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Hydrogen sulphide (H\n                      <jats:sub>2<\/jats:sub>\n                      S), a well\u2010studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H\n                      <jats:sub>2<\/jats:sub>\n                      S donor in two preclinical models of cardiometabolic HFpEF was investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Nine\u2010week\u2010old C57BL\/6N mice received L\u2010NAME and a 60% high fat diet for five\u2009weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H\n                      <jats:sub>2<\/jats:sub>\n                      S donor, SG1002, for five additional weeks. Ten\u2010week\u2010old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8\u2009weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>SGLT2i treatment improved E\/e\u2032 ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end\u2010diastolic function (E\/e\u2032 ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow\u2010up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      SGLT2i monotherapy remediated pathological complications exhibited by two well\u2010established HFpEF models. Adjunctive H\n                      <jats:sub>2<\/jats:sub>\n                      S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow\u2010up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H\n                      <jats:sub>2<\/jats:sub>\n                      S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16493","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T02:19:51Z","timestamp":1720577991000},"page":"4294-4310","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Adjunctive therapy with an oral H\n                    <sub>2<\/sub>\n                    S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4584-4819","authenticated-orcid":false,"given":"Jake 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