The final IVs of the cardiometabolic mediators harmonized with SHBG ranged from 12 to 368, and genetically elevated levels of WC (β = −0.161; 95% CI: −0.200, −0.122; p = 3.82 × 10−16), WHR (β = −0.144; 95% CI: −0.189, −0.099; p = 3.56 × 10−10), TG (β = −0.152; 95% CI: −0.189, −0.115; p = 7.14 × 10−16), SBP (β = −0.003; 95% CI: −0.005, −0.002; p = 1.03 × 10−5), and T2DM (β = −0.071; 95% CI: −0.091, −0.051; p = 4.27 × 10−13) resulted in lower SHBG levels. Here, SHBG is linked to type 2 diabetes mellitus.