomach pain, uncomfortable swelling around the anus, or vomiting.
This medicine may increase your heart rate while you are at rest. Check with your doctor right away if you have fast or pounding heart beat.
Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your antidiabetic medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual.
This medicine may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Also tell your doctor if you have sudden or strong feelings, including feeling nervous, angry, restless, violent, or scared.
The SELECT Trial: Semaglutide's Impact on Cardiovascular Health and Weight Loss
The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) studied patients with established CVD and overweight or obesity but without diabetes.
In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events.
The Role of Lifestyle Changes
The fundamentals of obesity management will always be changes to diet and exercise. But having anti-obesity medications is another tool in the toolbox - depending on the person’s clinical history. 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.
GLP-1s can help you lose weight, but they aren’t a magic fix. There is a potential to regain the lost weight, but those chances decrease when you work with a healthcare provider to transition off the medication safely. All the clinical trials that showed these medications working also included education on eating and exercise.
The Future of Obesity Treatment
With fervent consumer demand for weight loss medications, combined with rising obesity rates, more medications are bound for the market in the coming years. Pharmaceutical platform Ozmosi predicts one to two GLP-1 launches annually starting in 2026. Lilly is developing at least two new options. The first, orforglipron, is an oral GLP-1 inhibitor that completed a Phase 3 clinical trial in early 2025. It could provide a welcome alternative for people who do not want injections. The other, retatrutide, targets GLP-1, GIP, and glucagon. At this writing, it is in Phase 3 clinical trials. In Phase 2, participants lost up to 24.2% of body weight at 48 weeks.
Compounded Semaglutide
FDA is aware that some patients and health care professionals may look to unapproved versions of GLP-1 (glucagon-like peptide-1 (GLP-1) receptor agonists) drugs, including semaglutide and tirzepatide, as an option for weight loss. This can be risky for patients, as unapproved versions do not undergo FDA’s review for safety, effectiveness and quality before they are marketed.
Compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug. Patients should obtain a prescription from their doctor and fill the prescription at a state-licensed pharmacy.
FDA has received multiple reports of adverse events, some requiring hospitalization, that may be related to dosing errors associated with compounded injectable semaglutide products. These dosing errors resulted from patients measuring and self-administering incorrect doses of the drug, and in some cases, health care professionals miscalculating doses of the drug.
The agency is aware that some semaglutide products sold by compounders may be the salt forms. These salt forms, including semaglutide sodium and semaglutide acetate, are different active ingredients than are used in the approved drugs. The agency does not have information on whether these salts have the same chemical and pharmacologic properties as the active ingredient in the approved drug, and we are not aware of any lawful basis for their use in compounding.