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
`
`
`
`Sawai Ex 1017
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`Page 1 of 21
`
`Contents
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`Sawai Ex 1017
`Page 2 of 21
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`Sawai Ex 1017
`Page 3 of 21
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`

`
`262
`Lipid-Lowering Drugs
`
`Acetate
`
`Cholesterol
`
`6
`
`Cholesterol
`esteriticotion 1
`LDL receptors;
`
`Doodeniiin I Jeiunum
`
`Chylomicrons
`
`Bile Acid Reobsorption
`
`Fig. 1. Metabolism and transport of Iipoprotoina in humans and the cettulnr changes that result from receptor-mediated uptake of
`low density lipoproteins.
`
`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-
`
`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
`
`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
`
`Sawai Ex 1017
`
`Page 4 of 21
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`Sawai Ex 1017
`Page 5 of 21
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`Sawai Ex 1017
`Page 6 of 21
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`Sawai Ex 1017
`Page 7 of 21
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`

`
`266
`Lipid-Lowering Drugs
`
`
`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 correct
`the underlying biochemical abnormality. In con-
`trast. patients with familial combined hyperlipid-
`aemia, who inherently overproduce LDL, may not
`respond as well to bile acid sequestrant therapy and
`in these patients nicotinic acid may be a more ef-
`fective hypocholesteroiaemic drug, Figure 2 illus-
`trates the comparative efficacy of colestipol and ni-
`cotinic acid in a patient with familial combined
`hyperlipidaemia.
`
`3.2 Nicotinic Acid (Niacin)
`
`Nicotinic acid is a first-line dnig for the treat-
`ment of patients with primary hypercholesterol-
`aemia, and is probably also the agent of initial
`choice for those patients with genotypic familial
`combined hyperlipidaemia.
`
`3.2.] Mechanism of Action
`The hypolipidaemic action of nicotinic acid has
`been recognised for 30 years (Altschul et al. I955)
`
`gr’ My:
`
`l
`D101
`"I cot ni: 50C
`:1
`
`Fig. 2. comparative efficacy of oolostipol and nicotinic acid (nia-
`cin) as single drug therapy tor a patient [52-year-old male) with
`primary hypevcholesterolaemia due to familial combined hyper-
`lipidaemia. Total cholesterol (U): LDL cholesterol (ll); HDL chol-
`esterol (I).
`
`and appears to be unrelated to its action as a men-
`zyme in intennediary metabolism. Nevertheless,
`the precise mechanism by which nicotinic acid re-
`duces plasma concentrations of VLDL and LDL is
`unknown. Considerable evidence, however, points
`to a primary effect to reduce hepatic synthesis of
`VLDL (Grundy et al. l98l), which in turn leads to
`a reduction in the synthesis of LDL, Factors re-
`sponsible for decreased hepatic production of
`VLDL include inhibition of lipolysis with a de-
`crease in free fatty acid levels in plasma, decreased
`hepatic esterification of triglycerides, and a possi-
`ble direct effect on the hepatic production of apo-
`protein B.
`
`3.2.2 Side Effects
`The primary side effects of nicotinic acid affect
`the skin and gastrointestinal
`tract. Cutaneous
`flushing occurs l5 minutes to 2 hours after this
`medication has been taken, but the duration and
`magnitude usually diminish with prolonged therapy
`and can be minimised by starting at a low dosage
`and always taking the medication following the
`ingestion of food. The flushing appears to be me-
`diated by prostaglandins and can be reduced by
`concurrent administration of small doses of aspirin
`(Olsson ct al. 1983). Nausea, abdominal discom-
`fort and diarrhoea constitute the most common
`
`gastrointestinal side effects and the drug is con-
`traindicated in patients with active liver disease. a
`prior history of peptic ulcer disease or hyperuric-
`aemia. Less common side effects include itching,
`rash, hyperpigmentation of the skin with devel-
`opment of acanthosis nigricans and blurred vision
`due to macula oedema The latter is reversible upon
`discontinuation of nicotinic acid, but precludes
`further use of this drug. Other side effects have in-
`cluded activation of peptic ulcer disease and ex-
`acerbation of both hyperuricaemia and diabetes.
`laboratory disturbances noted in patients on
`nicotinic acid are more common with higher doses
`(> 3 g/day). and include increases in alkaline phos-
`phatase and transaminases and an elevation in the
`serum concentrations of uric acid and glucose. The
`incidence of elevations in transaminases and al-
`
`kaline phosphatase may be higher in patients re-
`
`Sawai Ex 1017
`
`Page 8 of 21
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`
`Sawai Ex 1017
`Page 9 of 21
`
`

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`Sawai Ex 1017
`Page 10 of 21
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`Sawai Ex 1017
`Page 11 of 21
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