{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:15:13Z","timestamp":1789067713356,"version":"build-2803163510"},"reference-count":25,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>K\u2010757 and K\u2010833 are novel full agonists of GPR40 and GPR119, respectively, which are nutrient receptors co\u2010expressed on both pancreatic beta cells and gut enteroendocrine cells that signal through complementary mechanisms. We sought to assess the effects beyond glucose control of co\u2010agonism with K\u2010757 and K\u2010833.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      A Phase 1 study of the combination of K\u2010757 and K\u2010833 was conducted in overweight\u2013obese participants to identify dose regimens causing maximal secretion of multiple gut hormones. Subsequently, a randomised, double\u2010blind, parallel arm and 13\u2010week Phase 2a study was conducted to assess the effects of K\u2010757 alone and in combination with K\u2010833, in comparison to placebo (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009155 [51\u201352\/arm]).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Co\u2010administration of K\u2010757 120\u2009mg twice daily (BID) and K\u2010833 100\u2009mg BID resulted in elevations of circulating glucagon\u2010like peptide 1 (3.44\u00d7), active glucagon\u2010like peptide 1 (5.06\u00d7), peptide YY (8.63\u00d7), glucagon dependent insulinotropic peptide (1.65\u00d7), cholecystokinin (3.06\u00d7) and oxyntomodulin (5.66\u00d7) relative to placebo. In Phase 2a, placebo\u2010adjusted weight loss with the K\u2010757\u2009+\u2009K\u2010833 combination and K\u2010757 alone was \u22122.78% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and \u22121.42% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0756), respectively. Though blood pressure, an exploratory endpoint, was not elevated at baseline, placebo\u2010adjusted reductions were observed with the combination (\u22126.9\/\u22125.4\u2009mmHg) and K\u2010757 alone (\u22125.3\/\u22123.2\u2009mmHg). Gastrointestinal adverse events (AEs) and discontinuation due to AEs were more common in the active treatment arms. The combination and K\u2010757 alone were otherwise well tolerated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>K\u2010757, alone and in combination with K\u2010833, elicited robust elevations in circulating concentrations of multiple satiety peptides, which elicited some weight loss and blood pressure reductions that suggest potential for metabolic benefit independent of weight loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70120","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T04:45:38Z","timestamp":1757997938000},"page":"7198-7209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined agonism of nutrient receptors\n                    <scp>GPR40<\/scp>\n                    and\n                    <scp>GPR119<\/scp>\n                    with K\u2010757 and K\u2010833 results in weight loss and blood pressure reductions in obese subjects without\n                    <scp>type 2 diabetes mellitus<\/scp>"],"prefix":"10.1111","volume":"27","author":[{"given":"Michael","family":"Crutchlow","sequence":"first","affiliation":[{"name":"Kallyope, Inc.  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajun","family":"Liu","sequence":"additional","affiliation":[{"name":"Kallyope, Inc.  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Romero","sequence":"additional","affiliation":[{"name":"Headlands Research  Brownsville Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Watkins","sequence":"additional","affiliation":[{"name":"ProSciento  Chula Vista California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Zhang","sequence":"additional","affiliation":[{"name":"Kallyope, Inc.  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Arreglado","sequence":"additional","affiliation":[{"name":"Kallyope, Inc.  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