Semaglutide 

Semaglutide is a peptide that contains a linear sequence of 31 amino acids joined together by peptide linkage. It is an agonist of the glucagon-like peptide-1 receptor and is a polypeptide and lipopeptide. It has a role as a Hypoglycaemic agent, an anti-obesity agent, and a neuroprotective agent. 

Semaglutide was developed by Novo Nordisk and approved by the FDA for subcutaneous injection in December 2017, and tablet formulation was approved for oral administration in September 2019. Clinical trials have determined that this drug reduces glycosylated haemoglobin levels and reduces body weight, proving to be effective for patients with type 2 diabetes. In June 2021, Semaglutide was approved by the FDA for chronic weight management in adults with general obesity. The use of Semaglutide in weight management is also approved by Health Canada and the EMA 

How it works:  

Upon activation of the GLP-1 receptor, Semaglutide improves glucose-dependent insulin secretion, providing a physiological response to elevated blood glucose levels after a meal. Simultaneously, it slows gastric emptying, increases pancreatic β-cell proliferation, and reduces glucagon release, contributing to an overall reduction in appetite. 

Furthermore, Semaglutide interaction with GLP-1 receptors in the hypothalamus may mitigate sensations of hunger, alleviate food cravings, and to a comprehensive metabolic effect of Semaglutide in managing blood glucose levels and facilitating weight loss. 

Pharmacokinetics: 

Absorption: Subcutaneous Semaglutide has high bioavailability (89%), with peak concentration achieved within 1-3 days of initiation. Achieving steady–state exposure typically occurs after 4-5 weeks of weekly administration, demonstrating a proportional increase with escalating doses up to 2.4mg. 

 The oral Semaglutide exhibits an improved, although still minimal, bioavailability range of 0.4% to 1%. After oral dosage, the maximum concentration of Semaglutide is typically reached within 1 hour post-dose. Steady state exposure is typically achieved after 4-5 weeks of daily administration. Gastric fluid composition, influenced by food and increased water volumes, significantly affects oral Semaglutide absorption. 

Distribution: Following subcutaneous administration, the mean apparent volume of distribution for Semaglutide is approximately 12.5L. Incase of oral administration volume of distribution is estimated to be 8L. 

Metabolism: Semaglutide undergoes metabolism through the proteolytic cleavage of the peptide backbone, followed by β-oxidation of the fatty acid side chain. 

Elimination: Both oral and subcutaneous Semaglutide have an elimination half-life of approximately 1 week, remaining in circulation for about 5 weeks after the last dose. Clearance of subcutaneous form is about 0.05L/h and oral Semaglutide is 0.04L/h, approximately. It is eliminated through urine and faeces. 

Administration:  

Most popular in use is the injection form, which should be administered subcutaneously into the abdomen, thigh or upper arm. Within the same body region, the upper arm to avoid injecting in the same spot each week. 

Available Dosage form: 

It is available in two forms, subcutaneous injections by Ozempic and Wegovy and oral tablets by Rybelsus 

Available strengths: 

In Wegovy: 0.25mg/0.5ml, 0.5g/0.5ml, 1mg/0.5ml, 1.7mg/0.75ml, 2.4mg/0.75ml as prefilled single-dose injection pens. 

In Ozempic: 2mg/3ml, 4mg/3ml, 8mg/3ml as prefilled multidose injection pens 

In Rybelsus: 3mg, 7mg, 14 mg as an oral tablet form. 

Specific patient population:  

Hepatic impairment population: No dosage adjustment is needed for Subcutaneous or oral Semaglutide. 

Renal impairment: No dosage adjustments are required. However, caution should be exercised when initiating or escalating doses. 

Pregnancy consideration: There is insufficient data about the use of Semaglutide in pregnant women who are at risk of significant congenital defects, ectopic pregnancies. However, findings from animal studies indicate potential risk to the fetus with Semaglutide exposure during pregnancy. 

Breastfeeding stage: Insufficient data exist regarding Semaglutide and its metabolites in human milk. 

Adverse effects: 

Hypoglycemia: This will lower blood glucose levels. The risk of hypoglycemia increases significantly with escalating doses and also when Semaglutide is administered with other anti-hyperglycemic medications. 

Gastrointestinal: The most frequently reported and most associated with discontinuation of Semaglutide include nausea, vomiting, abdominal pain, constipation and Diarrhoea. 

Semaglutide has been associated with gallbladder and biliary tract issues like cholelithiasis. 

Tirzepatide

Tirzepatide sold under the brand name Mounjaro developed by Eli Lilly and company. It is a once weekly dual GIP and GLP-1 receptors agonist. This drug is a single molecule that activates the body’s receptors for GLP-1 and GIP, which are natural incretin hormones Both GLP-1 and GIP receptors are found in areas of the human brain important for appetite regulation. Tirzepatide alleviate calorie intake, and the effects are likely mediated by affecting appetite. 

Tirzepatide was approved by the U.S. FDA as Mounjaro for adults with type 2 diabetes to improve glycemic control on May 13, 2022, and as Zepbound for adults with obesity or excess body weight. This drug is also commercialized as Mounjaro in some global market outside the U.S. for adults with obesity or those who are overweight who also have a weight- related comorbid condition. 

How it works:  

Tirzepatide is a synthetic polypeptide dual agonist for GLP- and GIP. The medication comprises 39 amino acids and is an analogue of the gastric inhibitory polypeptide. Functionally, this drug stimulates insulin release from the pancreas and reduces hyperglycemia. In addition, Tirzepatide also increases the levels of adiponectin. 

The dual agonism ability decreases hyperglycemia significantly more than GLP-1 agonist agents and reduces the patient’s appetite. Among patients without diabetes, administering Tirzepatide 5to 15mg once weekly for managing obesity led to a remarkable reduction in body weight, ranging from 16.5% to 22.4% over 72 weeks. 

Pharmacokinetics: 

Absorption: This drug has a bioavailability of approximately 80%. The time it takes to reach peak serum levels can range from 8 to 72 hours. 

Distribution:  the mean steady state volume of distribution of tirzepatide is approximately 10.3L. This drug is highly bound to plasma albumin (99%). 

Metabolism: When injected, the peptide structure undergoes proteolytic cleavage. In addition, the C20 fatty di-acid composition undergoes β- β-oxidation and amide hydrolysis. It undergoes metabolism into individual amino acids in various tissues, including the liver. 

Elimination: Tirzepatide has a half-life of 5 days, facilitating weekly dosing and is cleared in urine and faces as metabolites. 

Administration and available dosage forms: 

Tirzepatide is administered through the subcutaneous route and is not yet available in an oral form. 

The available strengths are 2.5mg/0.5ml, 5mg/0.5ml, 7.5mg/0.5ml, 10mg/0.5ml, 12.5mg/0.5ml, 15mg/0.5ml. 

Specific Patient population: 

Hepatic impairment: No dosage adjustment of Tirzepatide is suggested for patients with hepatic impairment. 

Renal impairment: Tirzepatide is associated with gastrointestinal adverse drug reactions, which leading to dehydration, which may cause acute kidney injury. Usage must be cautious in patients prone to dehydration. 

Pregnancy consideration: information on Tirzepatide use in pregnant women is inadequate to evaluate for a drug-related risk of congenital disabilities and adverse maternal or fetal outcomes. Exposure to the mother and fetus is associated with poorly controlled diabetes in pregnancy. 

Breastfeeding:  No information exists on Tirzepatide in animal or human milk or its effects on the breastfed infant. Clinicians should consider the developmental and health benefits of breastfeeding, the mother's need for Tirzepatide, and the potential adverse impacts on the breastfed infant. 

Adverse effects:  

Gastrointestinal:  decreased appetite is often reported. Nausea and diarrhoea may occur in upto 10% patients, in addition to some infrequent reports of vomiting and acid reflux. 

Cardiovascular: sinus tachycardia is reported but may be blunted by concurrent medication use.  

Renal: infrequent cases of acute kidney injury have been reported, likely secondary to dehydration from gastrointestinal losses. These may occur in healthy and preexisting chronic renal disease patients. 

Dermatologic: Hypersensitivity reactions have been infrequently reported at the injection site. 

Drug-Drug Interactions: 

Patients using other GLP-1 agents, such as semaglutide or liraglutide, should not be prescribed Tirzepatide. Patients on insulin therapy can be initiated on tirzepatide therapy and cautiously have the insulin dose decreased to minimize the risk of hypoglycemia. 

The efficacy of oral hormonal contraceptives is decreased, so patients should be advised to use non-oral contraceptive methods or add a barrier contraceptive for 4 weeks after initiation and each dose escalation with Tirzepatide. 

Tirzepatide delays gastric emptying, impacting the absorption of concurrently administered oral medications. This is particularly significant in those with preexisting delayed gastric emptying, as it can exacerbate these symptoms. Caution is advised when using oral medications dependent on threshold concentrations or with a narrow therapeutic index (TI) and Tirzepatide. 

Contraindication: Relative contraindications also exist, such as gallbladder disease or diabetic retinopathy. Tirzepatide is only approved for those with T2DM and should not be used for those with T1DM.