Factors Affecting the Treatment Heterogeneity of PPARγ and Pan-PPAR Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Machine Learning-Based Meta-Regression Analysis

<b>Background/Objectives</b>: Significant heterogeneity in the treatment response to peroxisome proliferator-activated receptor γ (PPARγ) agonists exists, and predictive factors for their efficacy remain unclear. We aimed to assess the relationships between routinely available clinical features and the efficacy of PPARγ agonists and pan-PPAR agonists by meta-regression analysis. <b>Methods</b>: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) and included randomised controlled trials involving type 2 diabetes patients with 12-week or longer treatment durations with PPARγ agonists or pan-PPAR agonists published before 11 November 2023 (PROSPERO registration number: CRD42024578987). We conducted mixed-effect meta-regression analyses between baseline variables and treatment response. Moreover, we developed a machine learning-based meta-forest model and ranked the relative importance of each variable. <b>Results</b>: In 147 studies involving 29,250 participants, PPARγ and pan-PPAR agonists significantly reduced HbA1c (mean difference(MD) = -0.8876 [95% confidence interval (CI): -0.8999, -0.8754]; <i>p</i> < 0.0001, <i>I</i>² = 96.0%) and FPG = (MD = -1.7900 [95% CI: -1.9137, -1.6663]; <i>p</i> < 0.0001, <i>I</i>² = 92.0%). Multivariable association analysis suggested that a greater proportion of female participants (<i>β</i> = 0.0066 [95% CI: 0.0012, 0.0121]; <i>p</i> = 0.017), younger age (<i>β</i> = -0.0314 [95% CI: -0.05, -0.0129]; <i>p</i> = 0.0009) and lower HDL-C levels (<i>β</i> = -0.9304 [95% CI: -1.5176, -0.3431]; <i>p</i> = 0.0019) were significantly associated with a greater decrease in HbA1c. A greater proportion of female participants (<i>β</i> = 0.0112 [95% CI: 0.0019, 0.0205]; <i>p</i> = 0.0178) and lower baseline HDL-C levels (<i>β</i> = -1.8722 [95% CI: -2.812, -0.9323]; <i>p</i> < 0.0001) were significantly associated with a greater decrease in FPG. These variables also ranked among the top five most important predictors of drug response in the meta-random forest models. <b>Conclusions</b>: Our study demonstrated that female sex, younger age, and lower HDL-C levels were associated with greater glycaemic lowering effect from PPARγ and pan-PPAR agonists.