Many of today’s most powerful weight loss medications were initially intended to help people with type 2 diabetes control their blood sugar levels. Ozempic is a good example. It’s an injectable medication that provides the drug semaglutide.
The FDA approved Ozempic’s use as an antidiabetic medication in December 2017. It quickly became apparent that weight loss was a common side effect so doctors also began prescribing Ozempic as a weight loss jab.
Four and a half years later, in June 2021, the FDA approved Wegovy. As with Ozempic, semaglutide is the active ingredient. The only difference between Wegovy and Ozempic is the strength. Wegovy provides semaglutide in a higher dose. It’s presently one of the most popular weight loss medications in the USA.
Semaglutide Summary
Semaglutide, a GLP-1 receptor agonist, has gained widespread recognition for its efficacy in weight management, particularly for individuals with type 2 diabetes. Its ability to mimic the incretin hormones enhances insulin secretion, suppresses appetite, and leads to substantial weight loss. Despite its effectiveness, semaglutide has faced scrutiny in the press due to potential side effects, such as gastrointestinal disturbances, and its relatively high cost, which can be prohibitive for many patients. Additionally, some reports have highlighted a “rebound” effect, where patients may regain weight after discontinuing the medication. These factors have contributed to a growing market for natural over-the-counter alternatives that offer a more accessible and potentially gentler approach to weight management without the need for prescription medication, appealing to those seeking sustainable weight loss solutions.
In the forthcoming sections, we will explore the nuances of semaglutide’s application in weight loss, examining clinical trials, patient outcomes, safety profiles, and the implications of its use as a weight loss tool.
Discovery and Development of Semaglutide
The story of semaglutide’s development says much about the relentless pursuit of innovation in pharmacotherapy. Its story begins with the understanding of the incretin effect and the hormones that orchestrate this physiological phenomenon.
Incretins, particularly glucagon-like peptide-1 (GLP-1), are hormones produced in the gut. They amplify insulin release after meals, playing a key role in glucose homeostasis and blood sugar regulation. However, natural GLP-1 has a short half-life, being rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).
The Incretin Effect and Its Potential
The recognition of GLP-1’s significant but transient effect on insulin secretion sparked interest in harnessing its therapeutic potential. Scientists sought to develop a GLP-1 analog that could resist enzymatic degradation and remain active in the body for longer. This quest led to the first generation of GLP-1 receptor agonists, which demonstrated promising results in managing type 2 diabetes.
Semaglutide’s Unique Molecular Design
Building on this progress, researchers at the European pharmaceutical company Novo Nordisk began working on a GLP-1 receptor agonist capable of binding more strongly with GLP-1 receptors and resisting DPP-4 degradation. Semaglutide is the result.
To make Semaglutide bind more strongly and avoid being degraded, the researchers made a critical alteration to the synthetic hormone’s structure by substitution of amino acids and the addition of a fatty acid chain, which allows the drug to bind albumin in the bloodstream.
This binding prolongs the drug’s half-life, enabling once-weekly dosing—a significant improvement in terms of patient compliance and quality of life compared to earlier treatments requiring daily injections.
Clinical Trials and FDA Approval
Extensive clinical trials, including the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) series, evaluated the efficacy and safety of semaglutide in controlling blood glucose levels in patients with type 2 diabetes. These trials consistently demonstrated that semaglutide was effective in reducing hemoglobin A1c levels, with the added benefit of weight reduction.
The promising results of these trials led to the approval of semaglutide by the Food and Drug Administration (FDA) and other regulatory agencies worldwide for the treatment of type 2 diabetes. The approval marked a significant milestone, offering a new therapeutic option for patients and providing endocrinologists with a powerful tool to tackle the disease.
The Shift of Semaglutide Towards Weight Management
The weight loss observed in diabetic patients treated with semaglutide was compelling enough to investigate its potential as a standalone treatment for obesity. Subsequent trials were specifically designed to assess the effect of semaglutide on body weight in non-diabetic people. These studies revealed that semaglutide, through mechanisms such as appetite suppression and possibly other central pathways, could induce substantial weight loss.
With this evidence, semaglutide entered a new phase of development, switching from a diabetes medication to lower blood sugar to a dual-purpose drug that also addresses the needs of those struggling with obesity. This repurposing has not only expanded the therapeutic scope of semaglutide but also underscored the interconnected nature of metabolic diseases, bridging the gap between diabetes management and weight control.
Mechanism of Action – How Semaglutide Works for Weight Loss
Semaglutide operates in a complex way, harnessing the body’s regulatory systems to exert its therapeutic effects, influencing hunger levels, insulin secretion, and satiety.
GLP-1 Receptor Agonism
At its most basic, semaglutide is a drug that functions as a synthetic version of the hormone GLP-1.
Hormones are chemical messengers that need to bind with specific receptors to relay their signals.
GLP-1 receptors are present throughout the body. They are in the pancreas, gastrointestinal tract, central nervous system, and cardiovascular system. When semaglutide binds to these receptors, it triggers a cascade of metabolic effects that lower blood glucose levels and regulate appetite.
Insulin Secretion and Glucose Regulation
When semaglutide binds with GLP-1 receptors in the pancreas, it stimulates the beta cells causing them to release insulin in response to the blood glucose increases that occur after meals. This insulin release is glucose-dependent, which means that it occurs only when blood sugar levels become higher, reducing the risk of hypoglycemia (low blood sugar). Hypoglycemia is a common concern among those using certain diabetes medications.
Simultaneously, semaglutide suppresses the secretion of glucagon, a hormone that would otherwise signal the liver to release stored glucose into the bloodstream. By preventing the release of glucagon, the drug further supports healthy blood sugar levels.
Semaglutide Appetite Suppression and Satiety Enhancement
In addition to stimulating the pancreas and liver, semaglutide binds with receptors in the hypothalamus. This area of the brain is responsible for regulating appetite and food intake.
By acting on these receptors, semaglutide reduces hunger signals and increases feelings of fullness in the stomach. This neuroendocrine effect reduces the motivation to eat, helping to lower daily calorie intake. However, as with all weight management drugs, semaglutide users need to follow an appropriate diet and exercise program.
Semaglutide also slows down gastric emptying, causing food to remain in the stomach for longer after meals. Gastric emptying is the process by which food passes from the stomach into the small intestine. By delaying this process, the drug helps prevent post-eating blood sugar spikes and prolongs satiety.
Daily Calorie Intake and Weight Loss
The cumulative effect of increases in insulin secretion, lower glucagon levels, appetite suppression, and slower gastric emptying is a powerful combination that can support significant reductions in daily energy intake. When it obtains fewer calories than it expends, the body has to burn its stores of fat for energy instead, resulting in weight loss.
Data from clinical trials shows that participants using semaglutide, as part of a comprehensive weight management program that includes diet and exercise, can experience significant reduction in body weight. The degree of weight loss varies from person to person but is notably greater than that observed with lifestyle modifications alone or with many alternative weight loss drugs.
Semaglutide Clinical Trials and Efficacy
Semaglutide’s value as a weight loss drug has been rigorously assessed through a series of key clinical trials. Collectively, these studies highlight the drug’s effectiveness in reducing body weight by comparing its performance to placebos and other weight loss drugs.
Moving forward, let’s take a look at some of the most important clinical trials conducted so far.
Semaglutide Weight Management Trials (STEP Program)
The Semaglutide Treatment Effect in People with Obesity (STEP) program consists of a range of clinical trials designed to evaluate the efficacy and safety of semaglutide in people with obesity and those who are overweight and have weight-related health issues.
STEP 1: Semaglutide vs. Placebo
The STEP 1 trial is a cornerstone study that compared the way non-diabetic adults responded to semaglutide in comparison with a placebo. Over 68 weeks, participants receiving semaglutide achieved a mean weight reduction of 14.9%. This was significantly greater than the 2.4% losses seen in the placebo group. Data from this trial established semaglutide as a highly effective weight loss medication.
STEP 2: Semaglutide in Type 2 Diabetes Patients
STEP 2 focused on patients with type 2 diabetes, comparing semaglutide with placebo. Although glycemic control was a primary endpoint, significant weight loss was also observed. Patients using semaglutide experienced an average weight loss of 9.6%, compared to 3.4% in the placebo group, while also achieving better blood sugar control.
STEP 3: Intensive Behavioral Therapy and Semaglutide
STEP 3 combined semaglutide with intensive behavioral therapy. Participants in the semaglutide group lost an average of 16% of their baseline body weight, a remarkable outcome that underscores the benefits that are possible when using pharmaceutical drugs alongside appropriate lifestyle changes.
STEP 4: Sustained Weight Loss
STEP 4 examined the long-term efficacy of semaglutide after a 20-week run-in period. Participants who continued with semaglutide maintained their weight loss over an additional 48 weeks, while those who switched to placebo regained weight, demonstrating semaglutide’s role in weight maintenance.
Comparisons with Other Weight Loss Drugs
Comparative trials, comparing semaglutide to alternative weight loss drugs, show equally good results. In a head-to-head trial comparing semaglutide with liraglutide (another GLP-1 receptor agonist), semaglutide came out on top, with patients experiencing significantly greater weight loss.
The collective evidence from these trials shows that semaglutide can be very effective for weight loss. Its ability to induce double-digit percentage weight reduction in a substantial number of participants positions it as one of the most potent weight loss drugs presently available.
New Weight Loss Drugs With Semaglutide
CagriSema, a brand name for the combination of cagrilintide and semaglutide, brings together cagrilintide—a dual amylin and calcitonin receptor agonist—and semaglutide, a GLP-1 receptor agonist. Administered through a weekly injection, CagriSema is currently under investigation for its potential treatment benefits in type 2 diabetes and obesity.
Semaglutide Dosage and Administration
Semaglutide treatment typically begins with a low dose to reduce the risk and severity of gastrointestinal side effects. When using semaglutide for weight loss, the initial dosage is 0.25 mg once weekly. The dose gradually increases over several months.
During weeks 5-8 of the treatment, 0.5 mg per week is a common dose. The dose then increases every four weeks until patients reach the standard maintenance dose of 2.4 mg per week.
Semaglutide is administered via subcutaneous injection. It can be injected into the abdomen, thigh, or upper arm. It’s best to rotate the injection site. Doing so reduces the risk of skin irritations and bruising.
The injections are given once a week, on the same day each week, which can be with or without meals. The flexibility of the dosing schedule helps to improve the patient’s adherence to treatment.
The Importance of Professional Guidance
The need for professional guidance in the administration of semaglutide cannot be overstated. A healthcare provider should:
- Instruct patients on correct injection techniques to ensure the full efficacy of the medication and to minimize side effects or complications.
- Monitor patients closely during the dose escalation period to manage any adverse effects and to determine the optimal therapeutic dose.
- Advise on lifestyle modifications, including diet and exercise, that should accompany semaglutide treatment for weight loss.
- Evaluate the patient’s overall health status, contraindications, and potential drug interactions.
- Monitor the patient’s response to the medication, including changes in body weight, glycemic control (for those with type 2 diabetes), and other relevant health indicators.
- Adjust the dose of semaglutide or other concurrent medications where necessary based on the patient’s progress and any side effects.
Semaglutide patients should also be encouraged to stick to the prescribed dosing schedule and usage guidelines. A late or missed dose may result in poor results and/or increase the risk of adverse effects.
Semaglutide Side Effects and Health Risks
Like all the medicines healthcare professionals prescribe, semaglutide may cause side effects. The range and severity of side effects can vary from one semaglutide user to the next.
Although some of the potential side effects are mild, others may be severe or even life-threatening.
Common Side Effects
The most frequently reported side effects of semaglutide are gastrointestinal.
Common side effects may include:
- Nausea
- Vomiting
- Diarrhea
- Abdominal pain
- Constipation
Side effects such as these are often most pronounced during the early stages of treatment. They may also resurface each time the dose increases.
Most semaglutide users find these symptoms diminish over time as the body adjusts to the drug.
Other common side effects may include:
- Decreased appetite (obviously)
- Headache
- Fatigue
- Dyspepsia (indigestion)
- Gastroesophageal reflux disease (GERD)
Patients experiencing any of these common side effects should consult with their healthcare provider. There may be strategies to reduce or control the severity.
Rare But Serious Potential Adverse Reactions
Although less common, there are several serious adverse reactions associated with semaglutide. Anyone who experiences them will require immediate medical attention:
- Pancreatitis (inflammation of the pancreas): Symptoms of pancreatitis can include nausea, vomiting, and severe stomach abdominal pain that may radiate to the back. Pancreatitis can be life-threatening if left untreated.
- Thyroid cancer: The animals in early clinical trials involving GLP-1 receptor agonists succumbed to thyroid tumors. For this reason, medications that contain them have to be distributed with appropriate warnings. Recent data suggests drugs of this type may increase the risk of all thyroid cancer and medullary thyroid cancer, in particular after 1–3 years of treatment.
- Gallbladder problems: Reports of gallbladder-related issues, such as cholelithiasis (gallstones) and cholecystitis (inflammation of the gallbladder), have been noted.
- Hypoglycemia: In patients with type 2 diabetes, especially those also taking sulfonylureas or insulin, hypoglycemia (low blood sugar) can occur. Symptoms include dizziness, sweating, confusion, and shakiness.
- Diabetic retinopathy complications: Worsening or new onset of diabetic retinopathy has been observed in patients with type 2 diabetes; therefore, retinal changes need to be monitored.
- Kidney failure or impairment: Acute kidney injury and worsening of chronic renal failure are two more possible semaglutide complications.
- Serious allergic reactions: Symptoms of a severe allergic reaction to semaglutide may include rash, swelling, and trouble breathing.
When to Seek Medical Attention
Semaglutide users who experience an unusual or allergic reaction will need to seek immediate medical attention.
Symptoms to watch out for include:
- Persistent and severe stomach pain
- Symptoms of low blood sugar (hypoglycemia)
- Signs of a serious allergic reaction, such as trouble swallowing or difficulty breathing
- Unusual pain or discomfort in the abdomen that may indicate gallbladder problems
- Blurred vision, eye pain, or other symptoms that may indicate retinal complications
It’s important that all semaglutide users monitor for these symptoms and understand the importance of timely medical intervention if they occur.
How Semaglutide Compares to Other Weight Loss Drugs
Semaglutide isn’t the only the drug that can support weight loss by acting as a synthetic form of GLP-1. Several other prescription drugs do the same thing but semaglutide tends to get most of the attention.
Semaglutide vs. Alternative GLP-1 Receptor Agonists
- Liraglutide: Another GLP-1 receptor agonist, liraglutide (brand name Saxenda), also has FDA approval for weight loss. Although both drugs work similarly, semaglutide has a longer half-life, which allows for once-weekly dosing. Liraglutide has a much shorter half-life and requires daily administration. As far as efficacy goes, clinical trials show that semaglutide helps people to lose weight more efficiently.
- Exenatide: Available under the brand names Byetta and Bydureon, exenatide is another GLP-1 receptor agonist. Bydureon is the extended-release form that, like semaglutide, it’s an injectable prescription medicine that’s administered once weekly. However, clinical data shows that semaglutide has superior efficacy.
- Tirzepatide: Like semaglutide, tirzepatide is an injectable drug that’s primarily used to treat diabetes. It has FDA approval for use in this role under the Mounharo brand name. Due to its influence on appetite and body weight, doctors often use Mounjaro to treat their overweight and obese patients. Although semaglutide is solely a GLP-1 receptor agonist, tirzepatide is unique in that it is a dual GIP/GLP-1 receptor agonist that activates both the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. This dual action may provide additional benefits in lowering blood sugar and promoting weight loss. Data from clinical trials suggests tirzepatide is better at controlling blood sugar levels and body weight than standard GLP-1 receptor agonists like semaglutide.
Semaglutide vs. Phentermine
Phentermine is one of the most commonly prescribed weight loss medications. It’s a dill that works by suppressing appetite. As with similar oral medications, people who use phentermine need to take it daily.
Phentermine is a form of amphetamine and, as with all amphetamine drugs, it poses a threat of dependency and addiction. Because of this, doctors often only prescribe it for a few weeks. The maximum prescription period is 12 weeks. Many patients do not have access to it for that long.
Phentermine usage can result in significant weight loss but presents a risk of high blood pressure and cardiovascular strain. Semaglutide is a better option for long-term use but has a monthly usage cost that is $1000 (Ozempic) to £1300 (Wegovy) more than phentermine tablets, which cost less than $20 per month.
Semaglutide vs. Orlistat
Orlistat is available as a prescription diet pill under the Xenical brand name. The manufacturer also distributes a lower-strength over-the-counter version called Alli.
Orlistat is a lipase inhibitor that reduces the absorption of dietary fat. Unlike semaglutide, which affects appetite and insulin secretion, orlistat works directly in the gastrointestinal tract.
Although orlistat can be effective for weight loss and is taken orally, it often results in gastrointestinal side effects such as oily stools, flatulence, and frequent bowel movements. The drug can also cause its users to become deficient in the fat-soluble vitamins A, D, E, and K.
Semaglutide tends to have a more favorable effect on weight loss with a different side effect profile that is predominantly gastrointestinal but does not typically include the same issues caused by orlistat.
Overall Semaglutide Efficacy and Patient Preference
Generally, semaglutide is preferred over other GLP-1 receptor agonists for its greater efficacy in reducing body weight and the convenience of weekly dosing. When compared to traditional diet pills like phentermine and orlistat, semaglutide offers a longer-term weight management solution with a better safety profile for cardiovascular risk and without the dependency potential or unappealing long-term gastrointestinal effects.
However, it’s important to note that individual responses to weight loss drugs can vary. What works well for one patient may not be as effective for another.
Additionally, regardless of the medication in use, lifestyle modifications involving diet and exercise remain a key part of any effective weight management plan.
Safety and Tolerability
Each of these medications has its own safety and tolerability profile that should be considered:
- GLP-1 receptor agonists, including semaglutide, are generally well-tolerated but can cause gastrointestinal side effects and have rare but serious risks associated with pancreatitis and gallbladder disease.
- Phentermine can cause increased heart rate, palpitations, and elevated blood pressure, making it unsuitable for those with cardiovascular disease.
- Orlistat is generally safe but can cause uncomfortable and sometimes socially inconvenient gastrointestinal effects due to its mechanism of action.
Patients should consult with a healthcare provider to determine the most appropriate medication based on their health status, weight loss goals, and concerns about the potential side effects.
Semaglutide Eligibility Considerations
Several factors can influence semaglutide’s availability with a prescription. As with all approved weight loss drugs, the FDA only permits doctors to prescribe Wegovy to people who have a body mass index (BMI) of 30 or higher. They may also be able to prescribe it to people who have a BMI of 27 or higher but only if they also have at least one weight-related condition such as high blood pressure or heart disease.
Because Ozempic has approval as an antidiabetic, these restrictions do not apply so people who are unable to obtain Wegovy may be able to use Ozempic instead.
However, people with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) should not use medications that contain semaglutide or alternative drugs that mimic GLP-1. Nor are they suitable for people with a history of pancreatitis.
Before starting semaglutide, a thorough medical assessment by a health care provider is necessary to ensure its compatibility with existing medical conditions and current medications. This is to prevent potential drug interactions or adverse effects associated with comorbidities.
Pregnant or nursing mothers are typically advised not to use semaglutide, as its effects on the fetus or infant are not well studied.
Ultimately, the decision to prescribe semaglutide should be based on a comprehensive evaluation of the potential benefits and risks, considering the potential user’s health profile and weight loss goals.
Semaglutide Insurance and Cost Considerations
The cost of semaglutide can be significant. Insurance coverage is a critical factor that can influence access to it. Coverage for semaglutide varies widely between insurance providers and plans, with some covering it for diabetes but not for weight loss, and vice versa.
Potential semaglutide users will need to consult their insurance providers to understand the extent of coverage, copayments, and deductibles.
For those without insurance or adequate coverage, the cost can be prohibitive. Pharmaceutical assistance programs or discount coupons offered by the drug manufacturer may help reduce out-of-pocket expenses but using semaglutide for weight loss can still be a costly experience.
Conclusion
Semaglutide’s efficacy, particularly when compared to other weight loss drugs, offers a promising option for patients struggling with obesity and related health conditions. The convenience of its dosing and its dual benefits for blood sugar control and weight loss make it an attractive choice for suitable candidates.
However, using semaglutide for weight loss can be very expensive. It can also entail health risks that all potential users need to consider before accepting a prescription.
References and Further Reading
- Drug Trial Snapshot: Ozempic: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-ozempic
- FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
- A Quick Guide to the STEP Trials: https://diabetes.medicinematters.com/semaglutide/obesity/quick-guide-step-trials/18854832
- GLP-1 Receptor Agonists and the Risk of Thyroid Cancer: https://diabetesjournals.org/care/article-abstract/46/2/384/147888/GLP-1-Receptor-Agonists-and-the-Risk-of-Thyroid?redirectedFrom=fulltext
