The Weight Loss Stack: Semaglutide + Tesamorelin
Last updated: 2026-02-20
The Semaglutide and Tesamorelin weight loss stack combines two peptides with distinct but complementary mechanisms for reducing body fat. Semaglutide, a GLP-1 receptor agonist, reduces appetite and caloric intake through central nervous system satiety signaling, while Tesamorelin, a growth hormone-releasing hormone (GHRH) analog, specifically targets visceral adipose tissue through GH-mediated lipolysis.
This combination addresses the two primary challenges of weight management: caloric intake and metabolic fat burning. Semaglutide has demonstrated substantial weight loss in large-scale clinical trials (STEP program), with participants losing an average of 14.9% of body weight over 68 weeks. Tesamorelin is FDA-approved for reducing visceral adipose tissue in HIV-associated lipodystrophy, with studies showing a 15-18% reduction in trunk fat.[1]
By pairing an appetite-suppressing peptide with a fat-mobilizing peptide, this stack may offer a more comprehensive approach to body composition improvement than either compound alone. This guide covers the evidence-based rationale, complete dosage protocol, timeline of expected effects, safety considerations, and frequently asked questions.
Compounds in This Stack
Semaglutide
GLP-1 receptor agonist for appetite suppression and metabolic regulation
Semaglutide is a synthetic GLP-1 (glucagon-like peptide-1) receptor agonist with 94% homology to human GLP-1. It reduces appetite by acting on GLP-1 receptors in the hypothalamus and brainstem, slowing gastric emptying, and enhancing insulin sensitivity. Semaglutide has one of the strongest clinical evidence bases of any weight loss compound, with multiple Phase III trials demonstrating significant and sustained weight reduction.[1]
Mechanism in this stack: Semaglutide serves as the primary appetite-regulating agent. By activating central GLP-1 receptors, it reduces hunger, increases satiety, and decreases food reward signaling. This creates the caloric deficit necessary for weight loss. Its weekly dosing and long half-life (~7 days) provide sustained appetite control throughout the week.
| Parameter | Detail |
|---|---|
| Research Dosage | 0.25 mg/week (start) → titrate to 2.4 mg/week over 16–20 weeks |
| Administration | Subcutaneous injection, once weekly |
| Half-Life | ~7 days (supports weekly dosing) |
| FDA Status | FDA-approved as Wegovy® (2.4 mg) for chronic weight management |
| Key Trial Data | STEP 1: 14.9% mean body weight loss vs 2.4% placebo over 68 weeks |
Tesamorelin
GHRH analog for targeted visceral fat reduction via GH elevation
Tesamorelin is a synthetic analog of human growth hormone-releasing hormone (GHRH) consisting of 44 amino acids. It is the only FDA-approved GHRH analog and was specifically approved for reducing excess visceral adipose tissue (VAT) in HIV-associated lipodystrophy. Tesamorelin stimulates the pituitary gland to produce and release growth hormone in a physiological pulsatile pattern.[2]
Mechanism in this stack: Tesamorelin targets body composition from the metabolic side. By elevating growth hormone levels, it promotes lipolysis (fat breakdown), particularly in visceral fat deposits. GH increases the mobilization of free fatty acids from adipose tissue and shifts the body toward fat oxidation as an energy source. In clinical trials, tesamorelin reduced trunk fat by 15–18% without significant changes in subcutaneous fat or lean mass.
| Parameter | Detail |
|---|---|
| Research Dosage | 1–2 mg per day |
| Administration | Subcutaneous injection, once daily |
| Half-Life | 26–38 minutes (short-acting, stimulates natural GH pulse) |
| FDA Status | FDA-approved as Egrifta® for HIV-associated lipodystrophy |
| Key Trial Data | 15–18% reduction in visceral adipose tissue in Phase III trials |
How They Work Together
The Semaglutide and Tesamorelin combination targets weight loss through two fundamentally different pathways, which is why many researchers consider it a logical pairing for body composition optimization.
Appetite Reduction + Fat Mobilization
Semaglutide creates a caloric deficit by reducing appetite and caloric intake. However, weight loss from caloric restriction alone can result in loss of both fat mass and lean mass. Tesamorelin addresses this by promoting GH-mediated lipolysis, which preferentially mobilizes fat stores for energy. The growth hormone elevation from tesamorelin also has an anabolic effect on lean tissue, potentially preserving muscle mass during the caloric deficit created by semaglutide.[2]
Visceral Fat Targeting
Visceral adipose tissue (VAT) is the metabolically dangerous fat that accumulates around internal organs and is strongly associated with cardiovascular disease, insulin resistance, and chronic inflammation. Semaglutide reduces overall body weight but does not selectively target visceral fat. Tesamorelin, by contrast, has demonstrated specific efficacy in reducing VAT in clinical trials, making this combination effective for both overall weight loss and targeted visceral fat reduction.
Metabolic Synergy
Semaglutide improves insulin sensitivity and glucose metabolism through GLP-1 receptor activation. Tesamorelin, while potentially increasing insulin resistance via GH elevation, also reduces visceral fat, which is itself a major driver of insulin resistance. The net metabolic effect of the combination may be more favorable than either compound alone, though blood glucose monitoring is recommended.[1]
Lean Mass Preservation
A significant concern with GLP-1 agonist-driven weight loss is the proportion of lean mass lost alongside fat mass. Studies suggest that approximately 25–40% of weight lost on semaglutide alone may come from lean tissue. Tesamorelin's GH-elevating properties have an anabolic effect on muscle and connective tissue, potentially reducing lean mass loss during the weight loss phase. This body composition advantage is one of the primary rationales for combining these compounds.
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Protocol & Dosage Schedule
Dosage Schedule
| Phase | Semaglutide | Tesamorelin | Duration |
|---|---|---|---|
| Titration 1 | 0.25 mg/week | 1 mg/day | Weeks 1–4 |
| Titration 2 | 0.5 mg/week | 1–2 mg/day | Weeks 5–8 |
| Titration 3 | 1.0 mg/week | 2 mg/day | Weeks 9–12 |
| Titration 4 | 1.7 mg/week | 2 mg/day | Weeks 13–16 |
| Full Dose | 2.4 mg/week | 2 mg/day | Weeks 17+ |
Cycle Length
Semaglutide is typically used continuously for as long as weight management is needed, with gradual titration over the first 16–20 weeks. Tesamorelin cycles of 12–26 weeks are common, with 4–8 week breaks between cycles. Some protocols run tesamorelin continuously alongside semaglutide for the duration of the weight loss phase, then discontinue tesamorelin during maintenance. Blood work (IGF-1, fasting glucose, HbA1c) should guide cycle duration.
Timing & Administration
Semaglutide timing: Inject subcutaneously once weekly on the same day each week. Any time of day is acceptable. Can be administered with or without food. Choose a day that works consistently with your schedule (many choose Sunday or Monday). Rotate injection sites between abdomen, thigh, and upper arm.
Tesamorelin timing: Inject subcutaneously once daily on an empty stomach, ideally 30–60 minutes before breakfast or at bedtime (at least 2 hours after last meal). Fasted-state dosing is important because food intake and insulin can blunt the GH response. Abdominal injection is the standard site.
Sample daily schedule:
- 6:00 AM – Wake up (fasted)
- 6:15 AM – Inject Tesamorelin 1–2 mg subcutaneously
- 6:45–7:00 AM – Eat breakfast (30+ min after tesamorelin)
- Sunday evening – Inject Semaglutide (weekly dose) subcutaneously
What to Expect
Weight loss with this combination is gradual and progressive. The slow titration of semaglutide is essential for minimizing gastrointestinal side effects. Tesamorelin's fat-reducing effects build over weeks as sustained GH elevation drives lipolysis.
| Timeframe | Expected Observations |
|---|---|
| Weeks 1–4 | Mild appetite reduction from low-dose semaglutide. Possible nausea during GI adjustment. Tesamorelin begins elevating GH levels. Weight loss: 1–3 lbs typically. |
| Weeks 5–8 | Noticeable appetite suppression. Reduced portion sizes feel natural. Early body composition changes. Improved energy and sleep from GH elevation. Weight loss: 3–8% total body weight. |
| Weeks 9–16 | Substantial appetite control. Visible fat loss, particularly around the midsection (tesamorelin effect). Improved metabolic markers on blood work. Weight loss: 8–12% total body weight. |
| Weeks 17–28 | Full-dose semaglutide with maximum appetite suppression. Significant visceral fat reduction from sustained tesamorelin use. Continued progressive weight loss. Weight loss: 12–18% total body weight. Improved body composition ratio (fat vs lean mass). |
| Months 7–12+ | Weight loss stabilization approaching maximum effect. Transition to maintenance phase. Assessment for dose reduction or continuation. Long-term metabolic improvements (A1c, lipids, blood pressure). |
Safety & Contraindications
Known Side Effects
Both compounds have been studied in clinical trials, providing a more robust safety profile than most research peptides.
Semaglutide side effects (from STEP trials):
- Nausea (44% of participants, typically transient during titration)
- Diarrhea (30%)
- Vomiting (24%)
- Constipation (24%)
- Abdominal pain (20%)
- Headache (14%)
- Fatigue and dyspepsia (11%)
GI side effects typically peak during dose escalation and subside with continued use. Slow titration significantly reduces their severity.[1]
Tesamorelin side effects (from Phase III trials):
- Injection site reactions (erythema, pruritus, pain)
- Arthralgia (joint pain)
- Peripheral edema (mild swelling)
- Myalgia (muscle pain)
- Paresthesia (tingling in extremities)
Contraindications and Cautions
- Personal or family history of medullary thyroid carcinoma (MTC) or MEN2 syndrome: Semaglutide carries a boxed warning for thyroid C-cell tumors based on rodent studies. This is the most critical contraindication.
- Pancreatitis history: GLP-1 agonists have been associated with rare cases of acute pancreatitis. Avoid in individuals with a history of pancreatitis.
- Active cancer: Tesamorelin elevates GH and IGF-1, which promote cell proliferation. Contraindicated in active malignancy.
- Diabetes (type 1): Semaglutide is not indicated for type 1 diabetes. Tesamorelin may worsen glucose control.
- Gallbladder disease: Rapid weight loss increases gallstone risk. Monitor for symptoms.
- Pregnancy and breastfeeding: Both compounds are contraindicated.
Monitoring Recommendations
- Blood work every 8–12 weeks: Fasting glucose, HbA1c, IGF-1, lipid panel, liver enzymes, amylase/lipase
- Body composition assessment: DEXA scan at baseline and every 3–6 months to track fat vs. lean mass changes
- Blood pressure monitoring: Regular checks, as weight loss typically improves but should be tracked
Important: Semaglutide (as Wegovy) is FDA-approved for chronic weight management. Tesamorelin (as Egrifta) is FDA-approved for HIV-associated lipodystrophy. The combination use described here is off-label and should only be undertaken under medical supervision. This information is for educational purposes only.
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Frequently Asked Questions
References
- Wilding JPH, Batterham RL, Calanna S, et al.. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021.
- Falutz J, Allas S, Blot K, et al.. Metabolic effects of a growth hormone-releasing factor in patients with HIV. New England Journal of Medicine, 2007.
- Marso SP, Bain SC, Consoli A, et al.. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine, 2016.
- Stanley TL, Feldpausch MN, Oh J, et al.. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation. JAMA, 2014.
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Our content is reviewed for accuracy and grounded in peer-reviewed research where available. We do not provide medical advice. Always consult a qualified healthcare professional.