Semaglutide: The FDA-Approved GLP-1 Revolution

What Is Semaglutide?

Semaglutide represents one of the most significant pharmaceutical breakthroughs in metabolic medicine of the past decade. As a glucagon-like peptide-1 (GLP-1) receptor agonist, it mimics the action of the naturally occurring hormone GLP-1, which plays crucial roles in glucose metabolism, appetite regulation, and energy homeostasis. What distinguishes semaglutide from earlier GLP-1 agonists is its extended half-life of approximately one week, achieved through strategic molecular modifications that protect it from enzymatic degradation.

The peptide consists of 31 amino acids with 94% structural homology to native human GLP-1. However, three key modifications transform it from a hormone with a half-life of minutes into a long-acting therapeutic agent: substitution of alanine with aminoisobutyric acid at position 8 (protecting against DPP-4 degradation), attachment of a C-18 fatty acid chain via a spacer to lysine at position 26 (enabling albumin binding), and substitution of lysine with arginine at position 34. These modifications allow for once-weekly subcutaneous administration, dramatically improving patient compliance compared to daily or twice-daily alternatives.

Semaglutide's clinical impact has been transformative. In the STEP (Semaglutide Treatment Effect in People with obesity) clinical trial program, participants achieved average weight loss of 15-17% of body weight over 68 weeks—results previously achievable only through bariatric surgery. The SUSTAIN trials demonstrated robust glycemic control in type 2 diabetes, with HbA1c reductions of 1.5-1.8%. Perhaps most remarkably, the SELECT cardiovascular outcomes trial showed a 20% reduction in major adverse cardiovascular events in people with established cardiovascular disease, establishing semaglutide as more than just a metabolic medication.

The mechanism underlying these effects involves multiple physiological pathways. Semaglutide activates GLP-1 receptors throughout the body, but its effects on appetite and satiety appear to be primarily mediated through receptors in the hypothalamus and brainstem. It slows gastric emptying, reducing the rate at which nutrients enter circulation. It enhances glucose-dependent insulin secretion from pancreatic beta cells while suppressing inappropriate glucagon release from alpha cells. These combined effects create a powerful metabolic shift toward improved glucose control and reduced caloric intake.

The commercial success of semaglutide has been unprecedented in pharmaceutical history. Marketed as Ozempic for type 2 diabetes and Wegovy for chronic weight management, it generated over $13 billion in sales in 2023, with demand far exceeding supply. This success has spawned an entire industry of compounded semaglutide products, raising important questions about quality control, appropriate medical supervision, and the distinction between FDA-approved formulations and compounded alternatives. The peptide has also entered popular culture, with widespread discussion of its use by celebrities and the general public for weight management.

Primary Applications

Semaglutide has two FDA-approved indications, each supported by extensive clinical trial data:

Type 2 Diabetes Management (Ozempic)

Approved in 2017, semaglutide for diabetes provides superior glycemic control compared to most other diabetes medications. The SUSTAIN clinical trial program enrolled over 8,000 participants and demonstrated consistent HbA1c reductions of 1.5-1.8% across diverse populations. Importantly, semaglutide's glucose-lowering effects are glucose-dependent, meaning it stimulates insulin secretion only when blood glucose is elevated, substantially reducing hypoglycemia risk compared to sulfonylureas or insulin.

Beyond glucose control, semaglutide addresses multiple aspects of the type 2 diabetes disease process. It promotes weight loss averaging 4-6 kg in diabetes trials, addressing a key driver of insulin resistance. It reduces systolic blood pressure by 3-5 mmHg through mechanisms that remain incompletely understood but may involve natriuresis and improved endothelial function. The cardiovascular benefits demonstrated in SUSTAIN-6 and SELECT trials have positioned semaglutide as a preferred agent for patients with diabetes and established cardiovascular disease or high cardiovascular risk.

Chronic Weight Management (Wegovy)

Approved in 2021 at a higher dose (2.4 mg weekly), semaglutide for weight management has revolutionized obesity treatment. The STEP trial program enrolled over 4,500 participants with obesity or overweight with weight-related comorbidities. Results were remarkable: average weight loss of 15-17% over 68 weeks, with nearly one-third of participants losing 20% or more of their body weight. These results approach those seen with bariatric surgery, previously considered the gold standard for substantial, sustained weight loss.

The weight loss achieved with semaglutide appears to be primarily fat mass rather than lean mass, though some muscle loss does occur as with any significant weight reduction. Importantly, the weight loss is accompanied by improvements in multiple cardiometabolic risk factors: reductions in waist circumference, improvements in lipid profiles, decreases in inflammatory markers, and improvements in liver fat content in patients with non-alcoholic fatty liver disease. Quality of life measures also improve significantly, including physical functioning, pain, and general health perceptions.

Off-Label and Investigational Uses

Beyond its approved indications, semaglutide is being investigated for several other conditions:

Non-Alcoholic Fatty Liver Disease (NAFLD/NASH)

Phase 2 trials have shown that semaglutide significantly reduces liver fat content and improves markers of liver inflammation and fibrosis in patients with non-alcoholic steatohepatitis (NASH). The mechanism likely involves both direct effects on hepatic metabolism and indirect effects through weight loss and improved insulin sensitivity. Phase 3 trials are ongoing to determine whether semaglutide can prevent progression to cirrhosis or reduce liver-related complications.

Polycystic Ovary Syndrome (PCOS)

Small studies suggest semaglutide may improve metabolic and reproductive outcomes in women with PCOS, particularly those with obesity and insulin resistance. Weight loss achieved with semaglutide can restore ovulatory cycles, improve androgen levels, and enhance fertility. However, semaglutide is contraindicated during pregnancy, requiring careful contraceptive counseling for women of reproductive age.

Cardiovascular Disease Prevention

The SELECT trial's demonstration of cardiovascular benefits in people without diabetes has sparked interest in semaglutide as a primary prevention strategy for cardiovascular disease in people with obesity. This represents a paradigm shift, positioning an obesity medication as a cardiovascular protective agent. Additional trials are exploring whether these benefits extend to other populations and whether they persist long-term.

Addiction and Substance Use Disorders

Emerging preclinical and anecdotal evidence suggests GLP-1 receptor agonists may reduce cravings and consumption of alcohol and other substances. The mechanism may involve GLP-1 receptors in brain reward pathways. Clinical trials are now underway to formally test whether semaglutide can aid in treatment of alcohol use disorder, though this remains highly investigational.

Clinical Evidence Quality

Semaglutide's evidence base is among the most robust of any peptide therapeutic. The development program included over 15,000 participants across multiple large-scale randomized controlled trials. The SUSTAIN program for diabetes included 10 trials comparing semaglutide to placebo, other GLP-1 agonists, and insulin. The STEP program for weight management included 5 major trials examining different populations and treatment durations. The SELECT cardiovascular outcomes trial enrolled over 17,000 participants and followed them for up to 4 years.

These trials were conducted to the highest regulatory standards, with rigorous inclusion/exclusion criteria, standardized outcome measures, independent adjudication of cardiovascular events, and intention-to-treat analyses. The consistency of results across trials, populations, and geographic regions strengthens confidence in the findings. Long-term extension studies have demonstrated sustained benefits for up to 2 years of continuous treatment, though questions remain about what happens after treatment discontinuation.

The main limitation of the evidence base is the relative lack of head-to-head comparisons with other weight loss interventions, particularly bariatric surgery and intensive lifestyle modification programs. Most trials used placebo plus lifestyle modification as the comparator, making it difficult to determine semaglutide's incremental benefit over intensive behavioral interventions. Additionally, the trials enrolled predominantly white populations, with limited representation of certain ethnic groups who may respond differently to GLP-1 agonists.

Dosing and Administration

Semaglutide is available in both injectable and oral formulations, though the injectable form is far more commonly used due to superior bioavailability and efficacy.

Injectable Semaglutide (Ozempic, Wegovy)

Treatment begins with a low dose to minimize gastrointestinal side effects, then gradually escalates over 16-20 weeks to the target maintenance dose. For diabetes (Ozempic), the starting dose is 0.25 mg once weekly for 4 weeks, increasing to 0.5 mg weekly. If additional glycemic control is needed, the dose can be increased to 1 mg weekly after at least 4 weeks, and potentially to 2 mg weekly if tolerated and needed.

For weight management (Wegovy), the escalation schedule is more gradual: 0.25 mg weekly for 4 weeks, 0.5 mg weekly for 4 weeks, 1 mg weekly for 4 weeks, 1.7 mg weekly for 4 weeks, then the maintenance dose of 2.4 mg weekly. This slower titration helps minimize nausea and vomiting, the most common reasons for treatment discontinuation. Injections are administered subcutaneously in the abdomen, thigh, or upper arm, with rotation of injection sites recommended to prevent lipodystrophy.

Oral Semaglutide (Rybelsus)

Oral semaglutide is available only for type 2 diabetes, not weight management. It must be taken on an empty stomach with no more than 4 ounces of water, with no food, drink, or other medications for at least 30 minutes afterward. This strict administration requirement is necessary because semaglutide is a peptide that would normally be degraded in the gastrointestinal tract. The formulation includes an absorption enhancer (SNAC) that facilitates uptake across the gastric mucosa.

Dosing starts at 3 mg daily for 30 days, then increases to 7 mg daily. If additional glycemic control is needed after at least 30 days on 7 mg, the dose can be increased to 14 mg daily. The oral formulation is less effective than injectable semaglutide at equivalent doses, likely due to lower bioavailability (approximately 1% for oral vs. nearly 100% for subcutaneous injection).

Expected Outcomes and Timeline

Response to semaglutide follows a predictable pattern, though individual variation exists:

Weeks 1-4: Initial Adaptation

During the first month at the starting dose, most people experience reduced appetite and earlier satiety. Gastrointestinal side effects (nausea, occasional vomiting) are most common during this period but typically improve with continued use. Weight loss begins but is modest, typically 1-2% of body weight. Glucose levels begin to improve in people with diabetes, though the full effect is not yet apparent.

Weeks 5-16: Dose Escalation

As the dose increases, appetite suppression becomes more pronounced. Weight loss accelerates to approximately 0.5-1% of body weight per week. Some people experience a temporary increase in side effects with each dose increase, but these typically resolve within 1-2 weeks. Energy levels may fluctuate as the body adapts to reduced caloric intake. For diabetes, HbA1c begins to show meaningful improvement.

Weeks 17-68: Maintenance Phase

Once the target dose is reached, weight loss continues but at a gradually slowing rate. Most weight loss occurs in the first 60 weeks, with weight typically stabilizing thereafter. In clinical trials, average weight loss at 68 weeks was 15-17% for the 2.4 mg dose. Glucose control reaches its maximum effect, with HbA1c reductions of 1.5-1.8% in people with diabetes. Cardiovascular risk factors continue to improve throughout this period.

Long-Term Maintenance

Extension studies show that weight loss can be maintained for at least 2 years with continued treatment. However, weight regain typically occurs if semaglutide is discontinued, with most people regaining about two-thirds of lost weight within one year of stopping. This has led to discussions about whether semaglutide represents a chronic treatment for obesity, similar to how hypertension or diabetes medications are used long-term.

Important Considerations

Cost and Access

Brand-name semaglutide is expensive, with list prices exceeding $1,000 per month in the United States. Insurance coverage varies widely, with many plans covering Ozempic for diabetes but not Wegovy for weight management. This has led to widespread off-label prescribing of Ozempic for weight loss and a booming market for compounded semaglutide, which costs substantially less but lacks FDA oversight for quality and consistency.

Supply Shortages

Unprecedented demand has led to persistent supply shortages of both Ozempic and Wegovy since 2022. Novo Nordisk has invested billions in manufacturing capacity expansion, but shortages continue. This has created challenges for patients trying to initiate or maintain treatment and has fueled the compounded semaglutide market.

Compounded Semaglutide

During FDA-declared shortages, compounding pharmacies are legally permitted to produce semaglutide. However, compounded products are not FDA-approved and may vary in purity, potency, and sterility. Reports of adverse events from compounded semaglutide have raised safety concerns. Patients considering compounded semaglutide should ensure they are working with a reputable compounding pharmacy that follows USP standards and provides certificates of analysis.

Lifestyle Modification

Semaglutide is most effective when combined with lifestyle modifications including dietary changes and increased physical activity. The medication facilitates adherence to reduced-calorie diets by suppressing appetite, but it does not eliminate the need for healthy eating patterns. Protein intake should be maintained to preserve lean muscle mass during weight loss. Resistance exercise is particularly important to minimize muscle loss.

Related Peptides

Semaglutide is part of a broader class of GLP-1 receptor agonists and related peptides:

• Tirzepatide - Dual GIP/GLP-1 receptor agonist with potentially superior weight loss
• Liraglutide - Earlier GLP-1 agonist requiring daily dosing
• Exenatide - First GLP-1 agonist approved, derived from Gila monster venom