Snapshot A 40-year-old man presents to his primary care physician for high cholesterol levels. Six months ago, at his last clinic visit, he was found to have high levels of LDL cholesterol. Since then, he has tried to change his diet and exercise more frequently but admits that this has been difficult for him. He reports recently starting a “natural” treatment for high cholesterol and that it is “a healthy vitamin.” Since starting this treatment, however, he reports having a flushed face. (Niacin) Introduction Key enzymes in lipid physiology lipoprotein lipase (LPL) degrades triglycerides (TG) that are circulating around the bloodstream in chylomicrons and very low-density lipoproteins (VLDL) hormone-sensitive lipase degrades TG stored in adipose tissues HMG-CoA reductase converts HMG-CoA into mevalonate, a precursor of cholesterol peroxisome proliferator-activated receptor-α (PPAR-α) activated during starvation and catabolizes fatty acids increases synthesis of LPL, causing a reduction in TG raises high-density lipoprotein (HDL) Lipid-lowering agents acts on the liver HMG-CoA reductase inhibitors PCSK9 inhibitors acts peripherally fibrates niacin acts on intestinal absorption bile acid resins ezetimibe Relative Effects of Lipid-Lowering Agents on LDL, HDL, and TG Drug LDL HDL TG HMG-CoA reductase inhibitors ↓↓↓* ↑ ↓ PCSK9 inhibitors ↓↓↓ ↑ ↓ Fibrates ↓ ↑ ↓↓↓* Niacin ↓↓ ↑↑* ↓ Bile acid resins ↓↓ ↑ ↑ Ezetimibe ↓ ↑/- ↓/- * = best therapy HMG-CoA Reductase Inhibitors Drugs lovastatin, pravastatin, simvastatin, rosuvastatin, and atorvastatin Mechanism prevents synthesis of mevalonate, a cholesterol precursor, by inhibiting HMG-CoA reductase this is the rate-limiting step of cholesterol synthesis increases LDL receptors Clinical use ↓ mortality in patients with coronary artery disease primarily lowers low-density lipoproteins (LDL) most effective drug for lowering LDL Toxicity hepatotoxicity myopathy especially when used in combination with fibrates and niacin inhibitors of P450 can ↑ serum concentration PCSK9 Inhibitors Drugs alirocumab and evolocumab Mechanism monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9) PCSK9 destroys LDL-receptor on hepatocytes, which results in decreases clearance of LDL inhibition of PCSK9 improves clearance of LDL Clinical use primarily decreases LDL Toxicity myopathy neurocognitive effects delirium dementia Fibrates Drugs gemfibrozil, bezafibrate, and fenofibrate Mechanism activates PPAR-α and upregulates lipoprotein lipase reduces levels of triglycerides induces HDL synthesis Clinical use primarily decreases TG most effective drug for lowering TG Toxicity myopathy cholesterol gallstones can ↑ LDL so, so fibrates are not often used as monotherapy Niacin (Vitamin B3) Mechanism inhibits hormone-sensitive lipase inhibits hepatic VLDL synthesis Clinical use primarily increases HDL most effective drug for increasing HDL levels Toxicity red and flushed face/upper body thought to be due to a release of prostaglandins and histamine treat with non-steroidal anti-inflammatory drugs (NSAIDs) ↑ glucose ↑ uric acid acanthosis nigricans pruritus Bile Acid Resins Drug cholestyramine, colestipol, and colesevelam Mechanism binds to bile acids and prevents reabsorption of bile acids in the distal ileum this forces the liver to make more bile acids by using the available cholesterol in the body Clinical use primarily decreases LDL Toxicity gastrointestinal upset malabsorption, especially of fat-soluble vitamins Ezetimibe Mechanism inhibits sterol transporter at the small intestine brush border, preventing the absorption of cholesterol this decreases the hepatic stores of cholesterol Clinical use primarily decreases LDL primarily used in combination with a statin Toxicity rare hepatotoxicity when used in combination with statins gastrointestinal upset