AimsTo evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) or a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta‐analysis, and analysis of a large international real‐world database.MethodsWe searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP‐1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane‐endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity‐score‐matched individuals who were treated for at least 1 year with pioglitazone and a GLP‐1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP‐1RA and SGLT2 inhibitor monotherapy. Outcomes were all‐cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack.ResultsThe average follow‐up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP‐1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences −1% (95% confidence interval [CI] −1.27, −0.74) and −1.19 kg (95% CI −1.80, −0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference − 1.56 mmHg (95% CI −4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07–1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences −0.48% (95% CI −0.67, −0.28), −2.3 kg (95% CI −2.72, −1.88) and −2.4 mmHg (95% CI −4.1, −0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30–10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real‐world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38–0.65; p < 0.001).ConclusionBoth our systematic review/meta‐analysis and the real‐world dataset show that combination of pioglitazone with either GLP‐1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

中文翻译：

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吡格列酮联合钠-葡萄糖协同转运蛋白-2抑制剂或胰高血糖素样肽-1受体激动剂对2型糖尿病结局的影响：来自国际联合数据库的系统评价、荟萃分析和真实世界研究

目的 通过进行一项试验，评估吡格列酮与胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 或钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂联合用药对 2 型糖尿病 (T2D) 患者的疗效和心血管结局。对大型国际真实世界数据库进行系统评价、荟萃分析和分析。方法我们搜索了 MEDLINE、SCOPUS 和 Web of Science，以确定要纳入的相关文章（PROSPERO [CRD：42023483126]）。确定了 19 项评估吡格列酮 + SGLT2 抑制剂或 GLP-1RA 与对照的研究，其中 16 项是随机对照试验。使用 Cochrane 认可的工具评估偏倚风险，并使用 GRADE 评估证据质量。我们还使用 TriNetX 平台对所有 18 岁或以上患有 T2D 的个体进行了回顾性队列研究。我们纳入了接受吡格列酮和 GLP-1RA 或吡格列酮和 SGLT2 抑制剂治疗至少 1 年的倾向评分匹配个体，与 GLP-1RA 和 SGLT2 抑制剂单一疗法进行比较。结果包括全因死亡率、心力衰竭、慢性肾病、复合性卒中和短暂性脑缺血发作。结果纳入研究的平均随访时间为 24 至 52 周。吡格列酮与 GLP-1RA 组合可降低糖化血红蛋白 (HbA1c) 和体重，高于对照组：平均差异 -1%（95% 置信区间 [CI] -1.27, -0.74）和 -1.19 kg（95% CI -1.80） ，-0.58），分别。各组之间的收缩压（SBP）或死亡率没有统计学上的显着差异：平均差− 1.56 mmHg（95% CI −4.48，1.35；p= 0.30），相对风险 (RR) 0.29（95% CI 0.07–1.15；p= 0.08），分别。吡格列酮与 SGLT2 抑制剂的组合比对照治疗更大程度地降低了 HbA1c、体重和 SBP：平均差异 -0.48% (95% CI -0.67, -0.28)、-2.3 kg (95% CI -2.72, -1.88) 和−2.4 mmHg (95% CI −4.1, −0.7;p= 0.01），分别。组间死亡率无统计学显着差异（RR 1.81，95% CI 0.30-10.97；p= 0.52）。纳入的试验表明联合治疗可降低心力衰竭的风险。同样，从现实世界的数据库（n= 25 230 例），与单独治疗相比，吡格列酮和 SGLT2 抑制剂联合治疗可降低心力衰竭风险（风险比 0.50，95% CI 0.38–0.65；p< 0.001）。结论我们的系统评价/荟萃分析和真实世界数据集均表明，与单一疗法相比，吡格列酮与 GLP-1RA 或 SGLT2 抑制剂的组合可增加体重减轻并降低心力衰竭风险。