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Goal for Treatment of Hyperlipidemias:

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- prevent the consequences of atherosclerosis, including heart attacks, angina, peripheral arterial disease, ischemic stroke

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Drugs for Treatment of Hyperlipidemias:

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1. HMG-CoA Reductase Inhibitors - Statins 2. Resins 3. Ezetimibe 4. Niacin 5. Fibrates

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Risk Factors for CVD

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1. Age: Male > 45 years, Female > 55 years 2. Family History of premature CHD: 1st degree relative - Male < 55 years or Female < 65 year before 1st CHD even occurs 3. Current Cigarette Smoking 4. HTN 5. Low HDL 6. Obesity

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Lipoproteins

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Macromolecular complexes in the blood that transport lipids

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Apolipoproteins

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Proteins on the surface of lipoproteins; they play critical roles in the regulation of lipoprotein metabolism and uptake into cells

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Low-density lipoprotein (LDL)

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Cholesterol-rich lipoprotein whose regulated uptake by hepatocytes and other cells requires functional LDL receptors; an elevated LDL concentration is associated with atherosclerosis

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High-density lipoprotein (HDL)

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Cholesterol-rich lipoprotein that transports cholesterol from the tissues to the liver; a low concentration is associated with atherosclerosis

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Very-low-density lipoprotein (VLDL)

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Triglyceride- and cholesterol-rich lipoprotein secreted by the liver that transports triglycerides to the periphery; precursor of LDL

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HMG-CoA reductase

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3-Hydroxy-3-methylglutaryl-coenzyme A reductase; the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis

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Lipoprotein lipase (LPL)

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- Breaks down endogenous triglycerides into glycerol and fatty acids; responsible for releasing free fatty acids from TGs from chylomicrons → VLDLs → IDLs → LDLs - found primarily along endothelial lining - Apolipoprotein C-II is a co-factor - free fatty acids are taken up into cells

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Proliferator-activated receptor-alpha (PPAR-alpha)

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- Member of a family of nuclear transcription regulators that participate in the regulation of metabolic processes; target of the fibrate drugs and omega-3 fatty acids

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Hyperlipoproteinemia: Pathogenesis

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- elevated concentrations of certain plasma lipoproteins, especially LDLs, that participate in cholesterol transport - strongly associated with premature or accelerated development of *atherosclerosis* - *Low HDL* levels also associated with increased risk of atherosclerosis. - In some families, hypertriglyceridemia is similarly correlated with atherosclerosis.

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Familial ligand-defective Apo B

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- *problem with ApoB -> LDL can't bind to receptor* - LDL is increased - most prevalent genetic mutation (2-3%)

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Lp(a) hyperlipoproteinemia

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LDL increased

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Lp(a)

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- has *Apo A* affiliation - interferes with clotting and can increase cholesterol

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Familial dysbetalipoproteinemia

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- increased levels of VLDL remnants and chylomicron remnants - deficiency in *apoE*

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Familial hypercholesterolemia

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- LDL significantly increased - *defect in LDL receptors prevents uptake of LDL* - *Heterozygous:* cholesterol level > 400mg/dL, die at 40 yrs - *Homozygous:* cholesterol level >800, die at 10 yrs without treatment - must treat with drugs that don't work via LDL receptor, such as Niacin

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Regulation of plasma lipoprotein levels

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- involves a complex interplay of dietary fat intake, hepatic processing, and utilization in peripheral tissues. - *Primary disturbances* in regulation occur in a number of *genetic* conditions involving mutations in apolipoproteins, their receptors, transport mechanisms, and lipid-metabolizing enzymes. - *Secondary disturbances* are associated with a Western *diet,* many endocrine conditions, and diseases of the liver or kidneys.

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Metabolism of lipoproteins of hepatic origin

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- The heavy arrows show the primary pathways. *Nascent VLDL* are secreted via the Golgi apparatus. They acquire additional *apoC* lipoproteins and *apoE* from *HDL.* VLDL is converted to *VLDL remnants* by lipolysis via *lipoprotein lipase* associated with capillaries in peripheral tissue supplies. In the process, *C apolipoproteins* and a portion of *apoE* are given *back* to *HDL.* Some of the VLDL remnants are converted to *LDL* by further *loss of triglycerides and loss of apoE.* - A major pathway for *LDL degradation* involves the *endocytosis of LDL by LDL receptors* in the liver and the peripheral tissues, for which *apoB-100 is the ligand.* (Dark color denotes cholesteryl esters; light color, triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins.)

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Diet treatment strategy

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- first method of management, may be enough to lower levels to safe range - Diet designed to *reduce the total intake of cholesterol and saturated fats* (primary dietary factors that contribute to elevated levels of plasma lipoproteins) - Because *alcohol raises triglyceride and VLDL levels,* it should be avoided by patients with hypertriglyceridemia

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Drugs that are most effective at lowering LDL cholesterol

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- HMG-CoA reductase inhibitors / statins - resins - ezetimibe - niacin

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Drugs that are most effective at lowering triglyceride and VLDL concentrations and raising HDL cholesterol concentrations

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- fibric acid derivatives (eg, gemfibrozil) - niacin - marine omega-3 fatty acids

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Statins

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- structural analogs of HMG-CoA that competitively inhibit the enzyme, HMG-CoA Reductase - Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. - Bottom: The structure of lovastatin and its active form, showing similarity to the normal HMG-CoA intermediate

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Which statins are prodrugs?

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Lovastatin and simvastatin

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Which statins are active as given?

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atorvastatin, fluvastatin, pravastatin, and rosuvastatin

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HMG-CoA Reductase Inhibitors: MOA and Effects

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- Although the *inhibition of hepatic cholesterol synthesis* contributes a small amount to the total serum cholesterol-lowering effect of these drugs, a much greater effect derives from the response to a reduction in a tightly regulated hepatic pool of cholesterol. - The liver compensates by *increasing the number of high-affinity LDL receptors,* which clear LDL and VLDL remnants from the blood. - also have direct anti-atherosclerotic effects, and have been shown to prevent bone loss.

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HMG-CoA Reductase Inhibitors: Effects

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- Since cholesterol is not made anymore, VLDL secretion and TGs decrease, liver increases LDL receptors - result: decreased risk of second heart attack - men: decreased mortality and decreased CV events in men who've never had one - women: decreased CV events - can prevent strokes - questionable for cancer prevention

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Other Actions of Statins

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1. stabilizes plaques 2. coronary vasodilator 3. decreases inflammation by decreasing C-reactive protein 4. decreases LDL oxidation (minor role) 5. works on diabetics to decrease mortality

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HMG-CoA Reductase Inhibitors: Toxicity

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- *Mild elevations of serum aminotransferases* are common but are not often associated with hepatic damage. - Patients with preexisting liver disease may have more severe reactions; Asians have higher risk of toxicity - *increase in creatine kinase* (released from skeletal muscle) is noted in about 10% of patients; in a few, *severe muscle pain* and even *rhabdomyolysis* may occur as a result of decreased muscle integrity - may be *teratogenic,* so these drugs should be avoided in pregnancy (stops growth of baby) - may lead to *breast cancer* in women - *complete memory loss* is now an FDA warning - can *increase blood glucose* in diabetics

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Rhabdomyolysis

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- possible toxicity from statins - muscle destruction -> material from muscle cell accumulates in the kidney -> damage -> death

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HMG-CoA Reductase Inhibitors: Drug Interactions

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- 1st and 2nd generations: metabolized by the CYP450 system; drugs or foods, like grapefruit juice, that inhibit CYP450 activity increase the risk of hepatotoxicity and myopathy. - others mainly metabolized in the bile, so not many drug interactions

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Pitavastatin, Livalo

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- *NEW* statin drug that might be the *best at increasing HDL* - better at reducing cholesterol - longer half-life than older statins

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Enterohepatic Circulation of Bile Salts

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- Synthesized by the liver → bile ducts → duodenum → emulsify fats → fat broken down by lipases → bile salt acts as carriers to transport fatty acids back into enteric cells - Bile salts are taken back up into the liver from blood (portal vein)

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Bile acid-binding Resins: MOA

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- Normally, over 90% of bile acids, which are metabolites of cholesterol, are reabsorbed in the GI tract and returned to the liver for reuse. - Examples: cholestyramine, colestipol, and colesevelam - these are large nonabsorbable polymers that *bind bile acids* and similar steroids in the intestine and *prevent their absorption*

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Bile acid-binding Resins: Effects

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- *Prevent the recycling of bile acids* and therefore divert hepatic cholesterol to *synthesis of new bile acids,* resulting in a reduction in the amount of cholesterol collected in a tightly regulated pool. This leads to a compensatory *increase in the synthesis of high-affinity LDL receptors,* which in turn *increases the removal of LDL from the blood.* - cause a modest reduction in LDL but have *little effect on HDL or TG.* In some patients with genetic predisposition for high TG and cholesterol, resins increase TGs and VLDL. - simultaneously *increases cholesterol synthesis* (opposite of statins)

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Bile acid-binding Resins: Clinical Use

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- used in patients with hypercholesterolemia - also been used to reduce pruritus (itching) in patients with cholestasis and bile salt accumulation

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Bile acid-binding Resins: Toxicity

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- bloating, constipation, and an unpleasant gritty taste. - *safe for pregnant women* because they're not absorbed into circulation - take with meals - *Impairs absorption of:* 1. *vitamins* - like vitamin K, dietary folates 2. *drugs* - such as thiazide diuretics, warfarin, pravastatin, fluvastatin

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Colesevelam

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- Bile acid resin - cholestyramine/colestipol - decreased drug binding - encapsulated

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Ezetimibe: MOA

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- *prodrug* converted in the liver to the *active glucuronide* form. - active metabolite *inhibits a transporter that mediates GI uptake of cholesterol and phytosterols* - Therefore, *prevents absorption of dietary cholesterol and cholesterol that is excreted in bile* -> also reduces the cholesterol in the tightly regulated hepatic pool. - leads to a compensatory *increase in the synthesis of high-affinity LDL receptors,* which in turn, *increases the removal of LDL* from the blood. - inhibits Neiman-Pick-like protein

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phytosterols

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- plant sterols that normally enter GI epithelial cells but then are immediately transported back into the intestinal lumen - transport blocked by Ezetimibe

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phytosterolemia

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- rare genetic disorder that results from impaired export of phytosterols - treated by Ezetimibe

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Ezetimibe: Effects

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- As monotherapy: *reduces LDL* cholesterol by about 18% - Combined with a statin, it is even more effective (says the book, not Greenspan)

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Ezetimibe: Clinical Use

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- used for treatment of hypercholesterolemia and phytosterolemia

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Ezetimibe: Toxicity

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- well tolerated - combined with statins, may increase the risk of hepatic toxicity

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Ezetimibe: Drug Interactions

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- Serum concentrations of the glucuronide form are: 1. increased by fibrates 2. reduced by cholestyramine

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Vytorin

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- combination of *Simvastatin and Ezetimibe* - lowers cholesterol even further, giving the BEST result (says book) - However, a Merck study showed that combination therapy was no different or maybe even WORSE than statin alone

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Liptuzet

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- Combination therapy including *Atorvastatin and Ezetimibe* - made by same company as Vytorin - no data shows it's beneficial to lower CVD - but it does decrease LDL (a little)

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Niacin, Nicotinic Acid: MOA

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- In the liver: *reduces VLDL synthesis -> reduces LDL levels* - In adipose tissue: activates a signaling pathway that *reduces hormone-sensitive lipase* activity and thus decreases plasma fatty acid and TG levels -> LDL formation is reduced -> decreased LDL - In capillary endothelial cells: *Increased clearance of VLDL by lipoprotein lipase* -> reduces plasma TGs even more - reduces the catabolic rate for HDL - decreases circulating fibrinogen and increases tissue plasminogen activator (plasminogen cleaves clots)

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Niacin: Effects

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- Decreases VLDL synthesis, TG, and LDL concentrations - Increases HDL cholesterol - decreases LPA (Apo A + LDL)

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Niacin: Clinical Use

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- treatment of: 1. hypercholesterolemia 2. hypertriglyceridemia 3. low levels of HDL

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Niacin: Toxicity

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1. *Cutaneous flushing;* pretreatment with aspirin or other NSAIDs reduces the intensity (so may be mediated by prostaglandin release). Tolerance to flushing usually develops within a few days 2. *Dose-dependent nausea and abdominal discomfort* 3. *Pruritus* and other skin conditions 4. *Moderate elevations of liver enzymes* and even severe *hepatotoxicity* may occur, primarily with extended-release preparation. 5. *Hyperuricemia* occurs in about 20% of patients, and *carbohydrate tolerance* may be moderately impaired.

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Niaspan

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- safer than Niacin, but it increases blood glucose and increases uric acid - may cause abdominal discomfort - pregnant women should not take it

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Advicor

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- Combination therapy including *Lovastatin and Niacin* - leads to NO CHANGE in CV death - no evidence that addition of Niacin is better than statin alone

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Simcor

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- Combination therapy including *Simvastatin and Niacin* - leads to NO CHANGE in CV death - no evidence that addition of Niacin is better than statin alone

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Fibric Acid Derivatives: MOA

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- Examples: gemfibrozil, fenofibrate - *ligands/agonists for the PPAR-alpha protein* - In adipose tissue: binding causes *increased synthesis of lipoprotein lipase,* which associates with capillary endothelial cells and *enhances clearance of TG-rich lipoproteins* - In the *liver:* 1. stimulate *fatty acid oxidation* -> limits the supply of TGs and decreases VLDL synthesis 2. *increases expression of apoA-I and apoA-II*-> increases HDL levels 3. *decrease expression of apoC-III,* which impedes the clearance of VLDL

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Fibric Acid Derivatives: Effects

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- In most, *lower TG but little or no effect on LDL* - However, can increase LDL in patients with familial combined hyperlipoproteinemia, which is associated with a combined increase in VLDL and LDL.

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Fibric Acid Derivatives: Clinical Use

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- treat *hypertriglyceridemia* - Because these drugs have only a modest ability to reduce LDL cholesterol and can increase LDL cholesterol in some patients, they often are combined with other cholesterol-lowering drugs for treatment of patients with elevated concentrations of both LDL and VLDL.

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Fibric Acid Derivatives: Toxicity

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1. Nausea = most common 2. Skin rashes = common with gemfibrozil. 3. Few patients show decreases in WBC or Hct 4. *Increased risk of cholesterol gallstones* -> use with caution in patients with a history of cholelithiasis 5. In combination with reductase inhibitors: significantly increase the risk of myopathy

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Fibric Acid Derivatives: Drug Interactions

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- can potentiate the action of anticoagulants

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Combination Therapy

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- Because resins interfere with the absorption of certain statins (pravastatin, cerivastatin, atorvastatin, and fluvastatin), these must be given at least 1 h before or 4 h after the resins. -The combination of reductase inhibitors with either fibrates or niacin increases the risk of myopathy.

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What is the only drug that inhibits cholesterol absorption in the GI?

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Ezetimibe

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Which drug class can actually INCREASE mortality due to it's induction of formation of gallstones?

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Fibrates

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Which fibrate has a better effect on lowering LDL?

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Fenofibrate

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Two facts we know about Lipid-Lowering drugs

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1. Statins decrease mortality 2. Niacin decreases mortality

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Fish Oil

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- thought to be a natural remedy to lower TG and affect platelet aggregation - but recent study showed it caused no statistically significant difference in levels

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Two New Drugs based on Fish Oil

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1. Lovaza 2. Vascepa

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Lovaza

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- Rx drug based on fish oil - omega-3-fatty acid ethyl ester - DHA and EPA - turns -> fatty acids in the body - could increase LDL

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Vascepa

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- Rx drug based on fish oil - ethyleicosapentanoic acid - EPA - no DHA - does NOT increase LDL, so works better than Lovaza - works similarly to Niacin

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Two NEW drugs to treat familial hypercholesterolemia

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1. Lomitapide, Juxtapid 2. Mipomersen, Kynamro

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Lomitapide, Juxtapid

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- made by Aegerion - *Inhibits Microsomal TG Transfer Protein, MTP: inhibits transfer of TG from one molecule to a pre-VLDL particle* - for familial hypercholesterolemia *homozygotes* - *decreases VLDL activity* -> direct effect on LDL synthesis - *decreases LPA significantly* - Toxicity: fat remains in liver -> *fatty liver*

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Mipomersen, Kynamro

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- drug to treat familial hypercholesterolemia - made by Genzyme - *Antisense oligonucleotide able to resist endonucleases* - *inhibit Apo B synthesis -> decreases LDL and VLDL* - *decreases LPA significantly* - Toxicity: fat remains in liver -> *fatty liver*

Pharmacology – Treatment of Hyperlipidemia – Flashcards

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