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| 2mg |
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Purity: ≥98%
Semaglutide TFA (NNC0113-0217; NNC-0113-0217), the trifluoroacetic acid salt form of semaglutide (brand name: Ozempic), is a human glucagon-like peptide-1 (GLP-1) analogue acting as a GLP-1 receptor agonist with longer duration of antidiabetic action. It was being developed clinically to treat type 2 diabetes. The FDA approved semaglutide in December 2017 with the goal of helping adults with type 2 diabetes mellitus achieve better glycemic control. Chemically, semaglutide and glucagon-like peptide-1 (GLP-1) are comparable in humans. The two amino acid substitutions at positions 8 and 34, where arginine and 2-aminoisobutyric acid, respectively, are present, are the only variations. Furthermore, lysine at position 26 is acylated with stearic diacid, indicating that it is in its derivative form. The pharmaceutical product semaglutide was created by Novo Nordisk, a Danish company, and is sold under the brand name Ozempic. It decreases blood sugar by stimulating the synthesis of insulin because it is an agonist of the glucagon-like peptide-1 receptor. It was identified as a longer-acting substitute for liraglutide in 2012 by a group of Novo Nordisk researchers. 2015 saw the beginning of clinical trials, and 2016 saw the completion of phase 3.
| Targets |
GLP-1 receptor
Semaglutide is derivatized at lysine 26 and differs from human GLP-1 in two amino acid substitutions (Aib8, Arg34). Semaglutide has an affinity for GLP-1R of 0.38±0.06 nM[1]. A GLP-1 analogue that is 94% sequence similar to human GLP-1 is semaglutide [3]. |
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| ln Vitro |
Semaglutide is derivatized at lysine 26 and differs from human GLP-1 in two amino acid substitutions (Aib8, Arg34). Semaglutide has an affinity for GLP-1R of 0.38±0.06 nM[1]. A GLP-1 analogue that is 94% sequence similar to human GLP-1 is semaglutide [3].
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| ln Vivo |
Semaglutide has an MRT of 63.6 hours after s.c. dosing to mini-pigs and a plasma half-life of 46 hours in mini-pigs after intravenous administration[1]. Motor impairments caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are ameliorated by semaglutide. Semaglutide also protects dopaminergic neurons in the substantia nigra and striatum by rescuing the decrease in tyrosine hydroxylase (TH) levels, reducing lipid peroxidation, alleviating inflammation, inhibiting the apoptosis pathway, and increasing the expression of autophagy-related proteins. Furthermore, semaglutide, a long-acting GLP-1 analogue, outperforms liraglutide in the majority of parameters[2]. Semaglutide reduces body weight and blood glucose by promoting the release of insulin[3].
In patients with type 2 diabetes at high cardiovascular risk, once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) significantly reduced the risk of the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared to placebo over a median 2.1 years of treatment. The hazard ratio was 0.74 (95% CI, 0.58 to 0.95; P<0.001 for noninferiority; P=0.02 for superiority). The number needed to treat (NNT) to prevent one primary outcome event over 24 months was 45. [1] The reduction in the primary outcome was driven by a significant 39% reduction in nonfatal stroke (HR 0.61; 95% CI, 0.38 to 0.99; P=0.04) and a non-significant 26% reduction in nonfatal myocardial infarction (HR 0.74; 95% CI, 0.51 to 1.08; P=0.12). The rate of cardiovascular death was similar between groups (HR 0.98; 95% CI, 0.65 to 1.48; P=0.92). [1] Semaglutide treatment also resulted in a lower risk of new or worsening nephropathy (HR 0.64; 95% CI, 0.46 to 0.88; P=0.005) but a higher risk of diabetic retinopathy complications (HR 1.76; 95% CI, 1.11 to 2.78; P=0.02) compared to placebo. [1] Significant improvements in glycemic control and body weight were observed. At week 104, glycated hemoglobin decreased by 1.1% (0.5 mg) and 1.4% (1.0 mg) from a baseline of 8.7% with semaglutide, versus 0.4% with placebo. Body weight decreased by 3.6 kg (0.5 mg) and 4.9 kg (1.0 mg) with semaglutide, versus 0.5-0.7 kg with placebo. [1] |
| Enzyme Assay |
HEK293‐SNAP‐GLP‐1R cells were labelled in suspension with SNAP‐Lumi4‐Tb (40 nM, Cisbio, Codelet, France) for 1 hour at room temperature in complete medium. After washing and resuspension in hanks' balanced salt solution containing 0.1% bovine serum albumin and metabolic inhibitors (20 mmol/L 2‐deoxygucose and 10 mmol/L NaN3) to prevent GLP‐1R internalization, binding experiments were performed by time‐resolved förster resonance energy transfer (FRET) using exendin (9‐39) with fluorescein isothiocyanate (FITC) installed at position K12 as previously described.[4]
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| Cell Assay |
Semaglutide activates the GLP-1 receptor in pancreatic beta cells leading to glucose-dependent insulin release. It also decreases glucagon secretion, slows gastric emptying, and promotes satiety.
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| Animal Protocol |
Mice: Male C57BL/6 mice 10 weeks old (20-25 g) are used throughout the study. Six groups of mice are randomly assigned (n = 12 per group). The treatments were as follows: (i) saline alone was given to the control group; (ii) NN-2211 group received saline and NN-2211 (25 nmol/kg ip. once daily for 7 days); (iii) Semaglutide group received saline and Semaglutide (25 nmol/kg ip. once daily for 7 days); (iv) MPTP group received MPTP alone (once daily 20 mg/kg ip. for 7 days); (v) MPTP (once daily 20 mg/kg ip. for 7 days) was immediately followed by NN-2211 treated group (25 nmol/kg ip. once daily for 7 days). (vi) MPTP (20 mg/kg i.p. once daily for 7 days), which was immediately followed by the group treated with semaglutide (25 nmol/kg i.p. once daily for 7 days). Measure behavioral changes, neuronal damage, inflammatory markers, and other biomarkers at the conclusion of drug treatments. [2]
Male C57BL/6 mice (10 weeks old) were used. Parkinson's disease was modeled by intraperitoneal (i.p.) injection of MPTP (20 mg/kg) once daily for 7 days. For the treatment groups, semaglutide was dissolved in saline and administered via i.p. injection at a dose of 25 nmol/kg, once daily for 7 days. The treatment started immediately after the daily MPTP injection. Behavioral assessments (open-field test, rotarod test, footprint test) were conducted on the 8th day after the start of MPTP injections. On the 9th day, mice were euthanized. Brain tissues (substantia nigra and striatum) were collected for subsequent immunohistochemistry and western blot analysis. For immunohistochemistry, brains were perfused with saline and fixed with paraformaldehyde. For western blot, brain regions were dissected and frozen at -80°C.[2] |
| ADME/Pharmacokinetics |
Absorption: In a clinical trial, semaglutide's Cmax was 10.9 nmol/L, AUC was 3123.4 nmol·h/L, and Tmax was 56 h, achieved within 1-3 days. Absolute bioavailability was 89%. Steady-state concentrations of oral tablets were reached within 4-5 weeks. The mean steady-state concentration of semaglutide refers to the mean steady-state concentration after administration of a dose from 0.5 mg to 1 mg, ranging from 16 nmol/L to 30 nmol/L. Elimination pathway: The drug is primarily cleared by the kidneys and can be excreted in urine and feces. The primary elimination route is urine, accounting for approximately 53% of the ingested radiolabeled dose, followed by feces, accounting for approximately 18.6%. A small amount (3.2%) is excreted via exhalation. Hepatic impairment does not appear to affect the drug's clearance, and no dose adjustment is required for patients with impaired hepatic function. Volume of distribution: Semaglutide has a volume of distribution of 8 to 9.4 liters. It crosses the rat placenta.
Clearance: According to a clinical study, the clearance of semaglutide is 0.039 L/h. The FDA label indicates that the clearance of semaglutide in patients with type 2 diabetes is approximately 0.05 L/h. Metabolism/Metabolites: Semaglutide is cleaved at the peptide backbone, followed by β-oxidation of the fatty acid chain. Naturally occurring GLP-1 is rapidly metabolized by dipeptidyl peptidase-4 (DPP-4) and other enzymes widely present in human tissues. Chemical modifications make semaglutide less susceptible to degradation by gastrointestinal DPP-4 enzymes. It is metabolized slowly and extensively, with approximately 83% of the administered dose present in plasma as the parent drug. Neuroendopeptidase (NEP) is another enzyme that metabolizes this drug. DPP-4 inactivates semaglutide by cleaving the N-terminal fragment, while NEP hydrolyzes peptide bonds. Six different semaglutide metabolites have been identified in human plasma. The major metabolite, P3, accounts for approximately 7.7% of the ingested dose. Biological half-life: One of the main characteristics of semaglutide is its long half-life of 168 hours. This long half-life is attributed to its binding to albumin. This reduces renal clearance and protects semaglutide from metabolic degradation. Semaglutide is a long-acting GLP-1 analog, administered subcutaneously once weekly for the treatment of type 2 diabetes. It is a modified version of liraglutide designed to resist protease degradation, thereby prolonging its biological half-life. Specific pharmacokinetic parameters (e.g., half-life, Cmax, AUC) were not provided in this study. [2] |
| Toxicity/Toxicokinetics |
Hepatotoxicity In large clinical trials, the incidence of elevated serum enzymes was not higher in the semaglutide treatment group compared to placebo or control drugs, and no clinically significant cases of liver injury were reported. In fact, semaglutide and other GLP-1 analogues often improve serum transaminase levels (and hepatic steatosis), making it a potential treatment for non-alcoholic fatty liver disease. Since its market launch, no case reports of hepatotoxicity caused by semaglutide have been published, and liver injury is not listed as an adverse event in the product information leaflet. Therefore, if liver injury caused by semaglutide occurs, it must be extremely rare. Probability score: E (unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of semaglutide during lactation. Because semaglutide is a peptide molecule with a molecular weight of 4113 Daltons and a protein binding rate of over 99%, its content in breast milk is likely to be very low. The likelihood of infants absorbing this drug is also very low, as it is likely to be destroyed in the infant's gastrointestinal tract. Until more data is available, breastfeeding women should use semaglutide with caution, especially when breastfeeding newborns or premature infants. ◉ Effects on breastfed infants No published information found as of the revision date. ◉ Effects on lactation and breast milk No published information found as of the revision date. View more◈ What is semaglutide? Protein Binding Semaglutide binds to plasma albumin with high affinity, thus ensuring the high stability of the drug. Its binding rate to albumin exceeds 99%. In the SUSTAIN-6 trial, the incidence of gastrointestinal disorders (e.g., nausea, vomiting, diarrhea) in the semaglutide group (50.7%-52.3%) was higher than that in the placebo group (35.2%-35.7%), resulting in a higher proportion of treatment discontinuation due to adverse events. |
COA