Semaglutide

Body Weight & Fat Mass Reduction

• Activates GLP-1 receptors to enhance satiety and reduce food intake.
• Induces significant fat loss — up to ~15% body weight reduction in non-diabetic individuals over 68 weeks.
• Decreases visceral and subcutaneous fat (~19% total fat mass and ~27% visceral fat reduction documented by DEXA).
• Preserves lean mass relative to fat loss, shifting body composition toward improved metabolic health.
• Reduces waist circumference, hunger, and cravings for energy-dense foods.

Glycemic Control & Insulin Sensitivity

• Enhances glucose-dependent insulin secretion and suppresses glucagon during hyperglycemia.
• Lowers HbA1c by ~1.8–2.1%, outperforming several GLP-1 comparators in type 2 diabetes trials.
• Improves fasting glucose, postprandial glucose, and time-in-range metrics.
• Reduces insulin resistance and fasting insulin levels (↓ HOMA-IR) in obese and insulin-resistant populations.
• Supports beta-cell function and glucose homeostasis without causing hypoglycemia.

Appetite Regulation & Gastric Motility

• Delays gastric emptying to prolong satiety and reduce post-meal glucose spikes.
• Crosses the blood-brain barrier to modulate hypothalamic appetite signaling.
• Reduces total caloric intake by ~24% in controlled studies.
• Lowers preference for high-fat/high-sugar foods and improves control over emotional eating.

Liver Function & NAFLD/NASH

• Resolves NASH (non-alcoholic steatohepatitis) in up to 59% of biopsy-confirmed patients over 72 weeks.
• Reduces liver fat content (MRI-PDFF), ALT, AST, and Pro-C3 in metabolic fatty liver models.
• Decreases hepatic inflammation, lipotoxicity, and insulin resistance — key drivers of NAFLD/NASH.
• May slow fibrosis progression by reducing hepatocellular injury and steatosis.

Cardiovascular & Vascular Health

• Reduces risk of major adverse cardiovascular events (MACE) by ~26% in high-risk diabetic patients.
• Lowers systolic blood pressure, LDL cholesterol, and triglycerides.
• Raises HDL and improves lipid ratios associated with atheroprotection.
• Decreases systemic inflammation (e.g., CRP), enhancing endothelial and vascular function.
• Reduces risk of stroke and myocardial infarction in long-term outcome trials.

Inflammation & Immune Modulation

• Downregulates inflammatory cytokines including IL-6, TNF-α, and MCP-1.
• Reduces C-reactive protein (CRP) across diabetic and obese populations in clinical trials.
• Suppresses macrophage activity (↓ CD163) and oxidative stress in adipose and hepatic tissue.
• May influence NLRP3 inflammasome signaling and T-cell cytokine profiles.
• Supports resolution of chronic low-grade inflammation linked to metabolic disease.

Metabolic Flexibility & Fuel Utilization

• Promotes greater reliance on fat oxidation during caloric restriction or fasting.
• Improves ability to switch between glucose and fat as fuel (lower respiratory quotient in studies).
• Induces browning of white adipose tissue in preclinical models (↑ UCP1 expression).
• Elevates adiponectin and improves insulin sensitivity, aiding nutrient partitioning.
• Reduces ectopic fat accumulation in liver, pancreas, and muscle tissue.

Neuroprotection & Cognitive Function (Investigational)

• Activates GLP-1 receptors in the brain and may improve neuronal insulin sensitivity.
• Reduces amyloid plaque formation and tau hyperphosphorylation in Alzheimer’s models.
• Lowers neuroinflammation (↓ IL-1β, IL-6, TNF-α) and oxidative stress in the CNS.
• Real-world data suggest up to 67% reduced Alzheimer’s disease risk compared to other diabetes medications.
• Currently under investigation in EVOKE & EVOKE+ Phase 3 trials for cognitive protection.

Epigenetic & Circadian Regulation (Emerging)

• Influences clock gene expression via metabolic regulation and improved sleep patterns.
• May modulate gene networks related to metabolism, appetite, and endocrine signaling.
• Reduces cortisol dysregulation and improves leptin/adiponectin balance.
• May have secondary effects on circadian feeding behavior and light-cycle regulation in rodent models.

To maximize the utility of Semaglutide in experimental models, researchers often combine it with compounds that enhance its metabolic, hepatic, or appetite-regulating effects, or that mitigate oxidative and inflammatory stress. These synergistic pairings are commonly studied in obesity, diabetes, fatty liver, cardiometabolic risk, and endocrine signaling.

Semaglutide Synergistic Compounds

Potential Research Use Cases for Semaglutide Combinations

•  Metabolic Syndrome & Obesity Research:
  Semaglutide + AOD-9604 + 5-Amino-1MQ + MOTS-c
  → Synergistic enhancement of fat oxidation, mitochondrial energy turnover, and glucose tolerance.
•  Muscle Preservation & Body-Composition Studies:
  Semaglutide + CJC-1295 (No DAC) + Ipamorelin
  → Supports lean-mass maintenance and anabolic recovery during adipose-reduction research.
•  Gastrointestinal & Organ Protection:
  Semaglutide + BPC-157 + TB-500
  → Improves gut barrier stability, angiogenesis, and tissue resilience under metabolic stress.
•  Antioxidant & Mitochondrial Support:
  Semaglutide + Glutathione + GHK-Cu
  → Explores gastric motility, gut-brain peptide interactions, and nutrient sensing during GLP-1 agonism.
•  Systemic & Inflammatory Regulation:
  Semaglutide + Thymosin Alpha-1 + MOTS-c
  → Investigates combined immune, metabolic, and mitochondrial synergy for chronic disease and aging research.

Semaglutide is a long-acting analog of glucagon-like peptide-1 (GLP-1) studied for its multifaceted effects on metabolism. It was originally developed for type 2 diabetes and obesity, and research has unveiled numerous physiological functions and potential benefits. Below is a detailed overview of semaglutide’s research-backed effects, organized by key domains:

Fat Loss & Body Composition

Significant Weight Reduction: Clinical trials in obese adults without diabetes have demonstrated robust weight loss with semaglutide. For example, the 68-week study (STEP 1) reported ~14.9 % average body weight loss on weekly semaglutide 2.4 mg, versus ~2.4 % with placebo. Over half of semaglutide-treated subjects lost ≥15 % of their body weight (versus ~4.9 % in placebo group). (Ref. 1)

Preferential Fat Mass Loss: Weight loss from semaglutide is predominantly from adipose tissue. DEXA-scan analyses show total fat mass reductions of ~19.3 % and visceral fat reductions of ~27.4 % with semaglutide therapy; lean body mass loss is comparatively smaller (≈9.7 %), meaning the proportion of lean mass actually increases. (Ref. 2)

Mechanism – Caloric Intake Reduction: Semaglutide’s impact on body weight is largely due to reduced calorie intake. In a 12-week trial, participants on semaglutide consumed ~24 % fewer calories per day than controls, reporting less hunger and fewer food cravings—resulting in ~5 kg of weight loss (primarily fat mass) in just 3 months. (Ref. 3)

Sustained Effects & Maintenance: Longer-term data show that weight loss is maintained while treatment continues; however, after withdrawal of semaglutide and lifestyle intervention, participants regained about two-thirds of prior weight loss by week 120 (Ref. 4)––emphasizing the chronic nature of obesity and the need for ongoing therapy.

Body Composition Meta-Analysis: In a 2025 systematic review and meta-analysis covering several RCTs, semaglutide produced significant non-linear weight loss (≈0.04 kg/day) primarily due to fat mass rather than fat-free mass. Fat-free mass declined at a smaller rate (~0.007 kg/day). (Ref. 5)
Together these findings support semaglutide not just as a “weight loss” drug, but as a modifier of body composition with preferential fat reduction and lean-mass preservation.

Glycemic Control & Insulin Sensitivity

Improved Blood Glucose and HbA1c: As a GLP-1 receptor agonist, semaglutide enhances glucose-dependent insulin secretion and lowers glucagon, leading to better glycaemic control. In patients with type 2 diabetes, semaglutide significantly lowers HbA₁c levels compared to other agents. (Ref. 6)

Enhanced Insulin Secretion (Glucose-Dependent): Semaglutide supports pancreatic β-cell response when glucose is elevated, increasing insulin release only in the fed state while suppressing inappropriate glucagon secretion. This coordinated action helps prevent hyperglycemia without excessive insulin when not needed, lowering hypoglycaemia risk. (Ref. 7)

Improved Insulin Sensitivity: Beyond stimulating insulin, semaglutide leads to lower endogenous insulin requirements over time thanks to weight loss and reduced insulin resistance. Studies in women with polycystic ovary syndrome (PCOS) found that 3 months of weekly semaglutide normalized fasting glucose in ~80 % of subjects and significantly reduced HOMA-IR, indicating markedly improved insulin sensitivity. (Ref. 8)
In essence, semaglutide acts both on insulin secretion and insulin sensitivity—making it relevant outside of pure glycaemic endpoints.

Cardiovascular Health

Reduced Major Cardiovascular Events: Semaglutide has demonstrated cardioprotective effects in high-risk populations. In the 2-year SUSTAIN-6 trial (type 2 diabetes patients with existing cardiovascular disease), semaglutide significantly lowered the incidence of major adverse cardiovascular events (hazard ratio ~0.74). Non-fatal stroke risk was significantly reduced (HR ~0.61). (Ref. 9)

Blood Pressure and Lipids: Weight loss induced by semaglutide is typically accompanied by improvements in blood pressure, triglycerides, HDL cholesterol and waist circumference – all of which contribute to a more favorable cardiometabolic profile. (Ref. 10)

Anti-Atherosclerotic Effects: There is evidence that GLP-1 analogues improve endothelial function and reduce atherosclerotic inflammation. Semaglutide use was associated with slower progression of renal disease in diabetes (reduced new or worsening nephropathy) and lowered inflammatory markers that drive plaque formation. (Ref. 11)
These findings support the notion of semaglutide as a cardiovascular therapy in addition to a metabolic therapy.

Liver Function & NAFLD/NASH

Reduction of Liver Fat and NASH Improvement: In a 72-week Phase II trial in patients with biopsy-proven non-alcoholic steatohepatitis (NASH), daily semaglutide led to histological resolution of NASH (elimination of inflammation/fat with no worsening of fibrosis) in ~59 % of patients at the highest dose, compared to ~17 % with placebo. (Ref. 12)

Improved Liver Enzymes: Consistent with reduced liver fat, semaglutide therapy is associated with declines in ALT and other liver enzyme markers of hepatic inflammation. Additionally, by improving insulin sensitivity and promoting weight loss, semaglutide addresses two major drivers of fatty-liver disease. (Ref. 12) These data position semaglutide as a promising agent for conditions of metabolic-associated fatty liver disease.

Appetite Regulation & Gastric Motility

Appetite Suppression: Semaglutide powerfully influences appetite-regulating centres in the brain (e.g., hypothalamus). In a controlled trial, subjects on semaglutide reported significantly lower appetite scores, reduced cravings for high-calorie foods, greater satiety and diminished preference for fatty foods. (Ref. 3)

Delayed Gastric Emptying: In a 12-week study, semaglutide-treated patients retained ~37 % of a standard meal in the stomach at 4 hours post-ingestion, compared to 0 % in the placebo group. The half-time of gastric emptying was significantly extended (~171 minutes vs ~118 minutes). (Ref. 13) Together, these mechanisms contribute substantially to reduced caloric intake and improved eating behaviour.

Anti-Inflammatory Effects

Lowering of Systemic Inflammation: A 2024 meta-analysis of 13 randomized controlled trials found that semaglutide significantly reduced C-reactive protein (CRP) in both diabetic and non-diabetic populations. (Ref. 14)

Cytokine and Immune Modulation: GLP-1 receptor activation (and thus semaglutide) suppresses pro-inflammatory cytokines (e.g., IL-6, TNF-α), macrophage activation, and endothelial adhesion molecules—thus improving vascular and immune health. (Ref. 15)
These effects may underlie parts of the cardiovascular and metabolic benefits beyond weight loss per se.

Metabolic Flexibility

Shift Toward Fat Oxidation: Preclinical models show that GLP-1-receptor signalling (as with semaglutide) promotes browning of white adipose tissue, mitochondrial biogenesis and enhanced thermogenesis. (Ref. 16)

Enhanced Mitochondrial Activity: Animal work suggests increased expression of uncoupling protein-1 (UCP1) and mitochondrial markers in adipose tissue treated with GLP-1 analogues—consistent with improved metabolic flexibility and higher fat oxidation. (Ref. 17)
While human data are still emerging, these mechanistic findings hint at semaglutide’s potential to improve metabolic resilience, not just reduce caloric intake.

Neuroprotection (Investigational)

Alzheimer’s Disease Models: Rodent studies have found GLP-1/semaglutide treatment reduces amyloid plaques, attenuates neuroinflammation, and improves cognition in Alzheimer’s-disease models. (Ref. 18)

Human Risk Reduction Data: Early observational data suggest semaglutide use is associated with a significantly lower risk of Alzheimer’s disease in large population studies. (Ref. 17)

Ongoing Clinical Trials: Phase III studies (e.g., EVOKE & EVOKE+) are currently investigating semaglutide for cognitive decline in early Alzheimer’s disease. (Ref. 18)
These data are preliminary and investigational, but hint at an expanded role of semaglutide in neuro-metabolic care.