Obesity has become a growing health concern, driving the search for effective treatments, including non-invasive pharmacotherapeutics. Wegovy (semaglutide) has emerged as a prescription medication to aid weight loss and mitigate cardiovascular risks in specific individuals. This article delves into the intricate mechanisms through which Wegovy exerts its effects on weight management and cardiovascular health.
What is Wegovy?
Wegovy is a prescription drug containing the active ingredient semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist. It is administered as a once-weekly subcutaneous injection. Approved by the FDA, Wegovy is indicated for chronic weight management in adults with obesity, defined by a body mass index (BMI) of 30 kg/m² or higher. It is also approved for overweight adults, with a BMI of 27 kg/m² or higher, who have at least one weight-related comorbidity, such as hypertension, type 2 diabetes, or dyslipidemia. Wegovy is also approved for use in pediatric patients aged 12 and older with a BMI corresponding to ≥95th percentile standardized for age and sex.
Mechanism of Action: How Wegovy Works
The way a drug works is known as its mechanism of action. Wegovy’s mechanism of action may vary depending on the condition it’s used to treat.
Mimicking GLP-1 to Regulate Appetite
Wegovy reduces appetite by mimicking the action of a natural hormone called glucagon-like peptide-1 (GLP-1). GLP-1 is an appetite hormone made primarily in your digestive tract that targets areas of the brain to regulate appetite, especially after eating. Semaglutide, which has a 94% homology with endogenous GLP-1, occupies the GLP-1 receptor in the brain that regulates appetite.
Specifically, Wegovy helps reduce appetite and food intake by mimicking the activity of GLP-1, a natural hormone in the body that works in the brain to regulate appetite. It stimulates meal-dependent insulin secretion by the pancreatic beta cells, decreases the secretion of glucagon, a hormone that raises blood sugar, decreases gastric emptying, and reduces food intake by creating a sensation of stomach fullness. These effects can help with weight loss.
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Slowing Gastric Emptying
Wegovy also slows the movement of food from your stomach to your intestines, which can help you feel full for longer. You will lose weight with Wegovy because you will typically eat less and feel fuller when you do eat.
Reducing Cardiovascular Risks
While it’s not known for certain how Wegovy works to lower cardiovascular (heart and blood vessel) risks, a couple of factors are thought to contribute. Wegovy reduces blood sugar levels by increasing insulin levels and blocking a chemical involved in glucose production. This can lower your risk of cardiovascular problems, such as heart attack, stroke, and cardiovascular death (death due to heart problems). If your weight and blood sugar levels are high, weight loss and blood sugar management can help lower your risk of serious cardiovascular problems.
Clinical Trial Evidence: SUSTAIN, PIONEER, and STEP Programs
The efficacy of semaglutide has been demonstrated through several clinical trial programs, including SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity).
SUSTAIN
The SUSTAIN clinical trial program investigated the safety and efficacy of subcutaneous semaglutide in patients with type 2 diabetes. Throughout the 10 studies reviewed, semaglutide was found to be superior at reducing hemoglobin A1c (HA1c) and reducing participants’ body weight when compared with placebo and with multiple antidiabetic medications, including insulin glargine, sitagliptin, exenatide extended release (ER), dulaglutide, canagliflozin, and liraglutide. Crucial to the present argument regarding semaglutide’s place as a weight loss medication, the SUSTAIN 10 trial showed that semaglutide also held superiority over liraglutide, which is currently marketed for weight loss as Saxenda, in overall weight loss, the number of participants achieving weight loss of ≥5%, and the number of participants achieving weight loss of ≥10%.
PIONEER
The PIONEER clinical trial program focused on obtaining data on glycemic control and weight loss in patients with type 2 diabetes while being treated with oral semaglutide versus comparators. It was repeatedly demonstrated throughout the PIONEER clinical trials that the decrease in both HA1c and body weight was significantly greater with oral semaglutide when compared with a placebo. The superiority of oral semaglutide was also observed when compared with other oral antidiabetic medications, such as sitagliptin and empagliflozin. This superiority was also found in studies comparing oral semaglutide with other agents from the same drug class (dulaglutide and liraglutide). Other successes, such as decreasing waist circumference and BMI of patients, were also observed. Regarding safety, oral semaglutide was reported as being non-inferior to treatment with placebo at lowering incidences of major adverse cardiovascular events.
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STEP
The STEP program is a phase III clinical trial program focused on the approval of semaglutide as a weight loss medication in patients with obesity. The experimental dose given during the trial was 2.4 mg, delivered subcutaneously once a week. The results from STEP 1 through 4 showed that semaglutide is superior at weight reduction when compared with placebo. STEP 2 compared 2.4 mg semaglutide with 1.0 mg semaglutide and found 2.4 mg semaglutide to cause more significant weight loss than 1.0 mg semaglutide. STEP 4 investigated the discontinuation of semaglutide treatment and found that those who were started on placebo after 20 weeks of treatment with the experimental dose of semaglutide experienced weight gain of around 6 kg. The safety profile of 2.4 mg semaglutide was found to be similar to 1.0 mg subcutaneous semaglutide and oral semaglutide, with mild to moderate GI symptoms being the predominating complaint among participants.
Oral vs. Subcutaneous Semaglutide
In the PIONEER trial, it was found that a 14 mg dose of oral semaglutide produced a significant weight loss of 2.3 kg, while 0.5 mg and 1.0 mg of subcutaneous semaglutide were associated with 3.73 kg and 4.53 kg reduction, respectively. Similarly, compared with sitagliptin, both oral semaglutide and subcutaneous semaglutide showed superiority in bodyweight reduction; however, in an indirect comparison of the results, we found that subcutaneous semaglutide produced even greater bodyweight reduction than oral administration. Both oral semaglutide and subcutaneous semaglutide showed similar adverse effects, and the most commonly reported were gastrointestinal (primarily mild to moderate nausea and vomiting). Treatment discontinuation due to GI events ranged from 4.9% to 12% and from 3% to 9.4% during the PIONEER and the SUSTAIN trials, respectively.
To ensure optimal absorption of oral semaglutide, it should be administered at least 30 minutes before the first consumption of food, beverages, or other medications of the day. The medication should be ingested with no more than 4 ounces (120 mL) of water.
Semaglutide vs. Other Antiobesity Medications
To adequately address the antiobesity potential of semaglutide, it is essential to consider if at least a 5% bodyweight reduction is achieved, which is regarded as a clinically significant weight loss parameter. A meta-analysis of 28 randomized, placebo-controlled clinical trials found that all four antiobesity medications met the FDA weight loss threshold of at least 5%. The PIONEER, SUSTAIN, and STEP clinical trials have shown similar weight loss effects in participants on semaglutide. In the primary placebo-controlled trial from the PIONEER program and SUSTAIN 1, around 40% of participants on semaglutide achieved a weight loss of 5% or more. The first STEP trial did include lifestyle modifications as part of their experimental requirements and found that 86.5% of participants on semaglutide achieved a weight loss of at least 5%.
As previously stated, the most commonly reported adverse effects of semaglutide during the SUSTAIN clinical trial were GI side effects, including nausea and vomiting. Patients taking semaglutide experienced these side effects more frequently than comparators (in the SUSTAIN, PIONEER, and STEP trials), but most episodes were transient. Higher nausea and vomiting rates were experienced at higher doses of semaglutide and lower baseline BMI.
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Administration and Dosage
Wegovy (semaglutide) is a once-weekly subcutaneous (under the skin) glucagon-like peptide-1 (GLP-1) receptor injection. The injection formulations should be administered subcutaneously into the abdomen, thigh, or upper arm. Patients should be advised to rotate injection sites within the same body region (eg, upper arm) to avoid injecting in the same spot each week. Although insulin and semaglutide injections may be administered in the same body region, patients should be cautioned against using the same injection site.
The recommended approach for weight management includes the integration of semaglutide with a balanced diet and regular exercise.
For individuals who are semaglutide-naive, the recommended starting dose is 3 mg daily for 30 days, followed by an increase to 7 mg daily. After 30 days on the 7 mg dose, patients may consider escalating to 14 mg daily to achieve their glycemic goals.
If a dose of weekly subcutaneous semaglutide is missed, it should be administered promptly within 5 days, and then the regular schedule should be resumed. If a dose of oral semaglutide is missed, the individual should skip the missed dose and resume with the next scheduled dose.
If the 2.4 mg weekly dosage is not well tolerated, healthcare providers may consider reducing the dose to 1.7 mg weekly for a maximum of 4 weeks. After this period, the dosage should be increased to 2.4 mg weekly. If the patient continues to experience intolerance, discontinuing semaglutide (Wegovy®) should be considered.
If a dose is missed and the next scheduled dose is more than 2 days away (48 hours), it should be administered as soon as possible. However, if a dose is missed and the next scheduled dose is less than 2 days away (48 hours), it should not be administered. In such cases, the patient should resume dosing on the regularly scheduled day of the week. If 2 or more consecutive doses are missed, the patient should resume dosing as scheduled.
Important Considerations
Potential Side Effects
As with any medication, Wegovy carries the risk of potential side effects. The most commonly reported adverse effects of semaglutide are gastrointestinal (GI) side effects, including nausea and vomiting. Patients taking semaglutide experienced these side effects more frequently than comparators, but most episodes were transient. Higher nausea and vomiting rates were experienced at higher doses of semaglutide and lower baseline BMI.
More serious adverse effects include pancreatitis and medullary thyroid carcinoma, although thyroid cancers have not been reported in human trials. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, Wegovy® and medicines that work like Wegovy® caused thyroid tumors, including thyroid cancer.
Wegovy may cause gallbladder problems, including gallstones. Some gallstones may need surgery.
Wegovy® can increase your heart rate while you are at rest.
GLP-1 agonists lower blood glucose and may cause hypoglycemia. Increased risk of low blood sugar (hypoglycemia), especially those who also take medicines for diabetes such as insulin or sulfonylureas. This can be a serious side effect. Talk to your healthcare provider about how to recognize and treat low blood sugar and check your blood sugar before you start and while you take Wegovy®.
Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse.
Stomach problems, sometimes severe, have been reported in people who use Wegovy®.
You should pay attention to any mental changes, especially sudden changes in your mood, behaviors, thoughts, or feelings.
Wegovy® may increase the chance of food getting into your lungs during surgery or other procedures.
Contraindications
Wegovy is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).
Use in Specific Populations
Current clinical trial data and pharmacovigilance reports on semaglutide use in pregnant women are insufficient to ascertain its association with significant congenital defects, miscarriage, or adverse outcomes for both the mother and the fetus. However, findings from animal reproduction studies indicate potential risks to the fetus with semaglutide exposure during pregnancy. In addition, the weight loss effects of semaglutide are not deemed beneficial for pregnant individuals and may pose a risk of harm to the fetus. As a result, the manufacturer recommends against the use of semaglutide during pregnancy due to the potential fetal risks. For the management of diabetes mellitus or weight loss, discontinuation of semaglutide is advised for a minimum of 2 months before attempting to conceive.
Insufficient data exist regarding semaglutide or its metabolites in human milk and the potential effects on breastfed infants and milk production. Semaglutide was identified in milk at levels 3 to 12 times lower than in maternal plasma in lactating rats. Although information on the impact of semaglutide in human milk is unavailable, it may be present in human milk if present in animal milk. The decision to use injectable semaglutide while breastfeeding should carefully consider the potential risk of infant exposure versus the benefits of breastfeeding.
The safety and efficacy of subcutaneous semaglutide (Ozempic®) and oral semaglutide (Rybelsus®) have not been established in individuals aged 18 or younger. However, Wegovy®, specifically indicated for weight loss, is approved for use in pediatric patients aged 12 and older with a BMI corresponding to ≥95th percentile standardized for age and sex.
No dosage adjustment is necessary for subcutaneous or oral semaglutide in mild-to-severe impairment. Caution should be exercised when initiating or escalating doses.
The manufacturer advises against adjusting the dosage of subcutaneous and oral Semaglutide for patients undergoing three or more weekly hemodialysis sessions. However, due to limited clinical evidence, caution is advised. Furthermore, the manufacturer recommends against adjusting the subcutaneous and oral semaglutide dosage for patients undergoing peritoneal dialysis.
Drug Interactions
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Wegovy® may affect the way some medicines work and some medicines may affect the way Wegovy® works. Tell your healthcare provider if you are taking other medicines to treat diabetes, including sulfonylureas or insulin.
Compounded Semaglutide
The FDA issued a postmarket drug safety alert regarding the prevalence of compounded and counterfeit preparations of semaglutide. The healthcare team should advise patients that they "should only obtain drugs containing semaglutide with a prescription from a licensed health care provider, and obtain medicines only from state-licensed pharmacies or outsourcing facilities registered with FDA."