Semaglutide

Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Incretins; Glucagon-Like Peptide-1 Agonists; GLP-1 Agonists

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

Danger

H302+H312+H332 (12.5%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

P203, P260, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 8 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In large clinical trials, serum enzyme elevations were no more common with semaglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Indeed, treatment with semaglutide and other GLP-1 analogues was usually associated with improvements in serum aminotransferase levels (and hepatic steatosis) making them possible treatments for nonalcoholic fatty liver. Since licensure, there have been rare, published case reports of hepatotoxicity attributed to oral and parenteral semaglutide with a prolonged cholestatic course. At least ten cases of hepatic injury attributable to semaglutide have been reported to the FDAs Adverse Event Reporting System (FAES). The FAES database has many instances of hepatobiliary complications attributed to GLP-1 agonists. Most of these reports, however, relate to gallstones and complications of cholecystitis and choledocholithiasis rather than hepatic injury. Furthermore, the increased rate of gallstone complications is probably due to the weight loss caused by the drug rather than a direct effect of the GLP-1 agonist on the biliary system. The product label for semaglutide does not list liver injury as an adverse event. Thus, liver injury due to semaglutide may occur but is very rare.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Semaglutide

vLess-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation

◈ What is semaglutide?

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Semaglutide reduces HbA1c, systolic blood pressure, and body weight. After 12 weeks of treatment, semaglutide decreased fasting and postprandial glucose by increasing insulin production and decreasing glucagon secretion (which is normally associated with increases in blood sugar). Semaglutide also lowers fasting triglycerides and VLDL cholesterol, exerting beneficial effects on cardiovascular health. Semaglutide has been shown to cause medullary thyroid cell carcinoma in rodents. While its clinical relevance to humans is unknown, the FDA advises not to administer this drug in those with a personal or family history of medullary thyroid carcinoma. Semaglutide also poses a risk of pancreatitis and dehydration. Patients must be adequately hydrated while on semaglutide and are advised to seek medical attention immediately in cases of abdominal pain radiating to the back. Because this drug delays gastric emptying, it is important to monitor for the efficacy or adverse effects of other drugs that are administered orally.

**Mechanism of glycemic control** GLP-1 is a physiological hormone that promotes glycemic control via several different mechanisms, including insulin secretion, slowing gastric emptying, and reducing postprandial glucagon secretion. The homeostasis of glucose is dependent on hormones such as insulin and amylin, which are secreted by the beta cells of the pancreas. Semaglutide is 94% similar to human GLP-1. Analogs of this hormone such as semaglutide stimulate the synthesis of insulin by stimulating pancreatic islet cells and reducing glucagon secretion. They directly bind with selectivity to the GLP-1 receptor, causing various beneficial downstream effects that reduce blood glucose in a glucose-dependent fashion. **Mechanism of cardiovascular benefit and weight loss** In hypercholesterolemia, semaglutide is believed to reduce the progression of atherosclerosis via decreased gut permeability and decreased inflammation. Weight loss is believed to occur via the reduction of appetite and food cravings after semaglutide administration.

Semaglutide is cleaved at the peptide backbone, followed by β‐oxidation of the fatty acid chain. Naturally occurring GLP‐1 is quickly metabolized by dipeptidyl peptidase‐4 (DPP‐4) and other enzymes, which is ubiquitous in human tissues. Chemical structure modifications render semaglutide less susceptible to enzymatic degradation by gastrointestinal DPP‐4 enzymes. It is slowly and extensively metabolized, with about 83% of the administered dose measured in the plasma as unchanged drug. Neural endopeptidase (NEP) is another enzyme that metabolizes this drug. DPP-4 inactivates semaglutide, truncating the N-terminal segment while NEP hydrolyzes peptide bondsSix different metabolites of semaglutide have been identified in human plasma. The major metabolite, named P3, accounts for about 7.7% of an ingested dose.

53AXN4NNHX

SEMAGLUTIDE

Established Pharmacologic Class [EPC] - GLP-1 Receptor Agonist

Chemical Structure [CS] - Glucagon-Like Peptide 1

Mechanisms of Action [MoA] - Glucagon-like Peptide-1 (GLP-1) Agonists

Semaglutide is a GLP-1 Receptor Agonist. The mechanism of action of semaglutide is as a Glucagon-like Peptide-1 (GLP-1) Agonist.

Compounds that stimulate the activity of GLUCAGON-LIKE PEPTIDE-1 RECEPTOR. Glucagon-like peptide-1 receptor agonists are used to treat TYPE 2 DIABETES and OBESITY.

Agents that increase energy expenditure and weight loss by neural and metabolic regulation.

The Cmax of semaglutide was 10.9 nmol/L, with AUC of 3123.4 nmol h/L and a Tmax of 56 h in one clinical trial, achieved within 1-3 days. The absolute bioavailability is 89%. Steady-state concentration of the oral tablet is achieved in 4-5 weeks. Average steady state concentrations of semaglutide are the mean steady state concentrations after dosing at 0.5mg to 1mg range from 16 nmol/L to 30 nmol/L.

This drug is mainly cleared by the kidneys, and is found excreted in both the urine and feces. The main elimination route is the urine by corresponding to 53% of an ingested radiolabeled dose, with 18.6% found in the feces. A smaller amount of 3.2% was found to be exhaled. Hepatic impairment does not appear to affect the clearance of this drug and dose adjustments are not required in patients with decreased liver function.

The volume of distribution of semaglutide is 8L to 9.4L. It crosses the placenta in rats.

The clearance rate of semaglutide is 0.039 L/h according to one clinical study. On the FDA label, semaglutide clearance is reported to be about 0.05 L/h in patients with type 2 diabetes mellitus.