AbstractBackground:Thiazolidinediones (TZDs) are a type of oral drug that are utilized for the treatment of type 2 diabetes mellitus (T2DM). They function by acting as agonists for a nuclear transcription factor known as peroxisome proliferator-activated receptor-gamma (PPAR-γ). TZDs, such as pioglitazone and rosiglitazone, help enhance the regulation of metabolism in individuals with T2DM by improving their sensitivity to insulin. Previous studies have suggested a relationship between the therapeutic efficacy of TZDs and thePPARGPro12Ala polymorphism (C > G, rs1801282). However, the small sample sizes of these studies may limit their applicability in clinical settings. To address this limitation, we conducted a meta-analysis assessing the influence of thePPARGPro12Ala polymorphism on the responsiveness of TZDs.Method:We registered our study protocol with PROSPERO, number CRD42022354577. We conducted a comprehensive search of the PubMed, Web of Science, and Embase databases, including studies published up to August 2022. We examined studies investigating the association between thePPARGPro12Ala polymorphism and metabolic parameters such as hemoglobin A1C(HbA1C), fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The mean difference (MD) and 95% confidence intervals (CIs) between pre- and post-drug administration were evaluated. The quality of the studies included in the meta-analysis was assessed by using the Newcastle–Ottawa Scale (NOS) tool for cohort studies. Heterogeneity across studies was assessed by using theI2value. AnI2value greater than 50% indicated substantial heterogeneity, and a random-effects model was used for meta-analysis. If theI2value was below 50%, a fixed-effects model was employed instead. Both Begg’s rank correlation test and Egger’s regression test were performed to detect publication bias, using R Studio software.Results:Our meta-analysis incorporated 6 studies with 777 patients for blood glucose levels and 5 studies with 747 patients for lipid levels. The included studies were published between 2003 and 2016, with the majority involving Asian populations. Five of the six studies utilized pioglitazone, while the remaining study employed rosiglitazone. The quality scores, as assessed with the NOS, ranged from 8 to 9. Patients carrying the G allele exhibited a significantly greater reduction in HbA1C(MD = −0.3; 95% CI = −0.55 to −0.05;p =0.02) and FPG (MD = −10.91; 95% CI = −19.82 to −2.01;p =0.02) levels compared to those with the CC genotype. Furthermore, individuals with the G allele experienced a significantly larger decrease in TG levels than those with the CC genotype (MD = −26.88; 95% CI = −41.30 to −12.46;p =0.0003). No statistically significant differences were observed in LDL (MD = 6.69; 95% CI = −0.90 to 14.29;p =0.08), HDL (MD = 0.31; 95% CI = −1.62 to 2.23;p =0.75), and TC (MD = 6.4; 95% CI = −0.05 to 12.84;p =0.05) levels. No evidence of publication bias was detected based on Begg’s test and Egger’s test results.Conclusions:This meta-analysis reveals that patients with the Ala12 variant in thePPARGPro12Ala polymorphism are more likely to exhibit positive responses to TZD treatment in terms of HbA1C, FPG, and TG levels compared to those with the Pro12/Pro12 genotype. These findings suggest that genotyping thePPARGPro12Ala in diabetic patients may be advantageous for devising personalized treatment strategies, particularly for identifying individuals who are likely to respond favorably to TZDs.