What is Semaglutide? Mechanism, effects, and research findings

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist originally developed as a treatment for type 2 diabetes and later approved for chronic weight management. It has since become one of the most studied peptide compounds in medical history, generating a body of clinical and preclinical data that is reshaping the understanding of metabolic regulation, appetite control, and cardiovascular risk.

What is GLP-1 and what does Semaglutide do to it?

Glucagon-like peptide-1 is an incretin hormone secreted by intestinal L-cells in response to nutrient intake. It performs several key roles: stimulating glucose-dependent insulin secretion from pancreatic beta cells, suppressing glucagon release from alpha cells, slowing gastric emptying to reduce post-meal glucose spikes, and acting centrally in the hypothalamus to promote satiety and reduce appetite.

The challenge with endogenous GLP-1 is its extremely short half-life — approximately 2 minutes in circulation, rapidly degraded by the enzyme DPP-4. Semaglutide is a modified version of GLP-1 with 94% structural homology to the native peptide, engineered with two key modifications: a C-18 fatty diacid chain attached via a linker to lysine at position 34, and an amino acid substitution at position 8 (alanine to alpha-aminoisobutyric acid) that confers resistance to DPP-4 degradation.

The result is a molecule with a half-life of approximately 168 hours — enabling once-weekly subcutaneous dosing while maintaining continuous receptor activation.

Mechanisms of action

Peripheral mechanisms

In the pancreas, Semaglutide binds GLP-1R on beta cells and stimulates insulin secretion exclusively in the presence of elevated glucose — the "glucose-dependent" property that distinguishes GLP-1 agonists from sulfonylureas and sharply limits hypoglycaemia risk. Simultaneously, it suppresses glucagon secretion, reducing hepatic glucose output during the fasting state.

Gastric emptying is significantly slowed, flattening the post-prandial glucose curve and contributing to early satiety through mechanoreceptor stimulation in the stomach.

Central mechanisms

The central effects of Semaglutide are increasingly understood as fundamental to its body weight effects. GLP-1 receptors are expressed in the hypothalamus (arcuate nucleus, paraventricular nucleus), brainstem (area postrema, nucleus tractus solitarius), and limbic regions involved in reward processing. Semaglutide activates these receptors to reduce appetite, decrease food reward valuation, and alter feeding behaviour.

Preclinical studies demonstrate that GLP-1R agonists reduce activation of dopaminergic reward circuits in response to high-calorie food cues — suggesting that appetite suppression involves not just caloric need signalling but also the hedonic drive to eat.

Research findings by domain

Weight and body composition

The STEP (Semaglutide Treatment Effect in People with Obesity) trial series represented landmark clinical research. STEP 1 demonstrated a mean body weight reduction of 14.9% over 68 weeks in adults with obesity, compared to 2.4% in the placebo group. STEP 5 extended these findings to show sustained weight loss over 104 weeks.

Critically, the weight lost with Semaglutide consists predominantly of fat mass rather than lean mass — a composition profile considerably more favourable than diet-only weight loss, where lean mass loss can be substantial.

Cardiovascular effects

The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) enrolled 17,604 participants and demonstrated a 20% relative risk reduction in major adverse cardiovascular events (MACE) with Semaglutide versus placebo in patients without diabetes. This was the first dedicated cardiovascular outcomes trial for a GLP-1 agonist in a non-diabetic population, and its findings have fundamentally altered the perceived scope of Semaglutide's research relevance.

Neurological and addiction research

An emerging and unexpected area of research is Semaglutide's apparent effects on addictive behaviour. Population-level database analyses have documented lower rates of alcohol misuse, substance use disorder, and compulsive eating behaviours in patients prescribed GLP-1 agonists. Animal models show reduced voluntary alcohol consumption, nicotine self-administration, and opioid-seeking behaviour following GLP-1R agonist treatment. The mechanism likely involves the shared dopaminergic reward circuitry that GLP-1 receptors modulate.

Sex-specific considerations

GLP-1 receptor expression is higher in female pancreatic islet cells, and women generally show greater weight loss per unit dose in clinical trials — a difference partly attributable to baseline receptor density and partly to differences in adipose tissue distribution. Female subjects also show more pronounced nausea at treatment initiation, which may itself contribute to short-term caloric reduction. Researchers should stratify cohorts and report sex-disaggregated outcomes.

Research-grade Semaglutide

For laboratory applications, research-grade Semaglutide is provided as a lyophilised powder requiring reconstitution with bacteriostatic water. Purity verification via HPLC and mass spectrometry is essential — Semaglutide's long half-life means that any structural modification (oxidation at methionine, racemisation, incomplete synthesis) will persist in the experimental system and confound results. Certificate of Analysis documentation should include LC-MS confirmation of molecular weight alongside HPLC purity percentage.

Semaglutide's transition from diabetes drug to metabolic, cardiovascular, and now neurological research tool illustrates how a well-characterised mechanism, rigorously studied, continues to reveal new dimensions of biology.

References

• Wilding, J.P.H. et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 384, 989–1002.
• Lincoff, A.M. et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine, 389, 2221–2232.
• Drucker, D.J. (2022). GLP-1 physiology informs the pharmacotherapy of obesity. Molecular Metabolism, 57, 101351.