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Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG\u2009+\u2009CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (\u0394) in \u03b2\u2010hydroxybutyric acid (\u03b2\u2010HBA) before and after the CANA or PIOG\u2009+\u2009CANA treatments. The secondary outcomes were \u0394changes in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and \u0394changes in factors related to SGLT2 inhibitor\u2010induced ketone body production including non\u2010esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention\u2010to\u2010treat principle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty\u2010five patients with a mean age of 49\u2009\u00b1\u20097.97\u2009years and a body mass index of 25.35\u2009\u00b1\u20092.22\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels\u00a0of ketone bodies (except for acetoacetate) in the PIOG\u2009+\u2009CANA group were significantly smaller than in the CANA group (219.84\u2009\u00b1\u200980.21\u2009\u03bcmol\/L vs. 317.69\u2009\u00b1\u200983.07\u2009\u03bcmol\/L,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001 in \u03b2\u2010HBA; 8.98\u2009\u00b1\u20094.17\u2009\u03bcmol\/L vs. 12.29\u2009\u00b1\u20095.27\u2009\u03bcmol\/L,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG\u2009+\u2009CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in \u0394changes in serum NEFA levels with the differences in \u0394changes in ketones of \u03b2\u2010HBA and acetoacetate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Supplementation of pioglitazone could alleviate canagliflozin\u2010induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.15641","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T03:48:37Z","timestamp":1714708117000},"page":"3137-3146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pioglitazone reduces serum ketone bodies in\n                    <scp>sodium\u2010glucose cotransporter<\/scp>\n                    \u20102 inhibitor\u2010treated non\u2010obese type 2 diabetes: A single\u2010centre, randomized, crossover trial"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2555-3507","authenticated-orcid":false,"given":"Min","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji 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