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Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1\u20135) have shown that tirzepatide at 5\u201315\u00a0mg per week reduces both HbA\n                    <jats:sub>1c<\/jats:sub>\n                    (1.24 to 2.58%) and body weight (5.4\u201311.7\u00a0kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA\n                    <jats:sub>1c<\/jats:sub>\n                    of &lt;\u20095.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA\n                    <jats:sub>1c<\/jats:sub>\n                    and body weight than the selective GLP-1 RA semaglutide (1.0\u00a0mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2\u00a0year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio &gt;\u20091.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were &lt;\u20091.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.\n                  <\/jats:p>","DOI":"10.1186\/s12933-022-01604-7","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T15:05:48Z","timestamp":1662044748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":398,"title":["Tirzepatide, a dual GIP\/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction"],"prefix":"10.1186","volume":"21","author":[{"given":"Michael A.","family":"Nauck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"D\u2018Alessio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"1604_CR1","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1210\/jc.2011-2525","volume":"97","author":"SJ Guyenet","year":"2012","unstructured":"Guyenet SJ, Schwartz MW. 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Diabet Care. 2021;44:1433\u201342.","journal-title":"Diabet Care"}],"container-title":["Cardiovascular Diabetology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-022-01604-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12933-022-01604-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-022-01604-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T17:03:05Z","timestamp":1662051785000},"score":1,"resource":{"primary":{"URL":"https:\/\/cardiab.biomedcentral.com\/articles\/10.1186\/s12933-022-01604-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,1]]},"references-count":94,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["1604"],"URL":"https:\/\/doi.org\/10.1186\/s12933-022-01604-7","relation":{},"ISSN":["1475-2840"],"issn-type":[{"value":"1475-2840","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,1]]},"assertion":[{"value":"11 July 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Menarini\/Berlin Chemie, Merck, Sharp & Dohme, NovoNordisk, Regor, and ShouTi Inc.\/Gasherbrum. He has received grant support from Merck, Sharp & Dohme. He is member of a data monitoring and safety board for Inventiva. He has also served on the speakers\u2019 bureau of Eli Lilly & Co., Medscape, Medical Learning Institute, Menarini\/Berlin Chemie, Merck, Sharp & Dohme, NovoNordisk, and Sun Pharmaceuticals. D.A.D. consults for Eli Lilly & Co. and Sun Pharmaceuticals.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"169"}}