Tirzepatide
Tirzepatide is an experimental drug proposed to help treat type 2 diabetes, obesity and non-alcoholic fatty liver disease. It is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism. The compound is administered as a weekly subcutaneous injection. It completed phase 3 trials globally in 2021. History. Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for  a method of glycemic control using tirzepatide back in early 2016, which was published late that year. After passing phase 3 clinical trials (the last phase before a company is able to seek FDA approval), Eli Lilly and Company applied for FDA approval in October 2021 with a priority review voucher. Following the completion of the pivotal SURPASS-2 trial no. NCT03987919, Eli Lilly and Company announced on the 28th of April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes. Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be  a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk. Mechanism of action. Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor. However, at the GLP-1 receptor tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP  receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion. Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% (10 mg dosage) from baseline after 26 weeks. Chemistry. Structure. Tirzepatide is an analog of the human GIP hormone (with a C fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound. The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain  of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin. Synthesis. The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company. This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment. Large-scale manufacturing processes have been reported. Efficacy. In industry-funded preliminary  trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%). A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin). Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity. A meta-analysis published by Dutta et. al. showed that over 1-year clinical use, tirzepatide was observed  to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed till date to tackle the global problem of "diabesity". Adverse effects. Preclinical, phase 1, and phase 2 trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract. The most frequently observed adverse effects are nausea, diarrhoea and vomiting which were linked to dosage amount (i.e. higher likelihood the higher the dose). The amount of patients  who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide. To a slightly lesser extent, patients also reported reduced appetite. Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.