In this study, we identify a potent HMGCR degrader, Cmpd 81 (also named as HMG499), elucidate the mechanism of Cmpd 81 action in stimulating HMGCR degradation and assess its therapeutic efficacy, when used alone or synergistically with stain, for treatments of hyperlipidemia and atherosclerosis. Here, HMGCR is linked to atherosclerosis.