PMID- 38425186 OWN - NLM STAT- MEDLINE DCOM- 20240508 LR - 20240508 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 26 IP - 6 DP - 2024 Jun TI - A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin. PG - 2188-2198 LID - 10.1111/dom.15526 [doi] AB - AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% +/- 0.72% to 7.27% +/- 0.82%) compared with placebo (from 7.79% +/- 0.76% to 7.69% +/- 0.86%, corrected mean difference: -0.42% +/- 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference. CI - (c) 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Lim, Soo AU - Lim S AUID- ORCID: 0000-0002-4137-1671 AD - Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea. FAU - Lee, Seung-Hwan AU - Lee SH AUID- ORCID: 0000-0002-3964-3877 AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Min, Kyung-Wan AU - Min KW AD - Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, South Korea. FAU - Lee, Chang Beom AU - Lee CB AD - Department of Internal Medicine, Hanyang University Guri Hospital, Guri, South Korea. FAU - Kim, Sang Yong AU - Kim SY AD - Department of Internal Medicine, Chosun University Hospital, Gwangju, South Korea. FAU - Yoo, Hye Jin AU - Yoo HJ AD - Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea. FAU - Kim, Nan Hee AU - Kim NH AUID- ORCID: 0000-0003-4378-520X AD - Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea. FAU - Kim, Jae Hyeon AU - Kim JH AD - Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. FAU - Oh, Seungjoon AU - Oh S AD - Department of Endocrinology and Metabolism, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, South Korea. FAU - Won, Jong Chul AU - Won JC AD - Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea. FAU - Kwon, Hyuk Sang AU - Kwon HS AUID- ORCID: 0000-0003-4026-4572 AD - Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Kim, Mi Kyung AU - Kim MK AD - Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea. FAU - Park, Jung Hwan AU - Park JH AD - Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea. FAU - Jeong, In-Kyung AU - Jeong IK AUID- ORCID: 0000-0001-7857-546X AD - Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, South Korea. FAU - Kim, Sungrae AU - Kim S AUID- ORCID: 0000-0001-6417-8412 AD - Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, South Korea. LA - eng GR - Yooyoung Pharmaceutical Company/ PT - Clinical Trial, Phase III PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20240229 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Glucosides) RN - X4OV71U42S (Pioglitazone) RN - 9100L32L2N (Metformin) RN - 0 (Benzhydryl Compounds) RN - 1ULL0QJ8UC (dapagliflozin) RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) RN - 0 (hemoglobin A1c protein, human) RN - 0 (Thiazolidinediones) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Blood Glucose) SB - IM MH - Humans MH - *Glucosides/therapeutic use/adverse effects/administration & dosage MH - *Pioglitazone/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/blood MH - *Metformin/therapeutic use/adverse effects MH - *Benzhydryl Compounds/therapeutic use/adverse effects MH - Double-Blind Method MH - Male MH - Female MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Glycated Hemoglobin/analysis/drug effects/metabolism MH - *Drug Therapy, Combination MH - Treatment Outcome MH - Thiazolidinediones/therapeutic use/adverse effects MH - Aged MH - Insulin Resistance MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - Blood Glucose/drug effects/metabolism MH - Waist Circumference/drug effects MH - Republic of Korea MH - Adult OTO - NOTNLM OT - dapagliflozin OT - diabetes OT - metformin OT - pioglitazone OT - randomized controlled trial EDAT- 2024/03/01 06:43 MHDA- 2024/05/08 06:44 CRDT- 2024/03/01 02:34 PHST- 2024/02/12 00:00 [revised] PHST- 2023/11/13 00:00 [received] PHST- 2024/02/12 00:00 [accepted] PHST- 2024/05/08 06:44 [medline] PHST- 2024/03/01 06:43 [pubmed] PHST- 2024/03/01 02:34 [entrez] AID - 10.1111/dom.15526 [doi] PST - ppublish SO - Diabetes Obes Metab. 2024 Jun;26(6):2188-2198. doi: 10.1111/dom.15526. Epub 2024 Feb 29.