Clin Pharm - Metabolic Disorders

is defined as elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG); low high-density lipoprotein cholesterol (HDL-C); or a combination of these abnormalities.

Dyslipidemia

Primary Dyslipidemia

Genetic defects resulting in hypercholesterolemia (e.g., Familial Hypercholesterolemia).

Secondary Dyslipidemia

Acquired via diet, medications (thiazides, steroids), or comorbidities (obesity, diabetes).

Key Lipoprotein Factors

• LDL-C

• HDL-C

• Triglycerides

What lipoprotein?
The primary carrier of cholesterol; strongly associated with ASCVD risk.

LDL-C

What lipoprotein?
Facilitates reverse cholesterol transport; low levels are an independent risk factor

HDL-C

What lipoprotein?
Transported via VLDL and chylomicrons; levels >500 mg/dL increase pancreatitis risk.

Triglycerides

Lipid-Protein Complexes

Apolipoproteins

Atherogenic Particles

HDL

__ are hydrophobic and require transport vehicles in the blood.

Cholesterol, triglycerides, and phospholipids

What Lipid-Protein Complexes?

Provide structural integrity and direct receptor binding.

Apolipoproteins

What Lipid-Protein Complexes?
Include LDL, VLDL, and remnant particles.

Atherogenic Particles

What Lipid-Protein Complexes?
Facilitates reverse cholesterol transport from vessels to liver.

HDL

is a progressive process initiated by migration of LDL-C and remnant lipoprotein particles into vessel walls.

Atherogenesis

Mechanism of Atherogenesis

LDL-C and remnant particles move into vessel walls.

Migration

Mechanism of Atherogenesis

Particles undergo oxidation and macrophage uptake.

Oxidation

Mechanism of Atherogenesis

Unregulated uptake leads to development of foam cells.

Foam Cells

Mechanism of Atherogenesis

Development of atherosclerotic plaques with a fibrous cap.

Plaque

Mechanism of Atherogenesis

Degradation of collagen leads to instability and thrombosis.

Ruptureasymptomatic

Dyslipidemic Patients are typically ___ for years until ASCVD develops.

asymptomatic

Dyslipidemia Ischemic Symptoms:

Chest pain, palpitations, shortness of breath.

Dyslipidemia Physical Signs:

○ Eruptive Xanthomas

○ Peripheral polyneuropathy

○ Abdominal obesity

Dyslipidemia Comorbid Assessment:

Hypertension, Diabetes, CKD status.

Adult Lipid Classification

For primary prevention (ages 40-79), use the ASCVD Risk Estimator Plus. A risk ___% suggests benefit from initiating statin therapy.

≥7.5

LDL estimation formula

Friedewald Equation

General Treatment Approach for dyslipidemia

• Lifestyle First

• Statins as Gold Standard

• Combination Therapy

• Risk-Based Decisions

General Treatment Approach for dyslipidemia:

__ are first-line for all lipoprotein disorders.

Therapeutic lifestyle changes (TLC)

General Treatment Approach for dyslipidemia:
___ are drugs of choice for reducing CV events.

HMG-CoA reductase inhibitors

General Treatment Approach for dyslipidemia:
Add ___ if LDL goals are not met with maximally tolerated statins.

ezetimibe or PCSK9 inhibitors

General Treatment Approach for dyslipidemia:
Initiate therapy based on individual __risk, not just plasma levels.

ASCVD

Non-Pharmacologic Treatment for dyslipidemia

• Nutrition: Mediterranean pattern; limit saturated/trans fats; increase fiber.

• Activity: Moderate-to-vigorous intensity activity 3-4x/week (40 mins/session).

• Counseling: Smoking cessation; weight management (target 5-10% loss).

Medications used in Dyslipidemia

• Statins

• PCSK9 Inhibitors

• Targeting Triglycerides (TG) [Fibrates (Gemfibrozil, Fenofibrate) and Omega-3 PUFAs]

• Cholesterol Absorption Inhibitors (Ezetimibe, Bile Acid Sequestrants)

• Adjunct and Non-Statin Therapies (Niacin,Mipomersen,Lomitapide)

Interrupt the rate-limiting step in cholesterol biosynthesis.

HMG-CoA Reductase Inhibitors

HMG-CoA Reductase Inhibitors LDL-C reduction:

20% - 60%.

HMG-CoA Reductase Inhibitors HDL-C increase:

6% - 12%.

Proven reduction in CV mortality

HMG-CoA Reductase Inhibitors

Potency Rank of statins:

Rosuvastatin > Atorvastatin > Pitavastatin >

Simvastatin > Lovastatin.

Pharmacologic Treatment for dyslipidemia LDL-C Lowering

High Intensity: Avg >=50% Reduction

Moderate Intensity: 30% to 49% Reduction

Low Intensity: <30% Reduction

High-Intensity Statins Dosing Examples

Atorvastatin 40-80 mg

Rosuvastatin 20-40 mg

Moderate-Intensity Dosing Examples

Atorvastatin 10-20 mg

Rosuvastatin 5-20 mg

Simvastatin 20-40 mg

Low-Intensity Dosing Examples

Simvastatin 10 mg

Pravastatin 10-20 mg

Lovastatin 20 mg

Simvastatin 80 mg is not recommended for initiation due to __.

myopathy risks

Reported by 10-25% of users. Includes myalgia (achiness/cramps) and weakness.

Statin-Associated Muscle Symptoms

Statin-Associated Muscle Symptoms:

Rare but fatal. CK > 10x ULN with "tea-colored" urine.

Rhabdomyolysis

Management Strategies Statin-Associated Muscle

Switch to hydrophilic statin (Rosuvastatin).

Every-other-day dosing with long half-life agents.

Rule out Vitamin D deficiency or hypothyroidism

Human Monoclonal Antibodies

Prevents LDL receptor degradation, allowing more receptors on the cell surface to clear LDL-C from circulation.

PCSK9 Inhibitors

LDL-C reduction of PCSK9 Inhibitors:

Up to 60%.

PCSK9 Inhibitors administration

Subcutaneous injection biweekly or monthly

PCSK9 Inhibitors Limitation

High cost and injection site reactions.

Targeting Triglycerides (TG) drugs

• Fibrates (Gemfibrozil, Fenofibrate)

• Omega-3 PUFAs

This drug’s Primary use is TG > 500 mg/dL to prevent pancreatitis

Fibrates (Gemfibrozil, Fenofibrate)

This drug increases statin concentrations (SAMS risk).

Gemfibrozil

Fenofibrate is preferred in __

combination therapy.

This drug in 2-4g/day reduces TG and VLDL secretion.

Omega-3 PUFAs

FDA approved for CV risk reduction.

Icosapent Ethyl (Vascepa)

Potential side effect of Omega-3 PUFAs:

Prolonged bleeding time.

Cholesterol Absorption Inhibitors

• Ezetimibe

• Bile Acid Sequestrants

What Cholesterol Absorption Inhibitors:

Reduces LDL-C (15-24%) by inhibiting NPC1L1 protein in the small intestine. Preferred adjunct therapy

Ezetimibe

What Cholesterol Absorption Inhibitors:

Reduce LDL by 13% - 20%

Reduce CV events when used as monotherapy.

First line during pregnancy

Bile Acid Sequestrants

Bile Acid Sequestrants examples

Colesevelam, Colestipol, Cholestyramine

Gemfibrozil should not be used with statins due to glucuronidation interference; use __if combination is required.

fenofibrate

What Adjunct and Non-Statin Therapies?
Lowers TG levels (20%–50%) by inhibiting lipolysis with a ↓ in free FA in plasma and ↓ hepatic esterification of TG.

Niacin

Niacin is contraindicated in?

px with active liver disease and active PUD

What Adjunct and Non-Statin Therapies?

An oligonucleotide inhibitor of apolipoprotein B-100 synthesis.

Mipomersen

What Adjunct and Non-Statin Therapies?

Indicated in patients with homozygous FH.

Mipomersen

What Adjunct and Non-Statin Therapies?

Adds 25% reduction in LDL-C when combined with other lipid-lowering therapy

Mipomersen

What Adjunct and Non-Statin Therapies?

A microsomal triglyceride transfer protein (MTP) inhibitor

Lomitapide

What Adjunct and Non-Statin Therapies?

Reduced LDL-c by 40% in patients on maximum tolerated lipid-lowering therapy and LDL apheresis

Lomitapide

Dyslipidemia in Diabetes Mellitus phenotype

Hypertriglyceridemia, low HDL-C, and dense, highly atherogenic LDL particles.

Dyslipidemia in Diabetes Mellitus first line tx

Statins are mandatory as they reduce mortality even if LDL is "near normal."

Dyslipidemia in Diabetes Mellitus combination therapy

Statin + Fibrate did not show additional CV benefit in trials (ACCORD).

Dyslipidemia in Diabetes Mellitus Glycemic Control

Colesevelam can modestly improve both A1C and LDL-C.

Hypertriglyceridemia Management

• Lifestyle: Weight loss, carb restriction, alcohol avoidance.

• Secondary: Address DM control and medications (e.g. Protease inhibitors).

• Statin: Initiate for ASCVD risk reduction if TG 175-499.

• Fibrate: Add if TG > 500 to prevent Pancreatitis.

Monitoring Intervals of dyslipidemia in Short-term:

Complete lipid panel 4-12 weeks after initiation or dose adjustment.

Monitoring Intervals of dyslipidemia in Long-term:

Repeat lipid panel every 3-12 months for adherence.

Dylipidemia safety monitoring

Routine liver enzyme and CK monitoring is NOT recommended unless symptomatic.

Dyslipidemia goals of treatment

The reduction of ASCVD-related events:

• Prevention of MI and Ischemic Stroke

• Reduction in revascularization procedures

• Improvement in intermittent claudication

• Reduction in CV-related mortality

Dyslipidemia Takeaways

● Statins are the primary tool for CV risk reduction.

● Lifestyle (TLC) is the foundation of all therapy.

● Risk-based treatment (ASCVD) is superior to number-base treatment.

● Monitor for safety (SAMS) and adherence at every visit.

Obesity occurs when there is a chronic imbalance between:

• Energy Intake: Dietary calories.

• Energy Expenditure: BMR, thermic effect of food, and physical activity.

Result of obesity based on energy homeostasis imbalance:

Increased Energy Storage Over time, this positive net balance leads to excess adipose accumulation.

Obesity Multifactorial Factors

• Genetic: Primary determinants of fat distribution and metabolic set-points in some individuals.

• Environmental: Sedentary lifestyles, high-fat food availability, and cultural/religious factors.

• Physiologic: Neurotransmitter regulation of appetite networks and leptin signaling.

The brain regulates caloric intake through complex neurotransmitter signaling:

Stimulators,Suppressors,Hormonal Input

What neurotransmitter signaling in obesity:

Neuropeptide Y (NPY), Agouti-related peptide (AgRP).

Stimulators

What neurotransmitter signaling in obesity:

Pro-opiomelanocortin (POMC), Serotonin, Dopamine.

Suppressors

What neurotransmitter signaling in obesity:

Leptin (satiety) and Ghrelin (hunger).

Hormonal Input

Secondary Causes of Weight Gain

Medical Conditions and Psychiatric/Genetic

Medical conditions as secondary cause of weight gain

• Cushing disease

• GH Deficiency

• Insulinoma

• Leptin Deficiency

• Polycystic Ovary Syndrome (PCOS)

Psychiatric/Genetic as secondary cause of weight gain

• Depression & Schizophrenia

• Binge-eating disorder

• Prader-Willi Syndrome

• Bardet-Biedl Syndrome