Triglycerides (TG) are synthesised in vivo from dietary fatty acids by the following synthetic pathway.

Similarly, cholesterol is synthesised by the multi-step pathway illustrated below.  The rate-limiting step in cholesterol synthesis is the reduction of hydroxy-methylglutaryl-CoA by HMG-CoA Reductase, as indicated.

Once ingested, dietary free fatty acids, triglycerides, and cholesterol are formed into micelles called chylomicrons within the intestine.  The chylomicrons are then absorbed into the systemic circulation with the aid of bile acids secreted into the intestine by the gall bladder.  Once in systemic circulation, the chylomicrons are acted upon by the enzyme lipoprotein lipase (LL) which breaks apart some of the fatty acids.  These fatty acids may be incorporated into adipose tissue for storage or taken to muscle where they may be used to synthesise the sarcolemma or used as an energy source.  The chylomicron lipoprotein remnants that remain are taken up into the liver through receptor-mediated endocytosis.  The above represents the exogenous pathway of lipid metabolism.  The endogenous pathway, summarised as follows, refers to the body's synthesis and handling of lipids.  Once the dietary fats have been taken up into the liver, they are formed into very low density lipoproteins (VLDLs) that are relatively high in triglycerides and relatively low in cholesterol.  VLDLs are encased in a protein "coat" that is made up of apoprotein B and apoprotein E, which impart to them their receptor specificity and function.  These lipids may then be acted upon either in the liver or in systemic circulation by LL, freeing fatty acids that again may be taken up into adipose or muscle.  The remnants are lower in TG that VLDLs and are called intermediate density lipoproteins (IDLs).  Circulating IDLs may then either be taken up in the liver via specific LDL/IDL receptors or acted upon by LL once again to cleave off even more TG and liberating additional free fatty acids.  This results in the formation of LDLs, or low density lipoproteins.  The ratio of TG to cholesterol is less still in LDLs.  Circulating LDLs comprise about 60-70% of total cholesterol in the blood.  The LDLs may also be taken up by the liver, again by specific receptors.  The apoprotein coat of LDLs is solely composed of apoprotein B.  Finally, lipoprotein(a) is a high density remnant formed by the combination of LDL with apolipoprotein(a).  High levels of this particular remnant also increases the risk of altheroma formation (see below).  NOTE that when the body needs additional cholesterol, liver uptake of LDLs will increase.  This is accompanied by an increase in LDL receptors.  When the body does not require additional cholesterol, the number of LDL receptors will decrease.  NOTE also that all of the lipids discussed thus far all have the apoprotein B and apoprotein E coat.  Any LDL that remains in circulation may once again be acted upon by LL.  This action (with additional cholesterol from cellular membranes) will form high density lipoproteins (HDLs).  HDLs have much more cholesterol, relative to TG, than the other lipids.  Additionally, their protein coat is composed primarily of apoprotein A.  This imparts different physiologic properties (e.g. receptor specificity) to HDL and may contribute to the "good" cholesterol effect reported for HDL.  One theory for the beneficial effects of HDL states that cholesterol normally deposited in vessel walls (as described below) will be taken up by the HDLs, therefore decreasing the plaque formation seen with atherosclerosis.  Additionally, HDLs participate in "reverse" lipid transport, taking cholesterol from the periphery back to the liver, effectively removing it from peripheral circulation.  (RECALL that every cell in the body requires cholesterol for its membrane AND that cholesterol is used to synthesise additional steroid-type hormones.  Without some cholesterol, the body would not function properly.)

HMG-CoA Reductase Inhibitors -- Mevastatin, Lovastatin, Simvistatin, Fluvistatin, Pravastatin, Cerivastatin, Atorvastatin.

Mevastatin was the first of these agents, synthesised from Penicillium mold.  The second, and first successful agent marketed, was lovastatin, biosynthesised from Aspergillus and Monascus spp.

Pharmacologic Response -- HMG-CoA Reductase Inhibitors lower circulating levels of LDL by 20-40%.  They also lower the amount of cholesterol in VLDLs/LDLs.  Additionally, they increase circulating HDLs by about 10%.  As a class, they have little effect on circulating TG.  Atorvastatin, however, lowers LDL by 60% and is also reported to lower circulating TG.

Mechanism of Action -- These agents inhibit the rate limiting step of cholesterol synthesis mediated by HMG-CoA reductase.  This initially results in a decrease in circulating cholesterol.  However, with long-term therapy, circulating cholesterol will return to near normal.  Therefore, the mechanism of these drugs is more complicated that a simple reduction in cholesterol synthesis.  When the liver detects that cholesterol synthesis has decreased, it responds by up-regulation of LDL receptors to synthesise more cholesterol.  This will increase the clearance of LDL and IDL from the circulation as it is taken up by the liver to synthesise more cholesterol.  This accounts for the increase in circulating cholesterol AND the decrease in circulating LDL that is observed with this class of drugs.

Kinetics and Sequelae to the Use of HMG-CoA Reductase Inhibitors -- These agents are highly bound to plasma proteins.  The adverse effects observed most often with these drugs include hepatotoxicity (baseline hepatic enzymes should be drawn on every patient prior to initiation of therapy and monitored closely at least every 6 months following), myotoxicity (similar in nature to rhabdomyolysis, accompanied by an increase in creatine phosphokinase activity and characterised by muscle pain, weakness, and fatigue -- NOTE that other anti-hyperlipidaemics will increase this effect, viz. nicotinic acid and gemfibrozil), and cataracts (by deposition of the drug in the eye).  The hepatotoxicity and myotoxicity is most likely related to the decreased synthesis of cholesterol, thereby disrupting normal cell structure and/or function.

The primary differences in these drugs in kinetic in nature.  Cerivastatin is the most potent of the drugs.  Since these drugs are primarily metabolised by the CYP450 system, the potential for drug interactions exists.  The metabolism of these drugs differs slightly as summarised below (indicating the specific P450 pathway for each drug)
Mevastatin -- 3A4
Lovastatin -- 3A4
Simvistatin -- 3A4
Fluvistatin -- 2C9
Pravastatin -- Relatively little CYP450 metabolism
Atorvastatin -- 3A4
Cerivastatin -- 3A4 and 2C8

Pharmacologic Response -- These agents will reduce circulating levels of VLDLs (and therefore, circulating TG).  They may produce a slight decrease in free cholesterol and LDLs (note that if initial VLDL levels are high and drug therapy greatly lowers them, an initial increase in LDL will occur).  Their effect on HDL is variable, with no change observed with clofibrate and an increase in HDL seen with gemfibrozil.  These agents are used primarily in familial Type III hyperlipoproteinaemia.

Mechanism of Action -- These drugs increase the activity of extrahepatic lipoprotein lipase (LL), thereby increasing the degradation of chylomicrons and VLDLs to LDLs and LDLs to HDL.  This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine.

Miscellanea & Adverse Effects -- Fibric acid derivatives are also highly plasma protein bound. These drugs will reduce clotting factors and may therefore increase the risk of bleeding in patients with haemophilia or taking warfarin.  Anti-coagulant dose may have to be lowered.  They may also produce a syndrome resembling flu (chills, headache, fever, muscle aches and pains) and may precipitate cholelithiasis (gall stones due to precipitation of cholesterol in the gall bladder).

Pharmacologic Response -- The binding resins will lower circulating levels of LDLs.  A slight increase in VLDL may be seen early, but these levels will generally fall to pre-treatment levels soon (2-3 months) after the initiation of therapy.  These agents have no effect on HDLs.  NOTE that if pre-treatment levels of VLDL and IDL TG is high, then they are generally NOT effective.

Mechanism of Action -- The binding resins bind to bile acids in the intestine.  This prevents the absorption of dietary fats (recall that bile acids are necessary for dietary fat and cholesterol absorption), effectively removing the exogenous pathway of lipid transport.  The liver detects this decrease in cholesterol and (similar to the HMG-CoA Reductase Inhibitors) up-regulates the LDL receptors, thus removing LDLs from the systemic circulation.  This theory of the mechanism of action is supported by the increase in LDL receptor number that has been reported with these agents.

Adverse Effects -- The great majority of adverse effects of the binding resins are GI in nature, since they are not absorbed to any great extent.  These include steatorrhoea (fatty diarrhoea, due to dietary fats remaining in the gut), constipation, and nausea.  They may also decrease the absorption of drugs which will bind to the resin, including fat soluble vitamins (A, D, E, K), digoxin, phenobarbitone, and oral anticoagulants.  Neomycin, an aminoglycoside antibiotic that also effectively binds bile acids is used rarely for this purpose.  If it is used, enough absorption may occur that in patients with renal failure, additional nephrotoxicity and ototoxicity may be seen.  Neomycin should not be used as an anti-hyperlipidaemic in patients with renal failure.

Pharmacologic Response -- Probucol will lower circulating levels of LDL and HDL.  Little change in seen with VLDLs or TG.

Mechanism of Action -- The exact mechanism of action of probucol is not known.  It does NOT affect the synthesis or catabolism of LDL.  It is theorised that probucol MAY decrease sterole synthesis or increase cholesterol mobilisation (possibly by increasing apo E proteins), however the means to accomplish these actions has not been suggested.  Probucol DOES exhibit anti-oxidant activity.  This action may account for its value in lipidaemic therapy.  Recall that lipid peroxidation contributes to the formation of atheromas.  The anti-oxidant effect of probucol would prevent the oxidation of LDL and its subsequent uptake and deposit in the plaque-building process.

Adverse Effects -- The majority of side effects seen with probucol are GI in nature and include nausea, diarrhoea, and flatulence.  A few patients may exhibit a prolongation of the QT interval in the ECG.  If this occurs, the drug should be discontinued.

Pharmacologic Response -- Nicotinic acid will reduce circulating levels of VLDL and LDL (slower response that VLDL).  It will increase circulating levels of HDL.

Mechanism of Action -- The exact mechanism of action of niacin is not known.  It is suggested that it may decrease synthesis of VLDL by either inhibition of lipolysis in adipose (reducing lipid mobilisation) or decreased esterification of TG.  It has also been suggested that niacin will increase LL activity.

Miscellanea -- NOTE that vitamin B₃ is available over the counter in two forms -- nicotinic acid (niacin) and nicotinamide (niacinamide).  The amide form is NOT effective in lowering plasma lipids.  Niacin is converted in vivo to niacinamide for the normal vitamin activity, but it MUST be taken in the acid form to lower plasma lipids.  The most common adverse effects associated with nicotinic acid are flushing (secondary to vasodilatation) and pruritus.  Both of these effects are mediated by prostaglandins and may be prevented by the administration of ASA (gr. v) 15 min prior to dosing with nicotinic acid.  It may also produce mild hepatotoxicity in some patients (monitor liver enzymes, especially in combination with the HMG-CoA reductase inhibitors). NOTE that dosing requirements for anti-hyperlipidaemic therapy (3 to 6 Gm daily, in divided doses) are higher than doses needed for dietary supplementation (100 mg daily) or for the treatment of niacin deficiency or pellegra (500 mg daily).

Regardless of the type of hyperlipoproteinaemia, extensive clinical studies have supported their value in reducing risk of future cardiovascular disease or attacks.

Scandanavian Simvistatin Survival Study -- Examined patients with previous MI and elevated cholesterol.  All patients undergoing simvistatin therapy benefitted from treatment (reduced risk of future disease).

West of Scotland Study -- Examined patients without prior MI and elevated cholesterol.  All patients benefitted from anti-hyperlipidaemic therapy (reduced risk).

CARE (Cholesterol and Recurrent Events) Study -- Examined patients with previous MI and normal cholesterol.  Again, all patients benefitted from therapy.

Air Force/Texas Coronoary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) -- Anti-lipidaemic therapy Reduced the incidence of first acute major coronary event.