Drugs Used to Lower Cholesterol

Kho Kashfi, PhD, MSc, LRSC

Cholesterol lowerings drugs

Hyperlipoproteinemias are conditions in which the
concentration of cholesterol or TG carrying
lipoproteins in plasma exceeds an arbitrary normal
limit, typically defined as the 95th percentile of a
random population.

An elevated concentration of lipoproteins can

accelerate the development of atherosclerosis.

Cholesterol lowerings drugs

2.1 million deaths each year.
~ Half are secondary to cardiovascular disease (CAD)
Heart attacks ~ 600,000 death/year.
Underlying pathology in ATHEROSCLEROSIS
accounts also for strokes, kidney failure,
peripheral vascular disease.

Cholesterol lowerings drugs

25% of people with their first heart attack die

within 3hrs. of the first symptoms.
20% die within 1 year.
Mortality rate is 3-5% per year after that.
Disability, lost productivity; direct medical care
expenses are very high.

Cholesterol lowerings drugs

clinical evidence strongly suggests that reduction of
the concentration of lipoproteins in plasma can
diminish the increased risk atherosclerosis that
accompanies hyperlipoproteinemias.
Therapy is thus recommended, particularly for
individuals with a family history of premature
atherosclerosis.

Cholesterol lowerings drugs

Risk factors for the development of atherosclerosis

The three major risk factors are:

1.

smoking (tobacco use in general)

2.

hypertension

3.

elevated cholesterol

Some estimates suggest that these 3 risk factors

account for 40-60 of CHD in the USA,
but

 Lack of exercise is a significant risk factor

for CHD
several studies indicate that MI is twice as
likely in sedentary individuals as it is in
people who exercise regularly
This risk factor is comparable to that of
smoking, hypertension and
hypercholesterolemia

Adult Americans:
Sedentary life styles, ~ 50%
Smoking, 30%
Hypertension, 15-20%
Moderately high cholesterol, 25%
lack of exercise may be the most important
risk factor for heart disease, and therefore,
a major target for change.

Lipid Metabolism

Triacylglycerols (TGs) and glycogen are the two

major forms of stored energy in vertebrates
Glycogen can supply ATP for muscle contraction for
less than an hour
Sustained work is fueled by metabolism of TGs
which are very efficient energy stores because:
(1) They are stored in an anhydrous form
(2) Their fatty acids are more reduced than
amino acids or monosaccharides

Adsorption and Mobilization of Fatty Acids

Fatty acids (FA) and glycerol for metabolic fuels

are obtained from triacylglycerols:
(1) In the diet
(2) Stored in adipocytes (fat storage cells)

Free fatty acids occur only in trace amounts in

cells

Absorption of Dietary Lipids

Most dietary lipids in mammals are TGs
In the small intestine, fat particles are coated with
bile salts and digested by pancreatic lipases
Lipases degrade TGs to free fatty acids and a
2-monoacylglycerol
Lipase catalyzes hydrolysis at the C-1 and C-3
positions of a TG

Bile salts
Taurocholate and glycocholate (cholesterol
derivatives) are the most abundant bile salts

Amphipathic: hydrophilic (blue), hydrophobic (black)

Action of pancreatic lipase

Dietary phospholipids are degraded by phospholipases

Triacylglycerol degradation

Dietary cholesterol

Most dietary cholesterol is unesterified

Cholesteryl esters are hydrolyzed by an intestinal
esterase
Free cholesterol is solublized by bile-salt micelles
for adsorption
Cholesteryl acyl CoA esters are formed in the
intestinal cells

Lipoproteins
TGs, cholesterol and cholesterol esters are insoluble in
water and cannot be transported in blood or lymph as free
molecules
These lipids assemble with phospholipids and apoproteins
(apolipoproteins) to form spherical particles called
lipoproteins with:
Hydrophobic cores: TGs, cholesteryl esters
Hydrophilic surfaces: cholesterol, phospholipids,
apolipoproteins

Structure of a lipoprotein

Definitions of lipoproteins

10

Class

Chylomicrons
Chylomicron
remnants
VLDL
IDL

LDL

HDL

Major Core
lipids

Dietary TGs

Major
Apoproteins

A1, A2, A4, B48

Dietary
cholesteryl
ester

B48 , E

Endogenous
TGs

B100, C, E

Endo TGs &

cholest ester

Transport
function

Dietary TGs
Dietary
cholesterol

B100, E

B100

Endo cholest
ester

A1, A2

Hydrolysis by
LPL
Receptor,
endocytoses in
liver

Endogenous
TGs

Hydrolysis by

Endogenous

50% Rec.
endo. Liver,

cholesterol

Endo cholest
ester

Mechanism of
lipid Delivery

Endogenous
cholesterol
Remove choles.
from extra

hepatic tissue

LPL

50%
LDL
Rec. endo.
Liver/extra
hepatic tissue
Cholest ester
from IDL &
LDL

11

Exogenous Pathway
Dietary fat

Endogenous Pathway

Bile Acids
+ Cholesterol

LDL
CE

LDL
Receptor

Intestine

Chylomicrons
TG>CE
E
C
B-48

B-100
Extrahepatic
Tissues

Remnant
Receptor

Remnants
CE>TG
E

L P L
FFA
Adipose Tissue
and Muscle

B-48

IDL
CE>TG

VLDL
TG>CE
E

B-100

L P L

HDL
Cholester

B-100

A1

A2

Plasma
LCAT

FFA
Adipose Tissue
and Muscle

Disorders of Lipid Transport

Hyperlipoproteinemia can result from excessive production/ diminished
removal from plasma (utilization), or both.
1.

Primary (see table 1): Generally familial, and show a genetic

predisposition, although they may be sporadic. Classification does
not indicate mechanism of the abnormality.

2.

Secondary: Important to differentiate between 1 and 2.

Secondary can be corrected by treatment of the original
disease, withdrawal of a drug or toxic agent, etc.
Common causes of 2: diabetes, hypothyroidism, hypopituitarism,
and acromegaly. They may be secondary to alcoholism, treatment
with corticosteroids, or with estrogens. Other 2 causes include
renal disease (nephritic syndrome, uremia) and liver disease.

12

Hyperlipoproteinemia:
increased production of the VLDL (Type IV).

Increased VLDL probably due to abnormal regulation,

resulting in increased production after ingestion of even
normal amounts of carbohydrate or fat.
In the 2 type, hyperlipoproteinemia may be associated
with excessive caloric intake, weight gain, pregnancy
(last trimester), treatment with estrogens (contraceptive
drugs), corticosteroid therapy, alcohol, diabetes mellitus.
Type IV is usually not associated with xanthomas.

13

Hyperlipoproteinemia:
defective removal of the VLDL
1.

LPL Deficiency: Types I and V. Impaired activity of lipoprotein lipase (LPL)

results in defective utilization of the VLDL and chylomicrons.

Type I is found primarily in infants and children.

Type V (increased VLDL + chylomicrons) usually seen in adults.
LPL deficiency can be congenital, but also seen secondarily in diabetes,
hypothyroidism, prolonged corticosteroid therapy, acute pancreatitis.
Diagnosis: Eruptive xanthomas on extensor surfaces of legs, arms, back,
buttocks. In laboratory, see cream layer on fresh plasma. Triglyceride usually
highly elevated. Subnormal postheparin lipolytic activity (PHLA) may be
measured.
2.

Impaired function of LPL: Usually seen in Type V, and occasionally in Type

IV. Common in diabetes, may be related to insulin deficiency, impaired
synthesis of enzyme.

Broad disease

Is characterized by Type III pattern: accumulation of IDL

(remnants). Diagnosis is based on Type III pattern,
increased triglyceride and cholesterol often in equal
amounts, tuberous and planar xanthomas. Often
extensive laboratory work must be done to make this
diagnosis (ultra centrifugation, electrophoresis; lipid
class analysis).

14

Hyperlipoproteinemia Type II:

(Hyperbetalioproteinemia, Incraese in or LDL)
Thought to result from a combination of increased
production and decreased removal mechanisms.
Defective uptake of LDL by various tissues of patients
with familial disease.
Homozygote patients lack LDL receptors.
Heterozygotes (~1:500 population) have half normal
LDL receptor number.

Identification of Patients and Criteria for Therapy

Lowering total and LDL cholesterol levels will reduce the occurrence
of CHD, and will slow or arrest the progression of established CHD.
Two approaches can be used to lower cholesterol in our population.
1st, a public health approach, seeks to shift the distribution of
cholesterol levels in the entire population through
nonpharmacologic, lifestyle measures.
2nd approach seeks to identify high risk patients who will benefit
from intensive intervention.
the National Cholesterol Education Program has establish clearly
defined criteria (Archives of Internal Medicine, 1988, 48, pp. 36-69)

15

The recommendations of the expert panel are

based on several important observations:
1)

Total cholesterol is useful as a screening tool.

2) Treatment decisions should be determined by

plasma LDL-C rather than total cholesterol. When
treating hypercholesterolemic patients, other
lipoproteins including VLDL, TG and HDL should be
considered.
3) CHD risk factors including hypercholesterolemia
are interactive; therefore, the patient with
hypercholesterolemia and multiple risk factors
should be treated more aggressively.

Screening, Initial Classification by Total Plasma

Cholesterol

Serum total cholesterol should be measured in all

adults at least once every five years.
Screening cholesterol measurements can be made in
the nonfasting state.
screening cholesterol may prompt either periodic rescreening or initiation of a dietary modification
program with follow up measurements including, if
needed, lipoprotein analysis.

16

17

Tendon xanthoma

Tendon xanthoma

18

Hepatic Cholesterol Metabolism

Cholesterol lowerings drugs

Coronary artery disease (CAD)
starts with development of a fatty streak in the
arterial wall, followed by deposition of fibrous plaque
As plaque grows it begins to occlude artery, blocks
blood flow, causes angina
May lead to formation of thrombi leading to MI
Risk of CAD directly related to levels of LDL
cholesterol in blood
In 1984 a 1% drop in serum cholesterol was found
to reduce the risk of CHD by nearly 2%.

19

Plaque Rupture with Thrombus

Thrombus

Fibrous cap

1 mm
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

Lipid core

Cholesterol lowerings drugs

Cholesterol
Component of all cell membranes
Required for synthesis of hormones (estrogen,
progesterone, testosterone, adrenal
corticosteroids)
Comes from dietary sources and liver cells
Dietary cholesterol produce only a small
amount of cholesterol in the blood; they
inhibit endogenous cholesterol synthesis.
Dietary saturated fat increase circulating LDL

20

Cholesterol lowerings drugs

Cholesterol synthesis
Cholesterol is synthesized in the liver
Hydroxymethylglutaryl Coenzyme A (HMG CoA)
reductase catalyzes this synthesis
Drugs that inhibit this enzyme are most effective at
lowering cholesterol (LDL)
During night cholesterol synthesis increases: give
drug at NIGHT

Cholesterol lowerings drugs

Plasma lipoproteins
Function
Carriers for transporting lipidscholesterol and triglycerides, in the
blood
Basic Structure
Apolipoproteins
Serve as recognition sites for cell
surface receptors
Activate enzymes that metabolize
lipoproteins
Increase the structural stability of
lipoproteins
A-I, A-II (deliver cholesterol to
nonhepatic cells); B-100 (deliver
cholesterol to hepatic cells)

21

Classes of Lipoproteins Used in Coronary Artery

Disease (CAD)
Very Low Density Lipoproteins (VLDL)
Triglycerides
Low Density Lipoproteins (LDL)
Cholesterol
Greatest contributor to CAD
Account for 60-70% of cholesterol in blood
Role of LDL is to deliver cholesterol to non-hepatic tissue
High Density Lipoproteins (HDL)
Cholesterol
Protects CAD
Account for 20-30% of all cholesterol in blood
Function to deliver cholesterol from peripheral tissues back to
liver

Role of LDL Cholesterol in Atherosclerosis

LDL initiates and fuel development of

atherosclerosis

The process
1. When cholesterol moves from arteriole lumen into
space that underlies the arterial epithelium the LDLs
undergo OXIDATION which causes
2. Attraction of monocytes from circulation which undergo
convertion to macrophages
3. Inhibition of macrophage motility, keeping them at the
site of atherogenesis

22

Role of LDL Cholesterol in Atherosclerosis

4. Macrophages take up cholesterol that has not been
oxidized
5. Macrophages become cytotoxic and damage
endothelium, become large and vaculated (foam
cells); produce fatty streak under the epithelium;
make arterial wall lumpy.
6. Continuous accumulation of foam cells cause rupture
of endothelium, blood platelet adhere; form
microthrombi
7. End result- a mature atherosclerotic lesion
characterized by large lipid core and a tough fibrous
cap.

Cholesterol Testing
Total cholesterol
< 200 mg/dldesirable
> 240 mg/dlhigh risk
HDL cholesterol
< 35 mg/dllow - undesirable
LDL cholesterol
< 100 mg/dldesirable

23

Hyperlipidemia
Types of hyperlipidemias
I

IIa

IIb

III

IV

N-

N-

N-

Lipids
Cholesterol

N-

Triglycerides

N-

Lipoproteins
Chylomicrons
VLDL

N
N-

N-

N
N-

LDL

N-

HDL
N = normal,

N
= increase;

= decrease;

N
= slight increase;

N= slight decrease

24

Management of high LDL cholesterol

Management of high LDL cholesterol
Diet Modification
Reduction of LDL cholesterol
Lower total fat to < 30% of fat intake
Limit saturated fats to < 10% of caloric intake
Limit cholesterol to < 300 mg/day

Reduction of body weight

25

Lipid Lowering Drugs

HMG CoA reductase inhibitors
Bile acid-binding resins
Nicotinic acid
Fibric acid derivatives (fibrates)
Cholesterol absorption inhibitors
Estrogen

Strategy for Controlling Hyperlipidemia

Biosynthesis

Diet

STATINS

HMG CoA reductase

Ezetimibe
Serum Cholesterol

LDL-R
Cellular Cholesterol

Conversion to
hormones within
cells or storage
as granules

Bile Acids
Re-absorption
Intestine

Feces

BILE ACID
SEQUESTRANTS

Lipoprotein
catabolism
FIBRATES

26

Anti-hyperlipidemic Drugs - Statins

HO
R'

O
O

CH3

CH 2CH 2
CH 3

R''

R'
Mevastatin H
Lovastatin
H
Simvastatin CH 3

R''
H
CH 3
CH 3

Statin (generic name)

Brand name(s)

Atorvastatin

Lipitor, Torvast

Cerivastatin

Lipobay, Baycol

Fluvastatin

Lescol

Lovastatin

Mevacor, Altocor

Mevastatin
Pitavastatin

Livalo, Pitava

Pravastatin

Pravachol, Selektine, Lipostat

Rosuvastatin

Crestor

Simvastatin

Zocor, Lipex

27

Several statins are administered in active acid form that can bind to
HMG-CoA reductase. Simvastatin, Mevastatin, and Lovastatin are
administered in lactone form and must first undergo conversion to active
acid form to produce their clinical effects.

Anti-hyperlipidemic Drugs - Statins

Collectively, statins represent the number 1 category of

prescribed drug in the United States in terms of dollar
volume (more than $14 billion annually) and the number 3
category in terms of new prescription volume (more than
120 million annually)
With approximately 15 million people in the United States
taking a statin at any given time, even infrequent adverse
events can affect tens of thousands of patients. Overall, the
record of safety with statins has been good. The main
adverse effects are myotoxicity and hepatotoxicity, both of
which appear to be dose related.

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HMG CoA Reductase Inhibitor

Lovastatin (Mevacor)
These are the most effective drugs available, with low
toxicity. Combination use with nicotinic acid &
cholesterol binding resins can reduce serum
cholesterol by two-thirds.
Mechanism:
Reduces hepatic synthesis of cholesterol at the rate
limiting step, net result is increased membrane LDL
receptors and more LDL uptake from the blood

HMG CoA Reductase Inhibitor

Lovastatin (Mevacor)

Adverse effects
Headache
Rash
Myotoxicity
Hepatoxicity (Rare)
effects are dose dependent

29

Statin-induced Myotoxicity
Myotoxicity, the most common form of statin-induced
toxicity, has traditionally been defined by 2 criteria:
the presence of muscle symptoms
elevations in creatine kinase (CK) levels.
Definitions
Myalgia refers to muscle aches, soreness, or weakness, with minimal
or no elevation in CK. These symptoms may be specific in terms of
discomfort at certain locations or general in terms of overall
weakness.The onset of myalgia does not automatically dictate a
change in therapy if CK levels remain normal, but close monitoring of
CK levels is advisable.

Definitions
Myopathy refers to muscle symptoms associated with elevations in CK at
least 10 times the upper limit of normal (ULN). Statin dose reduction,
switching to a different statin, or discontinuation of statin therapy is
indicated in such cases to allow resolution of symptoms and recovery of
normal laboratory values.
Rhabdomyolysis refers to myopathy extensive enough to cause spillage
of myoglobin into the urine; this nephrotoxic substance can induce acute
renal failure. Rhabdomyolysis is typically associated with extreme
elevations in CK, to values exceeding 10,000 U/L, which is more than 50
times ULN. This condition is potentially fatal, but the incidence is low ( <
0.1%).
These traditional definitions are not absolute. A normal CK level does not
rule out muscle pathology, and muscle symptoms associated with CK
elevations less than 10 times ULN are also clinically relevant and may
warrant a revision in therapy.

30

Risk Factors

Risk Factors

31

32

Monitoring Parameters and Follow-Up Schedule

Monitoring Parameters

Follow-Up Schedule

Statins Headache, dyspepsia

Muscle soreness,
tenderness, or pain

Evaluate symptoms initially, 6 to

8 weeks after starting therapy,
then at each follow-up visit.

Evaluate muscle symptoms and CK before starting therapy. Evaluate muscle

symptoms 6 to 12 weeks after starting therapy and at each follow-up visit.
Obtain a CK measurement when people have muscle soreness, tenderness,
or pain.
ALT, AST

Evaluate ALT/AST initially,

approximately 12 weeks after
starting therapy, then annually or
more frequently if indicated.

ALT=alanine transferase; and AST=aspartate transferase.

Bile Acid-Binding Resins

Cholestyramine (Questran)

This is a bile acid binding resin

Looks and tastes like sand
Patients must take 1230 grams/day
Compliance problems
Used with nicotinic acid for an additive effect, serum
cholesterol can be lowered 40 - 50%
Adverse Effects
Constipation
Decreased absorption of fat soluble vitamins

33

Bile Acid-Binding Resins

Cholestyramine (Questran)

Mechanism:
Binds the bile acid (anion) in the GI lumen,
lowering the bile acid re-absorption and increasing its
excretion.
Now cholesterol has to be used for producing more
bile, therefore, dropping blood cholesterol level.
This results in a typical 15% reduction in serum LDL
level.
Increases LDL receptors in the liver

Bile Acid-Binding Resins

Cholestyramine (Questran)

Adverse Effects
Constipation
Decreased absorption of fat soluble
vitamins
Steatorrhea due to binding bile acids
Abnormal liver function tests due to
unknown reasons

34

Nicotinic Acid (Niacin)

Nicotinic acid

Niacin, a vitamin, can be in the form of nicotinic acid or

nicotinamide, only the nicotinic acid form reduces
cholesterol.
Nicotinic acid as a vitamin is given in milligrams and as a
drug for reducing cholesterol is given in 28 grams/day
Studies have demonstrated a decreased risk of second
MI in patients taking nicotinic acid
Mechanism:
It lowers the LDL and increases the HDL
(lowers the VLDL).

Nicotinic Acid (Niacin)

Adverse effects

Skin (flushing, itching)

Increased uric acid resulting in gout

Hepatotoxicity
-Hyperglycemia

35

Fibrates
Gemfibrozil (Lopid)
Mechanism unknown
But, it is a ligand for the nuclear transcriptin
receptor (PPAR-).
Reduces high triglyceride levels
Adverse effects
Rashes
Pancreatitis
Gallstones
Hepatotoxicity

Chlorofibrate

Cholesterol Absorption Inhibitors

Inhibit absorption of dietary cholesterol
Inhibit reabsorption of biliary cholesterol
Lower LDL cholesterol
Mechanism: Inhibit LDL Formation

36

Cholesterol Absorption Inhibitors

Ezetimibe (Zetia)

Binds to a critical mediator of cholesterol absorption,

the Niemann-Pick C1-Like 1 (NPC1L1) protein on the
gastrointestinal tract epithelial cells as well as in
hepatocytes. In addition to this direct effect, decreased
cholesterol absorption leads to an increase in LDLcholesterol uptake into cells, thus decreasing levels in
the blood plasma.

Ezetimibe
Lymph

Intestinal
Lumen

Enterocyte

Cholesterol
ACAT

Cholestery
l
Ester

Ezetimibe

NPC1L1

ABCG5/G
8

37

Cholesterol Absorption Inhibitors

Lymph

Intestinal
Lumen

Enterocyte

CM
apoB48

Triglycerid
e

Cholesteryl
Ester

Cholesterol Absorption Inhibitors

LDL
apoB100

Liver
Duodenu
m

VLDL
apoB100

Ezetimibe

Jejunum

Ileum
CM Remnant
apoB48

CM
apoB48

Colon

38

Dual Inhibition
LDL
apoB100

Liver

Statin

Duodenum

X
VLDL
apoB100

Ezetimibe

Jejunum

Ileum
CM Remnant
apoB48

CM
apoB48

Colon

Conclusions
Cholesterol balance is regulated by both synthesis
and absorption
Inhibition of cholesterol absorption may be
compensated by increases in synthesis
Optimal LDL lowering may best be achieved by
inhibiting both pathways

39

Ezetimibe: Mechanism of Action

Ezetimibe selectively inhibits
intestinal cholesterol absorption
intestinal delivery of cholesterol to
the liver
expression of hepatic LDL
receptors
cholesterol content of atherogenic
particles
Ezetimibe and its active glucuronide
metabolite circulate
enterohepatically
Delivers agent back to the site of
action
Limits systemic exposure

Radiolabeled
ezetimibe localized
at brush border of
small intestine

Photo courtesy of Harry R. Davis, PhD

Bays H. Expert Opin Investig Drugs 2002;11:1587-1604.

Catapano AL. Eur Heart J Suppl 2001;3:E6-E10.

Pharmacokinetics

Bioavailability

3565%

Protein binding

>90%

Metabolism

Intestinal wall, hepatic

Half life

1930 hours

Excretion

Renal 11%, fecal 78%

40

Adverse effects

Headache
Diarrhea/constipation
Myalgia
Raised LFT
Angioedema
Myopathy

Vytorin
When a blockbuster drug is due to lose its patent
protection (sales over a billion dollars a year) the
drug company must find creative ways to keep the
profits high.
Vytorin illustrates one path commonly taken by drug
companies.
This drug is the creation of the pharmaceutical giant
Merck (Zocor, simvastatin, goes off patent soon) and
Schering-Plough (Zetia).

41

Vytorin Clinical Trial Controversy

ENHANCE
On January 14, 2008, it was reported that a clinical trial of
Vytorin that was designed to show that the drug could
reduce the growth of fatty plaques in arteries, had little
effect on the buildup of plaque.
Merck and Schering-Plough completed the clinical trial in
April 2006 and had initially planned to release the
findings no later than March 2007.

Vytorin Clinical Trial Controversy

ENHANCE
These results are both a surprise and a warning. The fact that the
trial showed a huge LDL reduction, but that it had no effect on
plaque buildup, shows that it matters how you lower cholesterol,
not just how much you lower cholesterol.
It's becoming clear, for example, that statins, may lower the risk
of heart disease by doing more than just lowering cholesterol
studies have shown that statins can also lower inflammatory
factors that can aggravate plaques, causing them to burst and
block heart arteries, as well as reduce amounts of triglycerides, a
particularly dangerous form of fat for the heart.
(Vytorin blocks absorption of cholesterol. But what else does it
block something else in the diet that could be beneficial? We
just don't understand fully how it works).

42

Estrogen
Estrogen
In postmenopausal women, estrogen therapy reduces
LDL cholesterol by 15-25%, increases HDL cholesterol
by 10-15%

Other agents
Antioxidants (PROCUCOL)
Lowers LDL and HDL only a little but is effective in
preventing heart attacks.
It is lipid soluble and stored in body fat.
Antioxidants are a new area of research.
Efficacy of vitamins C and E in prevention of
atherosclerosis is currently under study.
Allergic and GI side effects.

43

Other agents
3Omega Fatty Acids (Fish Oils)
A cold-salt-water fish diet results in a change in
body lipid composition and a decreased MI risk.
Epidemiological evidence suggests eating fish a
couple of times per week also decreases MI risk.
Supplementing diet with fish oil without
simultaneously lowering animal fat intake has no
effect..

Dietary recommendations of the American Heart

Association currently are used most commonly as
the
beginning
point
of
therapy.
The
recommendations are as follows:

44

HDL
This is the good guy.
Two things increase HDL levels
Exercise
Moderate alcohol intake

45