Meta-analyses in diabetic populations have found a correlation between reductions in HbA1c and GLP-1RA-mediated MACE risk reduction.[37, 38] The SELECT trial, which enrolled patients without diabetes but with pre-existing cardiovascular disease (CVD) and a BMI 27, found a significant reduction in MACE among those treated with semaglutide, leading to FDA approval for MACE reduction in individuals with established CVD.[18, 39] A meta-analysis incorporating SELECT and other CVOTs concluded that GLP-1RAs provide a significant MACE reduction in individuals without diabetes, though the reduction in individuals with diabetes is more pronounced.[12] These findings of benefit in populations without diabetes suggest that while the antihyperglycemic effects of GLP-1RAs likely contribute to MACE reduction, other mechanisms, such as systolic blood pressure reduction, likely also play a role.[40] Over time, clinical trials on GLP-1RA MACE reduction have shifted from a focus on secondary prevention, with over 80% of participants in earlier trials such as LEADER and SUSTAIN 6 having a history of established cardiovascular disease, to an emphasis on primary prevention in high risk participants, with less than a third of participants in REWIND having a history of established cardiovascular disease.[8, 10, 11, 41] While semaglutide is currently only FDA-approved for secondary prevention of cardiovascular disease, a meta-analysis of GLP-1RA outcome trials found no significant difference in cardiovascular event relative risk reduction between use for primary versus secondary prevention
Januvia is sometimes used in combination with other diabetes medications but is not for treating type 1 diabetes
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