Semaglutide — Research, Dosing & Price Guide

Semaglutide is a GLP-1 receptor agonist that has revolutionized the treatment of type 2 diabetes and obesity. FDA-approved as Ozempic (injectable, diabetes), Wegovy (injectable, obesity), and Rybelsus (oral, diabetes), it is the most widely prescribed and clinically validated peptide for metabolic disease. Semaglutide produces unprecedented weight loss of 15–17% in clinical trials and has demonstrated cardiovascular, renal, and potentially neuroprotective benefits beyond glycemic control.

Semaglutide is an acylated analog of human GLP-1 (glucagon-like peptide-1) with 94% homology to native GLP-1, engineered with three key modifications for clinical utility: an amino acid substitution at position 8 (Aib) that resists DPP-4 enzymatic degradation, an acyl fatty acid chain (C18 fatty diacid) that enables albumin binding for extended circulation, and a mini-PEG linker between the peptide and acyl chain. These modifications extend the half-life from 2 minutes (native GLP-1) to approximately 7 days, enabling once-weekly dosing. Upon binding to the GLP-1 receptor (GLP-1R), semaglutide activates multiple downstream pathways. In the pancreas, it potentiates glucose-dependent insulin secretion from beta cells and suppresses glucagon release from alpha cells — critically, this is glucose-dependent, meaning hypoglycemia risk is minimal. In the gastrointestinal tract, semaglutide slows gastric emptying by 10–30%, prolonging nutrient absorption and enhancing post-meal satiety. The most significant effects for weight loss occur in the central nervous system. Semaglutide crosses the blood-brain barrier and acts on GLP-1 receptors in the hypothalamic arcuate nucleus and paraventricular nucleus, reducing appetite and food reward signaling. It also modulates the mesolimbic dopamine system, reducing the hedonic drive to eat — patients report decreased food cravings, particularly for high-fat and high-sugar foods. Emerging research shows GLP-1R activation has anti-inflammatory effects, reducing CRP and IL-6, as well as direct cardiovascular benefits through improved endothelial function, reduced atherosclerotic plaque inflammation, and decreased left ventricular remodeling. These pleiotropic effects explain the cardiovascular and renal outcomes benefits observed in large trials.

• STEP 1 trial (2021, NEJM, n=1,961): 2.4 mg weekly semaglutide produced 14.9% body weight loss vs. 2.4% placebo at 68 weeks in adults with obesity
• STEP 5 (2022, Nature Medicine): Sustained 15.2% weight loss at 104 weeks, demonstrating long-term durability
• SELECT trial (2023, NEJM, n=17,604): 20% reduction in major adverse cardiovascular events (MACE) in overweight/obese adults without diabetes — the first obesity drug to show CV mortality benefit
• SUSTAIN-6 (2016, NEJM): 26% reduction in MACE in type 2 diabetes patients, establishing cardiovascular safety
• FLOW trial (2024): Semaglutide reduced kidney disease progression by 24% in patients with type 2 diabetes and chronic kidney disease
• OASIS 1 trial (2023): Oral semaglutide 50 mg daily produced 15.1% weight loss, approaching injectable efficacy
• Brain imaging studies (2023, Nature Metabolism) showed semaglutide reduces food-cue reactivity in the insula and amygdala, confirming central appetite mechanisms
• Post-hoc analyses suggest potential benefits for NASH/MAFLD, with significant liver fat reduction and fibrosis improvement
• STEP-HFpEF (2023, NEJM): Improved heart failure symptoms, exercise capacity, and quality of life in HFpEF patients with obesity

• Ozempic (diabetes): Start 0.25 mg SC weekly for 4 weeks → 0.5 mg weekly for 4 weeks → 1 mg weekly maintenance; max 2 mg weekly
• Wegovy (obesity): Escalation over 16 weeks: 0.25 mg → 0.5 mg → 1 mg → 1.7 mg → 2.4 mg SC weekly
• Rybelsus (oral): 3 mg daily for 30 days → 7 mg daily → 14 mg daily; take on empty stomach with ≤4 oz water, 30 min before food
• Research protocols: some use compounded semaglutide at doses up to 2.4 mg weekly subcutaneously
• Inject subcutaneously in the abdomen, thigh, or upper arm; rotate sites weekly
• Administer on the same day each week, at any time of day regardless of meals (for injectable)
• Slow dose escalation is critical — rushing titration dramatically increases GI side effects
• If a dose is missed, administer within 5 days of the missed dose; if >5 days, skip and resume schedule
• No specific cycle length — used continuously for chronic disease management

Known Side Effects

• Nausea is the most common side effect (30–44% in trials), typically worst during dose escalation and improving over 4–8 weeks
• Vomiting (15–25%), diarrhea (20–30%), and constipation (15–25%) are common GI effects
• Decreased appetite — intended effect but can lead to nutritional deficiency if food intake is severely restricted
• Injection site reactions (redness, swelling) in ~5% of users
• Gallbladder events including cholelithiasis and cholecystitis (1.6% vs. 0.7% placebo in STEP trials), particularly with rapid weight loss
• Pancreatitis: rare but reported (0.1–0.3%); monitor for persistent severe abdominal pain
• Muscle mass loss alongside fat loss — lean body mass decreases by approximately 25–40% of total weight lost, emphasizing the need for resistance training
• Facial volume loss ('Ozempic face') due to significant fat reduction

Safety Profile

Semaglutide is FDA-approved and has the most extensive safety database of any peptide in clinical use, with over 30,000 patients in clinical trials and millions of real-world users. The SELECT trial established cardiovascular safety and benefit in the obesity population. The primary safety concern is the boxed warning regarding thyroid C-cell tumors — GLP-1 agonists cause dose-dependent thyroid C-cell tumors in rodents, though no causal link has been established in humans after 15+ years of GLP-1RA class experience. Semaglutide is contraindicated in patients with personal/family history of medullary thyroid carcinoma or MEN2 syndrome. Acute pancreatitis is a rare but serious adverse event; discontinue if pancreatitis is suspected. Retinopathy complications were observed in diabetes patients with pre-existing retinopathy in SUSTAIN-6 — likely due to rapid glycemic improvement rather than a direct drug effect. Weight regain upon discontinuation is significant (approximately two-thirds of lost weight regained within one year), supporting long-term use for sustained benefit. Drug interactions are minimal, but absorption of oral co-medications may be affected by delayed gastric emptying.

Week 1–4 (0.25 mg): Subtle appetite changes begin. You may notice feeling full sooner at meals and reduced interest in snacking. Mild nausea is common, especially after eating large or fatty meals. Weight loss of 1–3 lbs is typical. Week 5–8 (0.5 mg): Appetite suppression becomes more pronounced. Food noise — the constant background thinking about food — quiets significantly. Many users describe this as the most transformative change. GI side effects may flare briefly with each dose increase. Weight loss of 3–6% is typical at this stage. Week 9–16 (1.0–1.7 mg): Weight loss accelerates. Cravings for calorie-dense foods diminish markedly. Energy levels often improve as metabolic parameters normalize. Blood glucose and HbA1c show meaningful improvement in diabetic patients. Week 17–20 (2.4 mg maintenance): Full therapeutic dose. Weight loss of 8–12% from baseline. GI side effects have typically resolved or are manageable. Fasting glucose, triglycerides, and blood pressure often improve. Week 20–68: Steady continued weight loss approaching 15–17% at one year. Body composition changes become visually apparent. Metabolic health markers continue improving. Benefits plateau around 60–68 weeks for most patients.

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