Review Article
`
`Drugs 33: 259-279 (1987)
`0012-6667/87/0003-0259/$10.50/0
`0 ADIS Press Limited
`All rights reserved.
`
`Lipid-Lowering Drugs
`An Overview of Indications and Optimum Therapeutic Use
`
`D. Roger Illingworlh
`Division of Endocrinology, Metabolism and Clinical Nutrition, Department of
`Medicine, Oregon Health Sciences University, Portland
`
`
`Summary ..................................................................................
`l. Physiology of Lipid and Lipoprotein Tnnsport....
`2. Criteria for the Diagnosis of Hyper-lipoproteinaemia ..........
`3. Drug Therapy of Primary Hypencholesterolaemia ................. ..
`3.1 Bile Acid Sequestr-ants: Colesripol and Cholestynsmine
`3.1.1 Mechanism of Action ................................................ ..
`3.1.2 Side Eflects ...............................................
`3.1.3 Clinical Use of Bile Acid Sequesuants
`3.2 Nicotinic Acid (Niacin) ....................................
`3.2.1 Mechanism of Action ....................
`3.2.2 Side Efiects .............
`3.2.3 Cliniml Use .......... ..
`3.3 Probucol ...................................
`3.3.1 Mechanism of Action
`3.3.2 Side Effects .............
`3.3.3 Clinical Use
`3.4 Neomycin .............. ..
`3.4.1 Mechanism of Action
`3.4.2 Side Effects .....................
`3.4.3 Clinical Use ................
`3.5 d-Thyroxine .............
`..
`3.5.1 Mechanism o1‘Action....
`3.5.2 Side Effects .................
`3.5.3 Clinical Use....
`4. Drug Therapy of Combined Hyperlipoproteinaernia ...............
`4.1 Gemfibrozil ..............................
`4.1.1 Mechanism of Action
`4.1.2 Side Effects ................... ..
`4.1.3 Clinical Use ......................................................................
`5. Drug Therapy of Type III Hyperlipoproteinaemia..
`5.1 Clofibrate ...................................................................
`5.1.1 Mechanism of Action
`5.1.2 Side
`........
`5.1.3 Clinical Use....
`6. Drug Therapy of Hypertriglyeeridaemic.
`7. Future Advances in the Therapy of Hypercholesterolaemia
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`Sawai Ex 1017
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`Page 1 of 21
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`Contents
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`260
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`7.1 Fibric Acid Derivatives ........................................................................................... ..275
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`7.2 I-{MG Co-A Reductase Inhibitors: Mevinolin and Related Compounds .. . . ...
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`8. Conclusions ............................................................................................................................ ..276
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`Summary
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`Drug treatment ofpatients with hyperlipoproteinaemia is indicated to reduce the risk
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`ofatherosclerosis in patients with increased concentrations ofatherogenic lipoproteins, and
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`to lower the plasma concentrations oftriglyceride-rich lipoprateins in patients with severe
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`hypertriglyceridaemia who are at risk ofabdominal pain and pancreatitis. Such therapy
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`should be initiated only after satisfactory exclusion of secondary causes of hyperlipo
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`proteinaemia, and should be regarded as an adjunct to rather than a substitute for ap-
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`propriate dietary therapy. Drug therapy should be strongly considered in those patients
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`with concentrations of atherogenic lipoproteins which exceed the 90th to 95th percentile
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`for age.
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`In patients with increased plasma concentrations of low density lipoproteins (LDL),
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`agents which enhance the rate ofLDL catabolism (cholestyramine and colestipol) or reduce
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`the rate of LDL synthesis [e.g. nicotinic acid (niacin)] are the ‘drugs ofchoice’. For those
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`patients with concurrent hypenriglyceridaemia, nicotinic acid is the preferred initial drug,
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`and in both patient groups combined drug therapy is often necessary to attain optimal
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`reductions in LDL cholesterol concentrations. .Cloflbrate remains the ‘drug of choice‘ for
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`the rare patient with type III hyperlipoproteinaemia. whereas the newer agent gemfibrozil
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`should be used in patients with plasma triglyceride concentrations above 1000 mg/dl who
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`are at increased risk of abdominal pain and pancreatitis.
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`Although currently limited to investigational use, mevinolin and related compounds,
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`which are specific inhibitors ofthe rate-limiting enzyme in cholesterol biosynthesis (HMG
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`Co-A reductase), offer considerable promise in the therapy ofpatients with primary hyper-
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`cholesterolaemia due to elevated levels of LDL cholesterol.
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`The term hyperlipoproteinaemia refers to con-
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`ditions in which the concentrations of cholesterol-
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`and/or triglyceride-rich lipoproteins in plasma are
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`elevated above normal levels. There are 4 import-
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`ant clinical reasons for concern about the correct
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`diagnosis and treatment of hyperlipoproteinaemia.
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`The first is the strong causal relationship between
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`elevated concentrations of cholesterol-rich lipopro-
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`teins and accelerated rates of atherosclerosis of both
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`the coronary and peripheral circulation. The sec-
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`ond reason is the correlation of certain hyper-
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`lipoproteinaemias with the occurrence of xantho-
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`mas in the skin and tendons, which may present
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`cosmetic problems, and in the case of tendon xan-
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`thomas, are frequently associated with recurrent
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`episodes of tendinitis. The third reason for concern
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`lies in the causal relationship between severe hy-
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`pertriglyceridaemia and symptoms of abdominal
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`pain and acute pancreatitis. The fourth and final
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`reason for clinical concern is that the occurrence
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`of hypercholesterolaemia or hypertriglyceridaemia
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`may point to another disease to which the lipo-
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`protein abnormality is secondary (e.g. hypothyr-
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`oidism). Thus, the assessment of a patient with
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`hyperlipoproteinaemia should include a detailed
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`history (including family history), physical exam-
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`ination, and blood tests to exclude secondary causes
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`of hyperlipoproteinaemia.
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`Determination of the plasma concentrations of
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`cholesterol and triglyceride constitutes the basic
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`lipid profile which is obtained in most patients. In
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`discussing hyperlipoproteinaemic states as they
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`penain to a given patient, this review uses the basic
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`cholesterol and triglyceride determinations as a
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`starting point and divides the discussion of treat-
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`ment into 3 categories: (a) patients with hyper-
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`cholesterolaemia in whom triglyceride concentra-
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`tions are normal (type IIA phenotype) [section 3];
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`Lipid—Lowering Drugs
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`261
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`(b) patients with combined elevations of choles-
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`terol and triglyceride wherein the triglyceride levels
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`are up to twice the cholesterol values (phenotype
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`IIB and III) [sections 4 and 5]; and (c) conditions
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`associated with a primary elevation in the concen-
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`trations of triglyceride-rich lipoproteins and in
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`which cholesterol levels are nearly normal (type IV
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`phenotype) or increased to a much smaller extent
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`than are the triglycerides (phenotypes I and V)
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`[section 6]. Individual drugs are discussed in detail
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`in the sections that correspond to their primary
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`areas of use.
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`1. Physiologz of Lipid and Lipoprotein
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`Transport
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`Cholesterol and triglycerides, which are the 2
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`indices normally measured in assessing hyper-
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`lipoproteinaemias, are transported in plasma as
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`components of large globular particles termed lipo-
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`proteins. These particles contain other lipids (e.g.
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`phospholipids) and specific apoproteins. There are
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`4 broad categories of lipoproteins (chylomicrons,
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`very-low density lipoproteins, low density lipopro-
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`teins and high density lipoproteins), which differ
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`from each other in size and density as well as in
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`the relative proportions of triglyceride, cholesterol,
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`and protein and in the specific apoproteins which
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`they contain (Schonfeld 1983).
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`Chylomicrons, which are the largest of the lipo-
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`protein particles, are formed in intestinal mucosal
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`cells and constitute the form in which dietary (ex-
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`ogenous) lipids are transported from the intestine
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`to lymphatics and plasma. Chylomicrons are re-
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`sponsible for the lipaemia seen in postprandial
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`plasma samples and are not normally present in
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`plasma samples obtained 10 to 12 hours after a
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`meal. Chylomicrons are triglyceride-rich lipopro-
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`teins, and upon entry into the systemic circulation
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`much of the triglyceride is removed in peripheral
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`tissues by the action of the enzyme lipoprotein li-
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`pase. Apoprotein E on the remnant chylomicron
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`particle is recognised by specific hepatic receptors
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`(Mahley & Angelin 1984) which facilitates hepatic
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`uptake of the chylomicron remnant (fig. 1).
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`Very-low density lipoproteins (VLDL) are pro-
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`duced by the liver and serve as the major transport
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`form for endogenously synthesised triglycerides
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`from the liver. Increased plasma concentrations of
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`VLDL cause a slight turbidity in plasma, and like
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`chylomicrons these particles also contain triglyc-
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`eride as the major lipid component. Hydrolysis of
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`the triglyceride component of VLDL is dependent
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`on the enzyme lipoprotein lipase. Intravascular ca-
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`tabolism of VLDL particles leads to the formation
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`of progressively smaller lipoproteins (termed inter-
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`mediate density lipoproteins, IDL) and ultimately
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`to low density lipoproteins (LDL). Conversion of
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`VLDL to LDL also appears to require interaction
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`of the VLDL remnant particles with hepatic recep-
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`tors which recognise one specific apoprotein (apo-
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`protein B) present on the VLDL remnant particle.
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`The extent to which VLDL particles are converted
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`to LDL differs in dilferent hyperlipoproteinaemic
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`states, but most LDL is derived from the intra-
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`vascular catabolism of VLDL (fig. 1).
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`Increased plasma concentrations of triglyceride-
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`rich lipoproteins (VLDL and chylomicrons) can re-
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`sult from increases in the rate of hepatic produc-
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`tion of VLDL particles (which accumulate in
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`plasma and ultimately result in delayed catabolism
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`of intestinalderived chylomicron particles), or from
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`decreases in the rate of removal of both of these
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`triglyceride-rich lipoproteins from plasma. The use
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`of triglyceride-lowering drugs in patients with sev-
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`ere hypertriglyceridaemia aims to reduce hepatic
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`triglyceride production and/or enhance the rate of
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`triglyceride hydrolysis by lipoprotein lipase in peri-
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`pheral tissues. Cholesterol-rich VLDL and chylom-
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`icron remnant particles accumulate in the plasma
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`of patients with type III hyperlipoproteinaemia;
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`most patients with this disorder are homozygous
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`for one form of apoprotein E (E2) which has a re-
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`duced binding aflinity for specific hepatic receptors
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`which facilitate the catabolism of VLDL and chy-
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`lomicron remnant (Mahley & Angelin 1984). In
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`addition, most patients with type III hyperlipopro-
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`teinaemia overproduce VLDL, and therapy of this
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`disorder is directed at enhancing the rate of con-
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`version of VLDL to LDL and concurrently reduc-
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`ing the rate of VLDL production.
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`In humans most of the LDL in plasma is de-
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`262
`Lipid-Lowering Drugs
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`Acetate
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`Cholesterol
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`6
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`Cholesterol
`esteriticotion 1
`LDL receptors;
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`Doodeniiin I Jeiunum
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`Chylomicrons
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`Bile Acid Reobsorption
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`Fig. 1. Metabolism and transport of Iipoprotoina in humans and the cettulnr changes that result from receptor-mediated uptake of
`low density lipoproteins.
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`rived from intravascular catabolism of VLDL, and
`LDL may therefore be regarded as the end—product
`of VLDL metabolism (fig 1). Catabolism of LDL
`occurs in both peripheral cells and the liver (the
`latter being the major site of removal) and is fa-
`cilitated by both receptor- and non-receptor-me-
`diated pathways. The uptake of LDL by high af-
`finity LDL receptors results in suppression of
`endogenous cholesterol biosynthesis, an enhanced
`rate of intracellular cholesterol esterification and a
`reduction in the number of high affinity LDL re-
`ceptors expressed on the cell surface (fig. I). Func-
`tional high affinity LDL receptors are absent from
`the cells of most patients with homozygous fami-
`lial hypercholesterolaemia and are reduced by ap-
`proximately 50% in patients heterozygous for this
`disorder (Goldstein & Brown I983). Because the
`expression of high affinity LDL receptors on he-
`patocyte membranes is subject to metabolic regu-
`lation, factors which deplete the liver of cholesterol
`(for example, bile acid depletion or partial inhi-
`bition of cholesterol biosynthesis) stimulate pro-
`duction of an increased number of LDL receptors
`on the hepatocyte membrane. This in turn stim-
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`ulates the liver to catabolise LDL particles from
`plasma at a faster rate and concurrently reduces
`the plasma concentrations of this lipoprotein. lu-
`creased plasma concentrations of LDL can result
`from an inherent reduction in the number of high
`affinity LDL receptors (as occurs in patients with
`familial hypercholesterolaemia) or can be due to
`an enhanced hepatic production of VLDL and LDL
`(as occurs in patients with familial combined
`hyperlipidaemia).
`High density lipoproteins (HDL) constitute the
`fourth class of lipoproteins. HDL particles are de-
`rived from direct hepatic secretion and during the
`intravascular lipolysis of chylomicron particles
`(Nicoll et al. 1980). Clinical and epidemiological
`studies have shown an inverse correlation between
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`plasma concentrations of HDL cholesterol and
`atherosclerosis (Gordon et al.
`I977). Thus, high
`levels of HDL may enhance removal of cholesterol
`from tissues and protect against the development
`of atherosclerosis, whereas low levels of HDL chol-
`esterol appear to be an independent risk factor. It
`is currently unclear whether measures which raise
`HDL cholesterol have any long term therapeutic
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`263
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`Tlblo I. Normal values (mg/dl) for lipids and lipoproteins in
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`Amerlcan men and women‘
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`Total plasma LDL
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`cholesterol
`cholesterol
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`Age
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`MOI‘!
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`20-24
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`25-29
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`30-34
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`35-39
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`40-44
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`45-49
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`50-54
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`Women
`20-24
`68(—)
`52(—)
`98(—)
`162(-—)
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`25-29
`71 (128)
`56 (B1)
`106 (151)
`174 (222)
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`74 (1 38)
`55 (75)
`1 09 (148)
`174 (220)
`30-34
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`B9 (174)
`56 (B2)
`119 (173)
`186 (251)
`35-39
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`92 (179)
`57 (87)
`125 (174)
`196 (253)
`40-44
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`105 (1 92)
`58 (B6)
`1 30 (1 86)
`205 (267)
`45-49
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`112 (214)
`60 (89)
`145 (214)
`222 (292)
`50-54
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`132 (280)
`60 (86)
`1 50 (212)
`231 (296)
`55-59
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`a Data obtained from 11 communities across the United States.
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`Values given are means (and 95th percentiles) in mg/dl for
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`White males and females (data from the Lipid Research
`
`
`
`
`
`
`
`
`
`Clinics Population Studies Data Book 1980).
`
`
`
`
`
`
`
`
`
`
`HDL
`
`cholesterol
`
`
`
`Total plasma
`
`triglyceride
`
`
`162 (212)
`
`179 (234)
`
`193 (258)
`
`201 (267)
`
`205 (260)
`
`213 (275)
`
`213 (274)
`
`
`
`
`
`
`
`
`
`
`
`
`103 (147)
`
`1 17 (165)
`
`126 (185)
`
`1 33 (1 89)
`
`136 (186)
`
`144 (202)
`
`142 (197)
`
`
`
`
`
`
`
`
`
`
`45 (63)
`
`45 (63)
`
`46 (63)
`
`43 (62)
`
`44 (67)
`
`45 (64)
`
`44 (63)
`
`
`
`
`
`
`
`
`
`
`89 (165)
`
`1 04 (204)
`
`122 (253)
`
`141 (316)
`
`1 52 (318)
`
`143 (279)
`
`154 (313)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`should receive dietary advice and, in selected cases,
`
`
`
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`
`
`
`
`drug therapy, whereas those patients with total and
`
`
`
`
`
`
`
`
`LDL cholesterols exceeding the 90th to 95th per-
`
`
`
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`
`
`centile should be strongly considered for drug
`
`
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`
`
`treatment, if diet alone does not substantially re-
`
`
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`
`
`
`duce the magnitude of hypercholesterolaemia
`
`
`
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`(Consensus Conference 1985). Results from 2 re-
`
`
`
`
`
`
`cently reported randomised clinical
`trials have
`
`
`
`
`
`
`demonstrated that reduction in LDL cholesterol by
`
`
`
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`
`
`
`diet plus cholestyramine reduced the incidence of
`
`
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`
`
`fatal and non-fatal coronary heart disease in a pri-
`
`
`
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`
`
`
`mary prevention trial (Lipid Research Clinics Cor-
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`
`
`
`
`
`onary Primary Prevention Trial
`l984a,b), and a
`
`
`
`
`
`
`
`second study (Brensike et al. 1984) showed a re-
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`
`
`
`
`
`
`duction in the angiographic progression of coron-
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`
`
`
`ary artery disease in hypercholesterolaemic patients
`
`
`
`
`
`
`with pre-existent coronary artery disease. These
`
`
`
`
`
`
`studies support the view that if the premature de-
`
`
`
`
`
`
`
`
`velopment of coronary atherosclerosis in patients
`
`
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`with primary hypercholesterolaemia is to be pre-
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`Sawai Ex 1017
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`Page 5 of 21
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`benefit, and thus the primary aim of drugs used in
`
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`the treatment of hyperlipoproteinaemias is to re-
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`
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`
`duce the concentrations of known atherogenic lipo-
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`
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`proteins, rather than to increase HDL concentra-
`
`
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`
`
`
`tion.
`
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`
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`
`
`2. Criteria for the Diagnosis of
`
`Hyperlipoproteinaemia
`
`
`
`
`
`Accurate determination of cholesterol and tri-
`
`
`
`
`
`glyceride levels in plasma represents the basic test
`
`
`
`
`
`
`
`necessary for the diagnosis of most hyperlipopro-
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`
`
`teinaemias. Concentrations of plasma triglycerides
`
`
`
`
`
`increase postprandially, and for this reason reliable
`
`
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`
`
`
`determinations require the patient to have fasted
`
`
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`
`
`12 to 16 hours prior to venipuncture. Patients with
`
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`
`
`
`
`
`
`
`elevated levels of both cholesterol and triglyceride
`
`
`
`
`
`
`
`often require further lipoprotein characterisation
`
`
`
`
`
`by ultracentrifugation to distinguish between those
`
`
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`
`
`
`patients with combined elevations of VLDL and
`
`
`
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`
`LDL (phenotypic type IIB hyperlipoproteinaemia),
`
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`and those individuals with type III hyperlipopro-
`
`
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`
`
`teinaemia, in which VLDL remnants accumulate.
`
`
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`
`
`In most other patients with hypercholesterolaemia
`
`
`
`
`
`
`it is desirable to determine the concentrations of
`
`
`
`
`
`
`
`
`LDL and HDL cholesterol.
`
`
`
`
`In evaluating the results of lipid determinations,
`
`
`
`
`
`
`it is important to consider the age of the patient
`
`
`
`
`
`
`
`
`
`
`and appropriate normal values for that individual
`
`
`
`
`
`
`
`(with the reservation that values which are classi-
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`
`
`
`
`
`
`fied as ‘normal’ in Western societies may, in fact,
`
`
`
`
`
`
`
`
`
`be too high). Data from the Lipid Research Clinic’s
`
`
`
`
`
`
`
`
`
`programme which documents the mean and 95th
`
`
`
`
`
`
`
`percentile values of plasma lipid and lipoproteins
`
`
`
`
`
`
`
`are presented in table I.
`
`
`
`
`
`The question ‘what level of plasma cholesterol
`
`
`
`
`
`
`
`and/or LDL cholesterol warrants therapy with lipid
`
`
`
`
`
`
`
`lowering drugs?’ is one of considerable importance.
`
`
`
`
`
`
`
`Although no absolute values can be applied to every
`
`
`
`
`
`
`
`
`
`patient, a more aggressive approach is warranted
`
`
`
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`
`
`in males, in young people with a strong family his-
`
`
`
`
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`
`
`tory of early deaths from coronary artery disease,
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`
`and in patients with concurrent other risk factors
`
`
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`
`
`
`or atypically low concentrations of HDL choles-
`
`
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`
`
`terol. Patients with concentrations of total and LDL
`
`
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`cholesterol which exceed the 75th percentile for age
`
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`Sawai Ex 1017
`Page 5 of 21
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`

`

`Lipid-Lowering Drugs
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`264
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`
`
`premature coronary artery disease (Illingworth &
`
`
`
`
`
`
`Connor 1985). Biochemically, familial hyperchol-
`
`
`
`
`esterolaemia results from genetic mutations at the
`
`
`
`
`
`
`LDL receptor locus (Lehrrnan et al. 1985). Patients
`
`
`
`
`
`
`
`heterozygous for this disorder have a 50% reduc-
`
`
`
`
`
`
`
`tion in the number of high affinity LDL receptors
`
`
`
`
`
`
`
`
`expressed on hepatic and peripheral cells and this
`
`
`
`
`
`
`
`is responsible for the reduced fractional catabolic
`
`
`
`
`
`
`rate of LDL seen in this disorder.
`
`
`
`
`
`
`
`Familial combined hyperlipidaemia is also in-
`
`
`
`
`
`herited as an autosomal dominant trait which shows
`
`
`
`
`
`
`
`incomplete phenotypic expression in childhood.
`
`
`
`
`This disorder appears to be due to an inherent ov-
`
`
`
`
`
`
`
`
`
`erproduction of VLDL and LDL by the liver (Janus
`
`
`
`
`
`
`
`et al. 1980) and different family members may pre-
`
`
`
`
`
`
`
`
`sent with increased levels of LDL cholesterol, com-
`
`
`
`
`
`
`bined elevations of VLDL and LDL cholesterol or
`
`
`
`
`
`
`
`
`singular elevations in the concentrations of VLDL.
`
`
`
`
`
`
`
`Familial combined hyperlipidaemia is not associ-
`
`
`
`
`
`ated with tendon abnormalities, but is associated
`
`
`
`
`
`
`with an increased risk of premature coronary ar-
`
`
`
`
`
`
`
`tery disease (Goldstein et al. 1973).
`
`
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`
`
`
`
`
`
`vented, those patients who remain above the 90th
`
`
`
`
`
`
`
`to 95th percentile on optimal dietary therapy should
`
`
`
`
`
`
`
`be treated with lipid-lowering drugs.
`
`
`
`
`
`General guidelines for the institution of drug
`
`
`
`
`
`
`therapy are total plasma cholesterol values in ex-
`
`
`
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`
`
`cess of 240 to 250 mg/dl in children over the age
`
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`
`of 6 with heterozygous familial hypercholesterol-
`
`
`
`
`aemia, and cholesterol values greater than 260 mg/
`
`
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`
`
`dl in patients up to age 45 to 50. In adults between
`
`
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`
`
`
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`
`
`the ages of 45 and 65 years, drug therapy should
`
`
`
`
`
`
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`
`
`
`be considered in those patients whose cholesterol
`
`
`
`
`
`
`
`values remain above 250 to 270 mg/dl on diet
`
`
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`
`
`therapy, whereas a less aggressive approach is
`
`
`
`
`
`
`
`probably warranted in older (greater than 70 years
`
`
`
`
`
`
`
`
`of age) patients without clinical evidence of athero-
`
`
`
`
`
`
`
`sclerosis (Illingworth & Connor 1985). Aggressive
`
`
`
`
`
`
`treatment should also be directed to those patients
`
`
`
`
`
`
`
`
`who have already developed clinical evidence of
`
`
`
`
`
`
`
`atherosclerosis (e.g. patients who have suffered a
`
`
`
`
`
`
`
`myocardial infarction or have angina, or in patients
`
`
`
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`
`
`who have undergone coronary artery bypass sur-
`
`
`
`
`
`
`sew)-
`
`
`
`
`
`
`
`
`3. Drug Therapy of Primary
`
`Hypercholesterolaemia
`
`
`
`3.1 Bile Acid Sequestrants: Colestipol and
`
`
`
`
`
`Cholestyramine
`
`
`
`
`
`
`
`
`
`
`
`Increased concentrations of plasma cholesterol
`
`
`
`
`in the setting of nonnal triglyceride levels are usu-
`
`
`
`
`
`
`
`
`ally attributable to an increased number of LDL
`
`
`
`
`
`
`
`particles in plasma. Less commonly, hyperchol-
`
`
`
`
`
`esterolaemia reflects cholestasis in which an ab-
`
`
`
`
`
`
`normal lipoprotein accumulates (Sabesin 1982), or
`
`
`
`
`
`may be seen in the occasional patient with an
`
`
`
`
`
`
`
`
`atypically high level of HDL cholesterol; in the lat-
`
`
`
`
`
`
`
`
`ter case no treatment is indicated. Increased con-
`
`
`
`
`
`
`
`centrations of LDL cholesterol with normal tri-
`
`
`
`
`
`
`glycerides can be seen in patients with familial
`
`
`
`
`
`
`
`
`hypercholesterolaemia, familial combined hyper-
`
`
`
`lipidaemia, and so-called polygenic hypercholester-
`
`
`
`
`olaemia.
`
`Patients with heterozygous familial hyperchol-
`
`
`
`
`esterolaemia, an autosomal dominantly inherited
`
`
`
`
`
`disorder, typically have 2- to 4-fold elevations in
`
`
`
`
`
`
`
`the plasma concentrations of LDL cholesterol and
`
`
`
`
`
`
`
`this disorder is associated with tendon xanthomas
`
`
`
`
`
`
`
`and a marked prediliction for the development of
`
`
`
`
`
`
`
`
`
`
`
`The bile acid binding resins cholestyramine and
`
`
`
`
`
`
`colestipol are the drugs of choice for initial therapy
`
`
`
`
`
`
`
`
`of most patients with primary hypercholesterol-
`
`
`
`
`
`aemia, particularly those with heterozygous famil-
`
`
`
`
`
`ial hypercholesterolaemia. Notable exceptions in-
`
`
`
`
`clude patients with a history of severe constipation,
`
`
`
`
`
`
`
`which is often exacerbated by these drugs. Because
`
`
`
`
`
`
`
`
`they are not absorbed, cholestyramine and coles-
`
`
`
`
`
`
`tipol remain the only drugs that can be considered
`
`
`
`
`
`
`
`
`
`safe for use in children with heterozygous familial
`
`
`
`
`
`
`
`
`hypercholesterolaemia (Glueck 1986); such therapy
`
`
`
`
`
`should not be begun before 5 to 6 years of age,
`
`
`
`
`
`
`
`
`
`
`
`except in severe cases.
`
`
`
`
`
`3.1.1 Mechanism of Action
`
`
`
`
`The primary action of both cholestyramine and
`
`
`
`
`
`
`colestipol is to bind bile acids in the intestinal lu-
`
`
`
`
`
`
`
`
`
`men, with a concurrent interruption of the entere-
`
`
`
`
`
`
`
`hepatic circulation of bile acids and a markedly in-
`
`
`
`
`
`
`
`creased excretion of acidic steroids in the faeces.
`
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`Sawai Ex 1017
`
`Page 6 of 21
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`Sawai Ex 1017
`Page 6 of 21
`
`

`

`265
`Lipid-Lowering Drugs
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`
`The bile acid pool size is decreased and this re-
`
`
`
`
`
`
`
`
`
`duction stimulates increased hepatic synthesis of
`
`
`
`
`
`bile acids from cholesterol. Depletion of the he-
`
`
`
`
`
`
`
`patic pool of cholesterol results in 2 compensatory
`
`
`
`
`
`
`
`changes: an increase in cholesterol biosynthesis and
`
`
`
`
`
`
`an increase in the number of specific high affinity
`
`
`
`
`
`
`
`
`receptors for LDL on the hepatocytc membrane.
`
`
`
`
`
`
`Bile acid sequestrants are therefore attractive drugs
`
`
`
`
`
`
`to use in patients with familial hypercholesterol-
`
`
`
`
`
`
`aemia in whom the hypercholesterolaemia is due
`
`
`
`
`
`
`to an inherently reduced number of high affinity
`
`
`
`
`
`
`
`LDL receptors expressed on their cells. The in-
`
`
`
`
`
`
`
`creased number of high affinity LDL receptors ex-
`
`
`
`
`
`
`
`pressed on hepatocytes from patients treated with
`
`
`
`
`
`
`bile acid sequestrants simulates an enhanced rate
`
`
`
`
`
`
`of LDL catabolism from plasma and thereby low-
`
`
`
`
`
`
`
`ers the concentration of this lipoprotein (Shepherd
`
`
`
`
`
`
`et al. 1980). Bile acid sequestrants are ineffective
`
`
`
`
`
`
`
`in patients with homozygous familial hyperchol-
`
`
`
`
`
`esterolaemia, who lack the ability to make more
`
`
`
`
`
`
`
`high affinity LDL receptors. The increase in he-
`
`
`
`
`
`
`
`patic cholesterol biosynthesis which occurs during
`
`
`
`
`
`
`bile acid sequestrant therapy may be paralleled by
`
`
`
`
`
`
`
`
`an increase in hepatic VLDL production and often
`
`
`
`
`
`
`
`
`results in slight increases in the plasma concentra-
`
`
`
`
`
`
`
`tions of triglyceride and VLDL.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.1.2 Side Eflects
`
`
`
`The most common side effects of cholestyr-
`
`
`
`
`
`
`amine and colestipol consist of changes in bowel
`
`
`
`
`
`
`
`
`function including constipation, bloating, epigas-
`
`
`
`
`tric fullness, nausea and flatulence (Brown & Gold-
`
`
`
`
`
`
`
`stein 1985). Patients frequently complain that these
`
`
`
`
`
`
`
`medications are bulky and some find the sandy or
`
`
`
`
`
`
`
`
`
`gritty texture to be unpleasant and to exacerbate
`
`
`
`
`
`
`
`
`pre-existent haemorrhoids. Rare side effects have
`
`
`
`
`
`
`included intestinal obstruction and the develop-
`
`
`
`
`
`ment of hyperchloraemic acidosis. Decreased ab-
`
`
`
`
`
`sorption of fat-soluble vitamins and folic acid may
`
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`
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`
`
`
`occur with prolonged high doses of both medica-
`
`
`
`
`
`
`
`tions and oral supplementation with these vita-
`
`
`
`
`
`
`mins may be advisable in children. Both chole-
`
`
`
`
`
`
`
`styramine and colestipol may interfere with the
`
`
`
`
`
`
`
`absorption of other anionic drugs and it is advis-
`
`
`
`
`
`
`
`
`able to take other medications 1 hour before or 4
`
`
`
`
`
`
`
`
`
`
`hours after the bile acid sequestrants. Drugs whose
`
`
`
`
`
`
`
`
`
`bioavailability may be affected by this binding in-
`
`
`
`
`
`
`
`clude digoxin, thyroxine, coumadin and thiazide
`
`
`
`
`
`diuretics. Biochemical side effects include a mod-
`
`
`
`
`
`
`est increase in plasma triglyceride concentrations
`
`
`
`
`
`in many patients and an occasional mild increase
`
`
`
`
`
`
`
`in alkaline phosphatase and transaminases.
`
`
`
`
`
`
`
`
`
`
`
`3.1.3 Clinical Use of Bile Acid Sequestrants
`
`
`
`
`
`
`
`Both of the bile acid sequestrants are powders
`
`
`
`
`
`
`
`
`that must be mixed with water or fruit juice and
`
`
`
`
`
`
`
`
`
`
`are taken in 2 (or occasionally 3) divided closes with
`
`
`
`
`
`
`
`
`
`
`or just after meals. The cholesterol-lowering effects
`
`
`
`
`
`
`
`of cholestyramine 4g appear to be equivalent to
`
`
`
`
`
`
`
`
`that obtained with colestipol 5g. The dose-response
`
`
`
`
`
`
`
`curves for both cholestyramine and colestipol are
`
`
`
`
`
`
`
`non-linear. 12 to 20% decreases in the concentra-
`
`
`
`
`
`
`
`tions of LDL cholesterol are often seen with co-
`
`
`
`
`
`
`
`
`lestipol 5g (or cholestyramine 4g) taken twice daily.
`
`
`
`
`
`
`
`In adult patients the dose is usually increased up
`
`
`
`
`
`
`
`
`
`to 10g of colestipol twice daily; a maximal dose of
`
`
`
`
`
`
`
`
`
`
`15g twice daily may be used in severe cases, but
`
`
`
`
`
`
`
`
`
`
`the benefits from the additional 5 to 7% further
`
`
`
`
`
`
`
`
`
`decrease in LDL must be equated with the poorer
`
`
`
`
`
`
`
`
`
`patient compliance and greater incidence of gas-
`
`
`
`
`
`
`trointestinal side effects observed with this higher
`
`
`
`
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`dosage. The response to therapy in individual
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`patients is quite variable, but 15 to 30% reductions
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`in the concentrations of LDL cholesterol may be
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`achieved with colestipol 20 g/day or cholestyram-
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`ine 16 g/day (Kane & Malloy 1982; Shaefer & Levy
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`1985). Bile acid sequestrants have no place in the
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`therapy of disorders other than those associated
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`with elevated levels of LDL cholesterol, and in fact
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`these agents may aggravate the hypertrig1yceridae-
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`mia seen in patients with type III hyperlipopro-
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`teinaemia or in patients with chylomicronaemia.
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`Because the mechanism of action of cholestyram-
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`ine and colestipol is the same, selection of one or
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`other of these drugs is somewhat dependent on lo-
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`cal variations in cost, as well as individual patient
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`preference based on taste and palatability.
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`Knowledge of the aetiology of hypercholester-
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`olaemia in a given patient is often useful in decid-
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`ing which patients to initially treat with a bile acid
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`sequestrant compared with nicotinic acid (niacin)
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`[I-loeg et al. 1986]. Based on the causal factors re-
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`Sawai Ex 1017
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`Page 7 of 21
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`Sawai Ex 1017
`Page 7 of 21
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`

`266
`Lipid-Lowering Drugs
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`sponsible for hypercholesterolaemia, bile acid se-
`questrants constitute the logical drug of choice for
`patients with heterozygous familial hypercholester-
`olacmia, in whom the ability of these drugs to in-
`crease the number of high affinity receptors ex-
`pressed on hepatocyte membranes tends to