hypolipidemic agents

Hypolipidemic Agents

Sachin Kuchya, MD

Assistant Professor,

Department of Pharmacology

NSCB Medical College, Jabalpur

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Why do we need them?

• Low HDL & elevated LDL-c are known risk factor for CHD.

• Elevated TG’s are known to cause Pancreatitis.

• In well controlled clinical trials ,fatal & nonfatal CHD events & strokes was reduced by as much as 30-40% as per Scandinavian Simvastatin Survival Study.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Overview of Presentation

• Physiology

• Pharmacological targets

• Drugs

• Clinical states

• Special populations

• Combination Drug Regimens

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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GLOSSARY

• Lipid – water insoluble compounds, comprising of FFA, TG, CHL, CHL- esters.

• LIPOPROTEIN- complex of lipids + apoproteins

• Chylomicrons – largest of lipoproteins, carry TG & CHL- esters from the gut to other tissues

• VLDL- very low density lipoprotein, principal form secreted by liver, represents triglyceride content in lipid profile.

• LDL- low density lipoprotein, derived from VLDL, represents CHL.

• HDL- high density lipoprotein, extracts CHL from body tissues.

• Lp(a)- LDL + apoprotein a, is known to be atherogenic.• CETP- Cholesteryl Ester Transfer Protein.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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PHYSIOLOGY

Enterohepatic circulation

- Bile acids

CHL Pool

Dietary

CHL

De novo CHL synthesis

HMG CoA reductase enz.

VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

•Adipose tissue (Storage)

•Skeletal M

•Cardiac M

•Breast tissue during lactation

To various body tissues,

Gut

HDL2 HDL3

CHL ester

TG

LDLCETP

Tightly regulated

Diurnal variation

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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1. Dietary restriction

2. Cholesterol absorption inhibitor

3. Bile acid binding resin

4. HMG CoA reductase inhibitor

5. VLDL secretion inhibitor

6. Fibric acid derivatives

7. CETP inhibitor

Dietary

Atheroma

HDL2

CHL Pool

CHL VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

Gut

HDL3

CHL ester

TG

LDLCETP

Bile acids

Non Pharmacological & Pharmacological targets

1

2

3

4

5

6

7

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Statins – effect on lipids

• LDL-c

Lowers LDL-c by 20-50%

• TG

If >250 mg/dl, then significant reduction is seen.

• HDL-c

Increases HDL levels by 5- 10%.

• Lp(a)

No effect is seen.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Statins – additional effects

• Improved endothelial function

• Prevents weakening & rupture of atherosclerotic plaque.

• Reduces platelet aggregation.

• Lowers C- Reactive protein levels – anti-inflammatory action.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Statins – Clinical Pharmacokinetics

• Should be administered orally• Lo – sim – pra – fluvastatin, should be

administered in evening / with dinner.• Ator – Rosuvastatin, can be given at any

time of day.• All statins will need dose adjustments with

gemfibrozil, cholestyramine, niacin.• Role of CYP3A4 & CYP2C9 enz.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Statins – adverse effects

• Major side effects– Myopathy (Diabetes, Advancing age & Drug)– Hepatotoxicity – Teratogenicity (Lo - Fluvastatin).

• Minor – Dyspepsia– Generalized eczematous rash (Simvastatin)

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Statins – indications

• Effective in almost all patients with elevated LDC-c levels

• Exception – familial homozygous hypercholesterolemia.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Bile acid binding resins

• LDL-c

Lowers LDL-c by 12 –28 %.

• TG

May increase transiently.

• HDL-c

Increases HDL levels by 4 –5%.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Bile acid binding resins – adverse effects

No systemic absorption, no systemic toxicity.

Only local GI side effects• Bloating• Dyspepsia

• Constipation

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Bile acid binding resins

• Indications – safest,Hypolipidemic of choice during pregnancy.

As a second line agent, if elevated LDL-c is not adequately controlled with statins.

• Drug interactions – Inhibits GI absorption of thiazides, furosemide, thyroxine,

statins, ezetimibe, fibrates, warfarin etc.Any additional drug should be administered 1 hr before or 4

hrs after the resins.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Ezetimibe

• Lowers LDL-c by 15- 20%.

(should be combined with a statin)

• Increases HDL levels by 1- 2%.

• Lowers TG’s by 5%.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Ezetimibe

• Adverse effects – almost none, well tolerated.

• No enzyme induction /inhibition is seen.

• Precaution: should not be simultaneously administered with bile acid binding resins.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Niacin

• LDL-c

Lowers LDL-c by 20- 30%

• TG

Lowers TG levels by 35-45%

• HDL-c

Increases HDL levels by 30- 40%.

• Lp(a)

Lowers Lp(a) level by 40%.

Physiologic dose, as vitamin B3– 50mg/ day

Pharmacologic dose, as hypolipidemic agent – 2 – 6gm/day.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Niacin

• Adverse effects 1. Cutaneous flushing2. Dry skin, itching3. Gastritis4. Hepatitis5. Precipitation of acute gout6. Hyperglycemia

• Contraindications H/o of gastric ulcer, gout, diabetes milletus

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Niacin - indications

• Hypertriglyceridemia

• Elevated LDL-c,

Especially in those with low HDL-c levels.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Fibric acid derivatives

• LDL-c

Increases LDL-c by upto 10-30%.

• TG

Lowers TG’s by upto 50%

• HDL-c

Increases HDL levels by 15%.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Fibric acid derivatives

• Adverse effects – Gallstone (Clofibrate)– Dyspepsia & abdominal pain– Increased risk of myopathy (gemfibrozil +

statins)

• Contraindications– Hepatic & renal dysfunction

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Fibric acid - indications

• Hypertriglyceridemia

• Chylomicronemia

• Type III dysbetalipoproteinemia

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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CETP inhibitor - Torcetrapib

• Increases HDL levels by 45- 100%.

• Under clinical trial.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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ω3 – fatty acids

• EPA & DHA, found primarily in fish oils, when given in high doses upto 6 gm/day, result in inhibition of VLDL secretion.

• TG level falls upto 75%

• Are very useful in treatment of severe hypertriglyceridemia’s ( > 1000mg/dl).

• However, these often raise LDL-c levels, in a manner similar to that seen with fibric acid derivatives, the clinical impact is however unclear.

• Commonest side effect is belching with a fishy odour

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Clinical states

• In this section, we will have some clinical states.

• This exercise shall rationalize the use of hypolipidemic agents.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Chylomicronemia Dietary restriction 1

CHL Pool

Dietary

CHL VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

To various body tissues,

Gut

HDL2 HDL3

CHL ester

TG

LDLCETP

1

Bile acids

Clinical state - 1

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Hypercholesterolemia2

5

4

3

Cholesterol absorption inhibitor

Bile acid binding resin

HMG CoA reductase inhibitor

VLDL secretion inhibitor

CHL Pool

Dietary

CHL

De novo CHL synthesis

HMG CoA reductase enz.

VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

To various body tissues,

Gut

HDL2 HDL3

CHL ester

TG

LDLCETP

2

53

4

Bile acids

Clinical state - 2

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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CHL Pool

Dietary

CHL VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

atheroma

Gut

HDL2 HDL3

CHL ester

TG

LDLCETP

6

5

Hypertriglyceridemia

6

5 VLDL secretion inhibitor

Fibric acid derivatives

Clinical state - 3

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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CHL Pool

Dietary

CHL VLDL

Chylomicrons

50%

50%

VLDL

LDL

TG

CHL

Atheroma

Gut

HDL2 HDL3

CHL ester

TG

LDLCETP 7

5

Low HDL-c levels

VLDL secretion inhibitor

CETP inhibitor

5

7

Clinical state - 4

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Special Population

• Children

• Women – Adolescence / Pregnancy/ Lactation/ Postmenopausal.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Special population – Children

• Less than 2 yrs of age – no dietary restriction & no drug therapy.

• > 2yrs – 10yrs – Dietary restriction of saturated and total fats ; CHL restricted diet only.

• 10 yrs & above – Diet therapy

Drug therapy is indicated only after an adequate trial of dietary control for 6mo – 1 yr.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Special population – Children

• Drugs Bile acid sequestrants (resins) are the first line agents of

choice.

If not - tolerated then,Statins can be given,

Ator – lova – sim, approved for 11yrs & above.

Pravastatin, for 8 yrs & above.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Women

• Statins should be used with caution in adolescent girls / females, likely to conceive.

• Bile acid binding resins are the only CHL – lowering drugs used during pregnancy.

• In post menopausal women, who wish to have HRT, elevated TG’s if any should be controlled with Dietary restriction, weight control and fibrates/ statins + fibrates, prior to initiation of HRT.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Combination regimens – why?

• Maximize reduction of LDL & VLDL.• Minimize side effects by using smaller

doses of drugs.• Allow use of resins, patients with elevated

TG’s & LDL.• Treat increased LDL, found consequent to

treatment of elevated TG with fibric acid derivatives.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Combination regimens – when?

• After diet & a single drug have been found insufficient.

• Statins, being the most effective & well tolerated, should be the first drug.

• Effect on Plasma lipoprotein levels & side effects should be assesed only after 4 –8 weeks of therapy.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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LDL-c reduction

• Statin + Fenofibrate

• Statin + Niacin

• Statin + Resins

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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VLDL reduction

• Nicotinic acid + fibric acid

• Addition of fish oils, may be helpful.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Minimize doses and side effects

• Statin + Ezetimibe is the safest combination.

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Diabetic patient

The defect,• Elevated TG’s / LDL

• Low HDL-c

• Glycosylated LDL

The treatment,• Adequate glycemic control & dietary restrictions.

• Drugs

04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur

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Diabetic patient - drugs

Niacin – impairs glycemic control

Resins – increases TG

Fibric acid level – increases LDL

So, combination of hypolipidemics is must,

Statin + fenofibrate, is the ideal combination.

Thank you

Topic is open for queries