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Aim  To assess the impact of the HbA1c levels achieved with antidiabetic therapies (ADTs) on the risk of MACE.    Methods  A systematic search was performed in PubMed, Cochrane, and  ClinicalTrials. gov  for RCTs published up to March 2022 reporting the occurrence of MACE and all-cause mortality in individuals with T2DM treated with all marketed ADTs, including a sample size ≥100 individuals in each study arm and follow-up ≥24 weeks. A systematic review and additive-effects network meta-analysis with random effects and a multivariate meta-regression were utilized to assess the impact of achieved HbA1c on incident MACE.    Results  We included 126 RCTs with 143 treatment arms, 270,874 individuals, and 740,295 individuals-years who were randomized to an active treatment vs. control group. Among all ADTs, only therapy with SGLT2i, GLP1-RA, or pioglitazone similarly reduced the risk of MACE compared to placebo. The achievement of HbA1c ≤ 7.0% in RCTs with the 3 drug classes in the active arm was associated with an adjusted HR of 0.91 (95% CI 0.80, 0.97;  p  = 0.017) compared with HbA1c&amp;gt;7.0%, without affecting all-cause mortality. These results, however, were not maintained among all ADTs.    Conclusions  Achieving lower glucose levels with SGLT2i, GLP1-RA, or pioglitazone is linearly associated with a reduced risk of MACEs, without affecting all-cause mortality.    Systematic Review Registration   www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213127 , identifier: CRD42020213127.

Glucose-Lowering and the Risk of Cardiovascular Events With Antidiabetic Therapies: A Systematic Review and Additive-Effects Network Meta-Analysis