Hypolipidemic Agents

Question 1

Plasma lipids and Lipoproteins

Answer 1

• Relationships between plasma lipids and lipoproteins and the risk of having an atherosclerotic cardiovascular disease (ASCVD) event have been observed in human population studies for many years. Furthermore, there is an overwhelming body of evidence showing that interventions that target plasma lipids and lipoproteins have the potential to reduce ASCVD risk.
• It was shown 40 years ago that treatment with niacin reduced the risk of having an ASCVD event in high-risk men (Coronary Drug Project Research Group, 1975). It is more than 30 years since publication of the Coronary Primary Prevention Trial, which showed that reducing the concentration of low-density lipoprotein cholesterol (LDL-C) by treatment with cholestyramine significantly reduced the risk of having a coronary event (Lipid Research Clinics, 1984). It is 28 years since the Helsinki Heart Study, which was conducted in men with increased levels of atherogenic lipoproteins, revealed a significant reduction in ASCVD events after treatment with the fibrate, gemfibrozil (Frick et al., 1987). Finally, it is more than 20 years since publication of the Scandinavian Simvastatin Survival Study, which showed that treatment with simvastatin reduced ASCVD morbidity and mortality in men with elevated levels of LDL-C (Scandinavian Simvastatin Survival Study Group,1994).

Question 2

CLASSES OF DRUGS THAT MODIFY CHOLESTEROL LEVELS:

Answer 2

-
Inhibitors of HMG-CoA reductase (statins)
-
Bile acid–binding resins
-
Nicotinic acid (niacin)
-
Fibric acid derivatives (fibrates)
-
Inhibitor of cholesterol absorption (ezetimibe)
-
Omega-3 fatty acid ethyl esters (fish oil)
-
PCSK9 inhibitors
-
MTP inhibitor (lomitapide)
-
Inhibitor of apolipoprotein B-100 synthesis (mipomersen)

Question 3

What is vital for proper cellular and systemic functions?

Answer 3

Cholesterol Homeostasis

Question 4

Disturbed cholesterol balance underlies what?

Answer 4

underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers.

The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and
esterification — a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion
as constituents of lipoproteins.

Question 5

SECONDARY CAUSES OF DYSLIPIDEMIA

Answer 5

• In many patients, hyperlipidemia is caused by some underlying “nonlipid” etiology rather than a primary disorder of lipoprotein metabolism. Dyslipidemia due to secondary causes is common. In patients with type 2 diabetes mellitus, hyperlipidemia occurs in association with insulin resistance and frequently involves increased
  triglycerides and low serum high-density lipoprotein (HDL) cholesterol Primary biliary cholangitis and similar disorders may be
  accompanied by marked hypercholesterolemia that results from an accumulation of lipoprotein-X Marked hyperlipidemia can occur in the nephrotic syndrome due primarily to high serum total and lowdensity lipoprotein (LDL) cholesterol concentrations.
• Dyslipidemia is less prominent in chronic kidney disease (CKD), but CKD is associated with elevations in LDL cholesterol and triglycerides, and low levels of HDL cholesterol; hypertriglyceridemia (type IV hyperlipoproteinemia) occurs in 30 to 50 percent of cases of CKD.
• Hypothyroidism is a common cause of hyperlipidemia, most typically raising LDLcholesterol, but hypertriglyceridemia can also be seen. We advise screening for hypothyroidism in all patients with dyslipidemia.
• Obesity is associated with a number of deleterious changes in lipid metabolism, including high serum concentrations of total cholesterol, LDL cholesterol, very low-density lipoprotein (VLDL)
  cholesterol, and triglycerides, and a reduction in serum HDL cholesterol concentration.
• Cigarette smoking modestly lowers the serum HDL cholesterol concentrations and HDL atheroprotective properties.

Question 6

Table 33-5 page 1 of HA

Question 7

Why is it important to know the risk factors for atherosclerotic cardiovascular disease?

Answer 7

Cardiovascular disease (CVD) is common in the general population worldwide, affecting the majority of adults past the age of 60 years.

In 2012 and 2013, CVD was estimated to result in 17.3 million deaths worldwide on an annual basis [1-3]. The 2019 Heart Disease and Stroke Statistics update of the American Heart Association (AHA) reported that 48 percent of persons ≥20 years of age in the United States have CVD (which includes coronary heart disease [CHD] [4], heart failure, stroke, and hypertension) [4]. The reported prevalence increases with age for both women and men

Question 8

Risk Factors for Atherosclerotic Cardiovascular Disease:

Answer 8

Age
Male >45y.o.
Female >55 y.o.
Family Hx of Premature CHD
Current smoking
HPN
Low HDL
Obesity
Type 2 DM

Check table 33-4 page 16

Question 9

Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk:

Answer 9

• Lipids, principally cholesterol and triglycerides, are the water insoluble compounds that require larger protein-containing complexes called lipoproteins to transport them in blood.
• Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences.

Question 10

Apolipoproteins

Table on page 17

Answer 10

Characteristics of Plasma Lipoproteins

Table on page 17

Question 11

National Cholesterol Education Program ATP III

Answer 11

• National Cholesterol Education Program ATP III — Guidelines developed by the 2001 NCEP ATP III focused explicitly on the risk of cardiovascular disease (CVD) and did not require evidence of insulin or glucose abnormalities, although abnormal glycemia is one of the criteria.
• ATP III metabolic syndrome criteria were updated in 2005 in a statement from the American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI).
• ATP III criteria define metabolic syndrome as the presence of anythree of the following five traits:
  o Abdominal obesity, defined as a waist circumference ≥102 cm (40 in) in men and ≥88 cm (35 in) in women
  o Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides
  o Serum high-density lipoprotein (HDL) cholesterol <40mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drug treatment for low HDL cholesterol
  o Blood pressure ≥130/85 mmHg or drug treatment for elevated blood pressure
  o Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose

+ table 33-1

Question 12

Flowchart for assessing and managing ASCVD risk on page 17

Question 13

Regulation of Lipid Cholesterol Biosynthesis

Answer 13

• Sterol regulatory element binding proteins (SREBPs) were well documented as the basic-helix-loop helix-leucine zipper transcription factors that regulate the gene expressions involved in lipid cholesterol biosynthesis. These family of SREBP transcription factors have been reported to regulate the lipid cholesterol and fatty acid gene expressions via MAPK activation pathway. SREBP transcription factor is a critical regulator of lipid
  biosynthesis and sterol homeostasis in eukaryotes, where in mammals, SREBPs are highly active in the fed state to promote the expression of cholesterogenic and lipogenic genes involved in fat storage.
• Sterol regulatory element-binding protein 2 (SREBP-2) is an important nuclear transcription factor in the regulation of cellular cholesterol metabolism.

Question 14

What happens when intracellular cholesterol is decreased?

Answer 14

SREBP-2 is activated then, the synthesis of LDL receptor is increased and synthesis of PCSK9 is increased

Question 15

STATINS

Answer 15

-
The 2014 ACC/AHA guideline focuses on the use of statins to reduce ASCVD risk. However, several important clinical trials have evaluated whether fibrates, niacin, ezetimibe, and fish oil result in further reductions in ASCVD risk when used in addition to statins (ACCORD, 2010; AIMHIGH, 2011; Cannon et al., 2015; HPS2-THRIVE, 2014;
ORIGIN, 2012). The National Lipid Association released recommendations in 2015 that continued to emphasize specific LDL goals and encouraged the use of nonstatin therapies in addition to
statins in high-risk individuals (Jacobson et al., 2015). In April 2016, the FDA withdrew approval for niacin ER or fenofibrate when used in addition to statins, citing studies that demonstrated no additional reduction in ASCVD events versus monotherapy with a statin (FDA, 2016). In July 2016, the ACC also released an expert consensus
decision pathway to aid clinicians in the use of nonstatins (bile acid sequestrants, PCSK9 inhibitors, or ezetimibe) in addition to statins
for the management of ASCVD risk (Lloyd-Jones et al., 2016). The use of nonstatins in high-risk patient populations requires careful shared decision-making.
-
Elevated triglycerides are an important risk factor for pancreatitis.
Treatment with agents most effective at reducing levels of triglycerides (fibrate or fish oil) are recommended in patients with very elevated triglycerides (>1000 mg/dL) to reduce the risk of
pancreatitis. These therapies may be used in addition to statin treatment if the patient otherwise has risk factors for ASCVD that make the patient an appropriate candidate for statin therapy.
-
Although an understanding of optimal lipoprotein levels is helpful (see ranges in Table 33–6), the 2014 ACC/AHA guideline recommends the use of fixed statin doses for at-risk patients, instead
of titration to specific lipoprotein goals. The ACC/AHA guidelines identify four statin benefit groups or patient populations most likely to benefit from statin therapy.
-
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase,the ratelimiting enzyme in cholesterol synthesis.
-
Inhibition of cell cholesterol synthesis by statins transiently reduces the concentration of cholesterol in cells, which activates the sterol regulatory element binding protein (SREBP)-2. This leads to increased expression of the low-density protein (LDL) receptor on the cell surface, a consequent increase in the uptake of LDLs by the cell, and thus a decrease in the plasma concentration of LDL-C.
-
Lipid lowering, at least with statins, is beneficial for primary and secondary prevention of coronary heart disease in patients with dyslipidemias.

Question 16

MECHANISM OF ACTION OF STATINS

Answer 16

-
Statins exert their major effect—reduction of LDL levels—through a mevalonic acid–like moiety that competitively inhibits HMG-CoA reductase.
-
By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early and rate-limiting step in cholesterol biosynthesis.
-
Statins affect blood cholesterol levels by inhibiting hepatic cholesterol synthesis, which results in increased expression of the LDL receptor gene. Some studies suggested that statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. The reduction in hepatic VLDL production induced by statins is thought to be mediated by reduced synthesis of cholesterol, a required component of VLDLs. Occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme

Question 17

THERAPEUTIC EFFECTS OF STATINS

Answer 17

-
Most studies of patients treated with statins have systematically excluded patients with low HDL-C levels. In studies of patients with elevated LDL-C levels and gender-appropriate HDL-C levels (40–50 mg/dLfor men; 50–60 mg/dL for women), an increase in HDL-C of 5%–10% was observed, irrespective of the dose or statin employed.
However, in patients with reduced HDL-C levels (<35 mg/dL), statins may differ in their effects on HDL-C levels. More studies are needed to ascertain whether the effects of statins on HDL-C in patients with low HDL-C levels are clinically significant.

Dose-response relationships for all statins demonstrate that the efficacy of LDL-C lowering is log linear; LDL-C is reduced by about 6%
(from baseline) with each doubling of the dose. Maximal effects on plasma cholesterol levels are achieved within 7–10 days. The statins are effective in almost all patients with high LDL-C levels. The
exception is patients with hoFH, who have very attenuated responses to the usual doses of statins because both alleles of the
-
LDL receptor gene code for dysfunctional LDL receptors.
-
Most of the statins have modest high-density lipoprotein (HDL) cholesterol raising properties (about 5 percent), although rosuvastatin has a larger effect (see ‘Effect on HDL’ below).
Triglyceride concentrations fall by an average of 20 to 40 percent depending upon the statin and dose used (see ‘Effect on triglycerides’ below). The reduction in plasma triglycerides is due to a decrease in VLDL synthesis and to clearance of VLDL remnant particles by apolipoprotein B/E (LDL) receptors.

Question 18

ADVERSE EFFECTS OF STATINS

Answer 18

Hepatotoxicity
- Serious hepatotoxicity is rare and unpredictable, with a rate of about 1 case per million person-years of use. ACC/AHA guidelines recommend measuring ALT at baseline prior to initiation of statins.
However since 2012, the FDA has no longer recommended routine monitoring of ALT or other liver enzymes following the initiation of statin therapy because routine periodic monitoring does not appear to be effective in detecting or preventing serious liver injury. Liver enzymes should be evaluated in patients with clinical symptoms suggestive of liver injury following initiation or changes in statin treatment (FDA, 2012).

Myopathy
- The major adverse effect associated with statin use is myopathy.
Myopathy refers to a broad spectrum of muscle complaints, ranging from mild muscle soreness or weakness (myalgia) to life-threatening rhabdomyolysis. The risk of muscle adverse effects increases in proportion to statin doseand plasma concentrations. Consequently, factors inhibiting statin catabolism are associated with increased
myopathyrisk, including advanced age (especially > 80 years of age), hepatic or renal dysfunction, perioperative periods, small body size, and untreated hypothyroidism. Measurements of creatinine kinase are not routinely necessary unless the patient also is taking a drug that enhances the risk of myopathy. Concomitant use of drugs that diminish statin catabolism or interfere with hepatic uptake is associated with increased risk of myopathy and rhabdomyolysis.

Question 19

Drug interactions to Statin

Answer 19

• FIBRATES
• CYCLOSPORINE
• DIGOXIN
• WARFARIN
• MACROLIDE ANTIBITIOTICS
• AZOLE ANTIFUNGALS
• NIACIN
• HIV PROTEASE INHIBITORS
• AMIODARONE
• NEFAZODONE

Question 20

The most common statin interactions occur with

Answer 20

fibrates, especially gemfibrozil (38%),
and with cyclosporine (4%),
digoxin (5%),
warfarin (4%),
macrolide antibiotics (3%),
and azole antifungals (1%)

Other drugs that increase the risk of statin-induced myopathy include niacin (rare), HIV protease inhibitors, amiodarone, and nefazodone.

Question 21

What is the drug most commonly associated with statin-induced myopathy, both inhibits uptake of the active hydroxy acid forms of statins into hepatocytes by OATP1B1 and interferes with the transformation of most statins by glucuronidases?

Answer 21

Gemfibrozil

Question 22

Statin drug interactions:

Answer 22

Coadministration of gemfibrozil nearly doubles the plasma concentration of the statin hydroxy acids. When statins are administered with niacin, the myopathy probably is caused by an enhanced inhibition of skeletal muscle cholesterol synthesis (a pharmacodynamic interaction). In 2016, the FDA withdrew approval for statin drug combinations containing fibrates or niacin (FDA, 2016).

• Drugs that interfere with statin oxidation are those metabolized primarily by CYP3A4 and include certain macrolide antibiotics (e.g.,erythromycin); azole antifungals (e.g., itraconazole); cyclosporine; nefazodone, a phenylpiperazine antidepressant; HIV protease inhibitors; and amiodarone. These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites.
• Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYPs 3A4 and 3A5. Fluvastatin is mostly (50%–80%) metabolized
  by CYP2C9 to inactive metabolites, but CYP3A4 and CYP2C8 also contribute to its metabolism. Pravastatin, however, is not metabolized to any appreciable extent by the CYP system and is
  excreted unchanged in the urine. Because pravastatin, fluvastatin, and rosuvastatin are not extensively metabolized by CYP3A4, these
  statins may be less likely to cause myopathy when used with one of the predisposing drugs. However, the benefits of combined therapy with any statin should be carefully weighed against the risk of
  myopathy.

Question 23

GENETIC/RACE EFFECTS

Answer 23

• Part of the variability in the response to and side effects with statins may be related to genetic differences in the rate of drug metabolism.
  As an example, CYP2D6 is a member of the cytochrome P450 superfamily of drug oxidizing enzymes. CYP2D6 is functionally absent in 7 percent of Caucasians and African Americans, while deficiency is rare among Asians.
• The CYP2D6 phenotype appears to be important in patients treated with simvastatin, as it can affect both the degree of lipid lowering and tolerability. Polymorphisms in the gene coding for hydroxymethylglutaryl (HMG) CoA reductase also appear to affect the LDL cholesterol response to statins, but not the HDL cholesterol response.
• Concerns have been raised that Asians may have greater responses to low doses of statins than Caucasians. Prescribing information for rosuvastatin recommends starting therapy at a lower initial dose in Asians than in other groups, given observed differences in pharmacokinetics. There is no strong evidence supporting such an approach with other statins.

Question 24

ENTEROHEPATIC CIRCULATION OF BILE ACIDS

Answer 24

• Enterohepatic circulation of bile acids. In humans, about 0.2–0.6 g (averaging 0.5 g) bile acids are synthesized daily in human liver. Conjugated bile acids are secreted into bile and stored in the
  gallbladder. Some bile acids are spilled over into sinusoid blood and reabsorbed when passing through the renal tubules in the kidney and circulated back to the liver through mensenteric and arterial blood fl ow. Some bile acids secreted in the bile duct are reabsorbed in the cholangiocytes and recycled back to hepatocytes
  (cholangiohepatic shunt). After each meal, gallbladder contraction empties bile acids into the intestinal tract. When passing through the intestinal tract, some bile acids are reabsorbed in the upper intestine by passive diffusion, but most bile acids (95%) are reabsorbed in the ileum. Bile acids are transdiffused across the enterocyte to the basolateral membrane and excreted into portal
  blood circulation back to the sinusoid of hepatocytes. In the colon, DCA is reabsorbed by passive transport and recycled with CA and
  CDCA to the liver. A bile acid pool of about 3 g is recycled 4–12 times a day. Bile acids lost in the feces (0.2–0.6 g/day) are replenished by de novo synthesis in the liver to maintain a constant bile acid pool.
• Most patients for whom a prescription drug therapy is deemed advisable will have an elevation in their low density lipoprotein cholesterol (LDL-C) level and a statin is the established first line
  therapy. Other lipid lowering drugs are used to augment statin effects on LDL-C, substitute for statins when that class cannot be used, or to treat non-LDL-C disorders, primarily hypertriglyceridemia.
  The decision to use a non-statin drug can be influenced by clinical parameters other than the lipid values themselves.

Question 25

What are are amphipathic molecules synthesized from cholesterol in the liver?

Answer 25

Bile Acids

Question 26

What is a major pathway for hepatic cholesterol catabolism?

Answer 26

Bile Acid Synthesis

Bile acid synthesis generates bile flow which
is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids ad fat-soluble vitamins.

Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPAR, PPAR, PPAR) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as antidiabetic drugs for treatment of dyslipidemia and insulin insistence.

Question 27

BILE SEQUESTRANTS

Answer 27

• Bile acid sequestering agents have been used to reduce the concentration of LDL-C for many years. They act by binding to bile acids in the intestine, thus preventing their reabsorption. This results
  in increased formation of bile acids from cholesterol in hepatocytes, which transiently reduces cellular cholesterol levels and increases
  synthesis of LDL receptors. This increases the hepatic uptake of LDL from plasma and reduces the plasma concentration of LDL-C.
• Treatment with the bile acid sequestering agent, cholestyramine, resulted in a significant reduction in clinical cardiovascular events in the Coronary Primary Prevention Trial (Lipid Research Clinics, 1984).
• Bile acid sequestrants are used to reduce low density lipoprotein (LDL) cholesterol levels. After oral administration, they are not absorbed but bind to bile acids (which contains cholesterol) in the intestine and prevent their reabsorption into the body. The bound complex is insoluble and is excreted in the faeces. Decrease in bile acid leads to an increase in hepatic synthesis of bile acids from cholesterol. Depletion of cholesterol increases LDL receptor activity, therefore increases removal of LDL cholesterol from the blood.
  o Bile acid sequestrants are used in combination with HMG-CoA reductase inhibitors for patients whose lipid levels are challenging to normalize with the use of HMGCoA reductase inhibitors alone.
  o However, for pregnant women, bile acid sequestrants are the drug of choice in lowering cholesterol and lipid levels.

Question 28

CONTRAINDICATIONS AND CAUTIONS (BILE ACID)

Answer 28

• Allergy to bile acid sequestrants. Prevent severe hypersensitivity reactions.

• Complete biliary obstruction. Prevent bile from being secreted into the intestines.

• Abnormal intestinal function. Aggravated by the presence of bile acid sequestrants.

• Pregnancy and lactation. Potential decrease in absorption of fat and fat-soluble vitamins can be detrimental to fetus or neonate.

• Bile acid sequestrants have been reported to impair the absorption of numerous nutrients, including calcium, folate, iron, vitamin A, vitamin B 12 , and vitamin E. It appears, however, that only
  folate supplementation may be needed by individuals on long-term therapy with bile acid sequestrants. Although the bile acid
  sequestrant used in the studies interfered with the absorption of the other nutrients, their levels remained in the normal range. Just to be safe, though, making sure to get enough vitamin E and vitamin A (in the form of beta-carotene) would make sense

Question 29

Interactions of Bile Acids

Answer 29

Bile acid sequestrants delay the absorption of thiazide diuretics, corticosteroids, digoxin, warfarin, and thyroid hormones. Therefore,
if needed, these drugs are taken 1 hour before or 4-6 hours after a meal.

Question 30

What are several chemically unrelated families of organic substances that cannot be synthesized by humans and are essential in small amounts for normal metabolism?

Answer 30

Vitamins

Question 31

What may cause pellagra, which is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas), diarrhea, and dementia, and may progress to death?

the “4 Ds” serves as a mnemonic for the
manifestations of niacin deficiency

Answer 31

Niacin deficiency

Question 32

What are the water-soluble vitamins?

Answer 32

Vitamin B1 (Thiamine)
Vitamin B2 (Riboflavin)
Niacin (Nicotinic Acid)
Vitamin B6 (Pyridoxine, Pyridoxal)
Vitamin B12 (Cobalamin)
Folate
Biotin
Pantothenate
Vitamin C (Ascorbate)

Question 33

What are the fat-soluble vitamins?

Answer 33

Vitamin ADEK

A - retinol, retinal, retinoic acid
D - cholecalciferol, ergocalciferol
E - tocopherols
K - phylloquinone, menaquinone, menadione

Question 34

Deficiency syndrome: page 20 table

Question 35

Nicotinic Acid

Answer 35

• Niacin has been used to modify plasma lipid levels for more than 50 years. When given in pharmacological doses, niacin reduces the level of plasma triglyceride by about 35%, reduces LDL-C levels by 10%–15%, and increases the concentration of HDL-C by up to 25%.
  The precise mechanism of these effects remains uncertain. The reduction in plasma triglycerides may be the consequence of the ability of niacin to inhibit the release of nonesterified fatty acids
  (NEFAs) from adipose tissue. This results in a decrease in the plasma concentration of NEFAs, reduced hepatic uptake of NEFAs, and reduced formation of triglycerides in the liver. The mechanism by which niacin decreases LDL-C levels and increases HDL-C levels is not known. In a trial conducted in the prestatin era, treatment with
  niacin significantly reduced ASCVD events (Coronary Drug Project Research Group, 1975). However, in two recent large, randomized
  clinical outcome trials conducted in people taking statins, treatment with niacin did not reduce ASCVD events (Boden et al., 2011; Landray et al., 2014).
• VITAMIN B3 (NIACIN) Niacin (nicotinic acid and nicotinamide) is an essential nutrient involved in the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Question 36

Fibric acid derivated: PPAR activators

Answer 36

• Fibrates (Staels et al., 1998) have been in use for more than 50 years. They target and activate the hormone activated nuclear receptor, peroxisome proliferator– activated receptor a (PPARa). This
  increases the oxidation of free fatty acids in the liver and reduces the hepatic synthesis of triglyceride. Activation of PPARa also induces
  expression of lipoprotein lipase (LPL), the enzyme responsible for hydrolyzing triglycerides and phospholipids in very low-density lipoproteins (VLDLs) and chylomicrons (Heller and Harvengt, 1983).
• Thus, activators of PPARa reduce the level of plasma triglyceride by the combined effects of reducing its synthesis and increasing its rate
  of hydrolysis. Activation of PPARa also inhibits synthesis of apolipoprotein (apo) C-III (Staels et al., 1995), an apolipoprotein that delays the catabolism of triglyceride-rich lipoproteins.
• Fibrates also increase the concentration of high-density lipoprotein cholesterol (HDL-C) and increase synthesis of both apoA-I and apoA II, the two main HDL apolipoproteins, by a mechanism that is not fully understood. The results of clinical outcome trials of fibrates havevaried. Positive results were obtained for gemfibrozilin primary
  prevention in the Helsinki Heart Study (Frick et al., 1987) and in secondary prevention in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (Rubins et al., 1999). A neutral result was obtained for bezafibrate in secondary prevention in the Bezafibrate Infarction Prevention Study (Bezafibrate Infarction Prevention Study Group, 2000) and for fenofibrate in people with
  diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (Keech et al., 2005) and Action to Control Cardiovascular Risk in Diabetes (Ginsberg et al., 2010) studies. It should be noted
  that in the Fenofibrate Intervention and Event Lowering in Diabetes trial,there was a significantly greater use of statin therapy in patients allocated placebo than in those taking fenofibrate; in the Action to Control Cardiovascular Riskin Diabetes trial, patients in both the placebo and fenofibrate groups were taking a statin.
• Post hoc analyses of the fibrate trials have consistently shown that people with high levels of plasma triglyceride and low levels of HDLC derive a disproportionately large benefit when treated with these agents in terms of a reduction in cardiovascular events. These analyses indicate that there is a clear need for a clinicalcardiovascular outcome trial using fibrates in such individuals.
• Fibrates — Fibrates (fenofibrate, a specific peroxisome proliferatoractivated receptor [PPAR] alpha agonist, and bezafibrate, a pan-PPAR
  agonist) have been shown to improve liver biochemistries in treatment-naïve patients, as well as in patients with incomplete biochemical responses to UDCA

Question 37

What is the first compound approved for lowering total and LDLC levels that inhibits cholesterol absorption by enterocytes in the small intestine?

Answer 37

Ezetimibe

Question 38

Inhibitor of Cholesterol Absorption: Ezetimibe

Answer 38

-
It lowers LDL-C levels by about 20% and may be used as adjunctive therapy with statins.
-
Ezetimibe is a cholesterol absorption inhibitor that impairs dietary and biliary cholesterol absorption at the brush border of the intestine. It is the most commonly prescribed low density lipoprotein
cholesterol (LDL-C) lowering agent after statins.
-
Niemann-Pick C1-Like 1 (NPC1L1) is a protein in intestinal cells that promotes the absorption of cholesterol.
-
Mutations of the NPC1L1 gene that result in loss of function of NPC1L1 are associated with lower concentrations of LDL-C and a significantly reduced risk of having an ASCVD event (Stitziel et al., 2014). Inhibition of NPC1L1 by ezetimibe reduces the intestinal absorption of cholesterol, lowers the concentration of LDL-C, and reduces ASCVD events (Cannonet al., 2015).

Question 39

MOA of Ezetimibe

Answer 39

Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1).

This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood; decreases total C, LDL-cholesterol (LDLC), ApoB, and triglycerides (TG) while increasing HDL-cholesterol (HDL-C).

Question 40

THERAPEUTIC USE
- Ezetimibe

Answer 40

• Ezetimibe is available as a 10-mg tablet that may be taken at any time during the day, with or without food. Ezetimibe may be taken in combination with other dyslipidemia medications except bile acid sequestrants, which inhibit its absorption.
• The role of ezetimibe as monotherapy of patients with elevated LDLClevels is generally limited to the small group of statin-intolerant patients.
• The actions of ezetimibe are complementary to those of statins. Dual therapy with these two classes of drugs prevents both the enhanced
  cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorptioninduced by statins, providing additive reductions in LDL-C levels. A combination tablet containing ezetimibe, 10 mg, and various doses of simvastatin (10, 20, 40, and 80 mg) has been approved. LDL reduction at the highest simvastatin dose plus ezetimibe is similar to that of high-intensity statins.

Question 41

ADVERSE REACTIONS of Ezetimibe

Answer 41

• The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
• 1% to 10%:
• Central nervous system: Fatigue (2%)
• Gastrointestinal: Diarrhea (4%)
• Hepatic: Increased serum transaminases (with HMG-CoA reductase inhibitors; ≥3 x ULN: 1%)
• Infection: Influenza (2%)\
• Neuromuscular & skeletal: Arthralgia (3%), limb
  pain (3%)
• Respiratory: Upper respiratory tract infection (4%), sinusitis (3%)
• <1%, postmarketing, and/or case reports: Abdominal pain, anaphylaxis, angioedema, autoimmune hepatitis (Stolk 2006), cholecystitis, cholelithiasis, cholestatic hepatitis (Stolk 2006),
  depression, dizziness, erythema multiforme, headache, hepatitis, hypersensitivity reaction, increased creatine phosphokinase, myalgia, myopathy, nausea, pancreatitis, paresthesia,
  rhabdomyolysis, skin rash, thrombocytopenia, urticaria

Question 42

INHIBITORS OF CHOLESTERYL ESTER TRANSFER PROTEIN
The Biology of CETP

Answer 42

• CETP is found in the circulation mainly bound to high density lipoprotein (HDL). CETP allows equimolar transfer of neutral lipids (cholesterol esters [CE] and triglycerides [TG]) between plasma HDL and apolipoprotein B100–containing lipoprotein particles (Figure 1). The net effect of CETP is to transport CE from HDL to both very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), with TG moving in the opposite direction. The precise explanation for how CETP transfers neutral (i.e., no net charge) lipid between lipoproteins is not fully resolved. The commonly accepted hypothesis is that molecular forces lead to twisting and opening of a tunnel within the CETP molecule through which CE and TG can transfer 2, 3. According to this “tunnel mechanism” theory, bound CEs in the core of the CETP molecule change their shapes between bent and linear conformations, and these changes together lead to the spontaneous formation of a
  continuous tunnel across the entire length of the CETP molecule.

However, other studies have reached different conclusions, namely that either terminal (N or C) may bind to HDL and that a ternary structure and the presence of a tunnel is not necessarily required to explain CETP’s function

• The CETP gene is located on chromosome 16 and consists of ∼22 kilo base pairs with 16 exons.
• Reverse cholesterol transport is a mechanism by which the body removes excess cholesterol from peripheral tissues and delivers them to the liver, where it will be redistributed to other tissues or
  removed from the body bythe gallbladder. The main lipoprotein involved in this process is the HDL-c. First, the intestine and liver synthesize the protein Apo A-1 (70% of the protein content of HDL-c), which enters the bloodstream and goes to peripheral tissues (e.g., heart).
• Indirectly, mature molecules of HDL-c transfer its cholesterol content to apolipoproteins B-100 (Apo B-100), especially to the low-density lipoprotein (LDL), in exchange for triacylglycerol molecules. This process is catalyzed by the enzyme cholesteryl ester transfer protein (CETP). Thus, these lipoproteins can be associated with their liver
  receptors and deliver their cholesterol content (Cavelier et al., 2006; Rader, 2006). It is worth mentioning that CETP also catalyzes the reverse transference, i.e., triacylglycerol from HDL-c in exchange for Apo B-100 cholesterol.
• Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100–containing lipoproteins. Evidence from genetic studies that variants in
  the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested thatpharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated offtarget effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility.
  In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.
• Cholesteryl ester transfer protein (CETP) inhibitors increase serum high-density lipoprotein cholesterol (HDL-c) concentration; however, their impact on cardiovascular outcomes is not clear. This systematic review examines the effect of CETP inhibitors on serum lipid profiles, cardiovascular events, and all-cause mortality
• Overall, despite being efficient at increasing HDL-c, CETP inhibitors were not associated with improvements in cardiovascular outcomes overall or all-cause mortality. While pooled data suggest that there is a trend towards small reductions in nonfatal MI and cardiovascular death with the use of CETP inhibitors, the clinical significance of such reductions is likely modest, with anacetrapib driving the potential reduction in nonfatal MI. Further research is needed to clarify the relationship between raising HDL-c and cardiovascular events.

Question 43

What are used together with a proper diet to
lower very high triglyceride (fat-like substance) levels in the blood?

This medicine may help prevent medical problems caused by clogged blood vessels such as heart attacks and strokes.

Answer 43

Omega-3-acid ethyl esters

Question 44

MOA of Omega-3 fatty acids

Answer 44

Omega-3 fatty acids, commonly EPA and DHA ethyl esters, reduce VLDL triglycerides and are used as an adjunct to diet for treatment of adult patients with severe hypertriglyceridemia. The recommended daily oral dose for patients with severe hypertriglyceridemia is 3–4 g/d administered with food.

Question 45

Therapeutic Use of Omega-3-Fatty Acid Ethyl Esters

Answer 45

• Fish oil or other products containing omega-3 fatty acids are among the most common OTC herbal, vitamin, or nutritional supplements
  purchased by consumers each year. Doses and formulations of OTC items vary considerably. The AHA recommends that consumers eat a variety of fish at least twice a week and that fish oil supplements should only be considered for individuals with heart disease or high triglyceride levels in consultation with a medical professional. In addition to OTC fish oil products, several prescription-only products are available, generally at higher doses than those used OTC (1–1.2
  g) and containing a combination of EPA and DHA. Icosapent ethyl, an ethyl ester derivative of EPA, does not contain DHA. Mixtures containing both EPA and DHA have increased LDL-C in patients with severe hypertriglyceridemia, whereas studies of EPA-only products suggest they may not significantly increase LDL-C while still reducing
  triglycerides. Controversy exists about when to treat hypertriglyceridemia. Modifiable secondary causes of high triglycerides such as uncontrolled diabetes and excessive alcohol intake should always be addressed prior to initiating therapy.
• While prescription omega-3 products generally have FDA indications for triglycerides 500 mg/dL or greater, many professional organizations advocate that such products be limited to patients with
  levels of 1000 mg/dL or greater who are at greatest risk for pancreatitis. The ORIGIN trial found no additional reduction in ASCVD risk associated with the use of omega-3 fatty acids versus background therapy with statins alone, calling into question the common use of fish oil supplements for “heart protection” by consumers.
• Although there are a myriad of omega-3 FA dietary supplements on the market, as of 2008 there was only one omega-3 FA product approved by the Food and Drug Administration (FDA) for the treatment of HTG (Lovaza, BlaxaSmithKline, Research Triangle Park, NC; formerly Omacor, Reliant Pharmaceuticals, Liberty Corner, NJ).
  Referred to generically as omega-3 acid ethyl esters, this product is indicated as adjunct therapy along with diet and exercise for the treatment of severe HTG (TG >500 mg/dL). It has also been found to be effective and safe in reducing TG and non-HDL cholesterol in patients with TG or greater than 200 mg/dL despite ongoing statin therapy, but it is not currently indicated in this population. The approved dose of omega-3 acid ethyl esters is four 1-g capsules per day, which provides 3.4 g of EPA and DHA. To obtain this dose of EPA and DHA from dietary supplements (which range from 65% to 20% EPA and DHA per 1-g capsule) would require 5 to 17 capsules per day, respectively.

Question 46

PCSK9 Function and Physiology

Answer 46

• PCSK9 has exploded onto center stage plasma cholesterol metabolism, raising hopes for a new strategy to treat hypercholesterolemia. PCSK9 in a plasma protein that triggers increased degradation of the LDL receptor.
• Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease. Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels and protection from coronary heart disease.
• Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDL
• Proprotein convertase subtilisin/kexin-9 (PCSK9) indirectly regulates plasma LDL levels by controlling the LDL receptor expression at the
  plasma membrane

Question 47

MOA of PCSK9

Answer 47

• Proprotein convertase subtilisin/kexin type 9 is a protease that binds to the LDL receptor on the surface of hepatocytes and enhances lysosomal degradation of the LDL receptor, resulting in higher plasma LDL concentrations.
• Loss-of-function mutations of PCSK9 are associated with reduced LDL and lowered risk of ASCVD. Conversely, mutations leading to increased PCSK9 expression result in increased LDL levels and higher risk of ASCVD events.

Question 48

Therapeutic Use of PCSK9

Answer 48

• The effects of PCSK9 inhibitors are complementary to those of statins.
• While statins interfere with cholesterol production and stimulate the production of LDL receptors, PCSK9 inhibitors enable more LDL
  receptors to be available on the surface of liver cells. PCSK9 inhibitors reduce LDL-C in a dose-dependent manner by as much as 70% when used as monotherapy or by as much as 60% in patients already on statin therapy.

Question 49

ADVERSE EFFECTS AND DRUG INTERACTIONS OF PCSK9

Answer 49

• Several clinical trials have identified a small (<1%) risk of neurocognitive effects in patients treated with PCSK9 inhibitors compared to placebo.
• Additional studies are under way to better understand the longtermneurocognitive effects of these medications, if any. Unlike other medications used to treat dyslipidemias, PCSK9 inhibitors do not appear to substantially increase the risk of myopathies when used as monotherapy or in combination with statins. Similar to other monoclonal antibodies, risk of infections, including nasopharyngitis, urinary tract infections, or
  upper respiratory infections, is slightly increased. Injection site reactions are the most frequent adverse effect, although these occur in less than 10% of patients. There are no expected drug interactions with PCSK9 inhibitors.

Question 50

Inhibitor of Microsomal Triglyceride Transfer
(Lomitapide)
MOA

Answer 50

Lomitapide mesylate is the first drug that acts by inhibiting MTP, which is essential for the formation of VLDLs.

Question 51

Therapeutic Use of Inhibitor of Microsomal Triglyceride Transfer (Lomitapide)

Answer 51

Lomitapide is FDA-approved as an adjunct to diet for lowering LDL-C, total cholesterol, apo B, and non–HDL-C lipoproteins in patients with hoFH. Lomitapide reduces LDL by up to 50% and should be used in combination with maximally tolerated statin therapy. The recommended starting oral dose (5 mg/d) is titrated upward at 4-week intervals to a maximum dose of 60 mg daily. The long-term
cardiovascular effects of lomitapide are currently unknown.

Question 52

ADVERSE EFFECTS AND DRUG INTERACTIONS Inhibitor of Microsomal Triglyceride Transfer
(Lomitapide)

Answer 52

• Reported adverse effects commonlyinclude significant diarrhea, vomiting, and abdominal pain in most patients. A strict low-fat diet may improve tolerability. Serious concerns also exist regarding
  hepatotoxicity and liver steatosis.
• Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases. The agent is used under an FDA risk evaluation and mitigation strategy due to its concerning side-effect profile. Lomitapide may be embryotoxic, and women of childbearing potential should have a negative pregnancy test before starting treatment and use effective contraception during treatment.

Conclusions:
Treatment with lomitapide in homozygous familial
hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

Question 53

Inhibitor of Apolipoprotein B-100 Synthesis
(Mipomersen) MOA

Answer 53

MECHANISM OF ACTION
- the first antisense oligonucleotide inhibitor of apo B-100 synthesis

• binds to the mRNA of apo B-100 in a sequence-specific manner, which results in degradation or disruption of the apo B-100 mRNA, thereby reducing expression of apo B-100 protein.

Question 54

ADVERSE EFFECTS AND DRUG INTERACTIONS Inhibitor of Apolipoprotein B-100 Synthesis
(Mipomersen)

Answer 54

• Injection site reactions are common (80%) and include erythema, pain, itching, and hematoma.
• Other common adverse effects include flu-like symptoms (30%), fatigue, and headache (15%).
• The agent is used under an FDA risk evaluation and mitigation strategy due to concerns about hepatotoxicity.
• Elevations in liver enzymes greater than three times the upper limit of normal occurred in approximately 10%–15% of patients in clinical
  trials.

Question 55

Table 33-6 Classification of Plasma Lipid Levels Page 24

Answer 55

Table on page 25: Average effects of different classes of lipid lowering drugs

+ researches