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Triglycerides

Pathmaja (Bobbie) Paramsothy, MD MSPacific Medical Center

Volunteer Faculty University of Washington

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No disclaimers

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Goals

• Understand diagnosis and etiologies of hypertriglyceridemia (HTG)

• Understand the relationship of HTG and ↑ CVD risk

• Understand when and how to ↓ triglycerides and ↓ CVD risk

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Triglycerides (TG)

• Three fatty acid chains linked to one glycerol molecule

• Important lipid constituent in lipoproteins

– TG are most abundant in chylomicrons and VLDL

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The Lipoprotein

• Lipoprotein: soluble protein that transports cholesterol and triglycerides in the blood

– Atherogenic lipoproteins are Non-HDL: LDL, IDL, VLDL, Chylomicron remnants, Lp(a)

– Triglyceride rich lipoproteins are VLDL and chylomicrons (90% tg)

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Lipoprotein

Apolipoprotein B

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HTG2018 AHA/ACC Classification

• Mild: 150-174mg/dL

• Moderate: 175-499 mg/dL (2.0 -5.6 mmol/L)

• Severe: ≥ 500 mg/dL (≥ 5.6 mmol/dL)

• Prevalence in US population of hypertriglyceridemia >30%

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TG and Triglyceride Rich Lipoproteins (TRL) and Causative Role in CVD

• Association Studies– Incident fatal and nonfatal CVD (adjusted for HDL)

• Men: RR: 1.14 (95% CI: 1.05-1.28; p <0.05)

• Women: RR: 1.76 (95% CI: 1.50-2.07, p<0.05)

• Mutation Studies

• GWAS

• Mendelian Randomization Studies

» 2018 AHA/ACC Management of Blood Cholesterol and M. Budoff AJC 2016:118:138-145

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TRL and Atherosclerosis

VLDL & Chylomicrons LPLVLDL & Chylomicrons

Remnants

Liver & Enterocytes

LPL&HL

LDL

AtheroscleroticPlaque

LDL receptor

Oxidative modification

Apo C-V

Apo C-III

Apo C-III

Apo C-III

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Phenotype/Prevalence

Defect Elevated Lipoprotein (s)

Totalcholesterol

Triglycerides Risk

I: 0.0001%FamilialChylomicronemia

↓LPL or ↓Apo CII

chylomicrons Normal to ↑ (LDL

is low)

↑>1000

Pancreatitis, eruptive,lipemiaretinalis, xanthomas, hsm

IIb: 2-5%Familial Combined Hyperlipidemia

IIa↓ LDL receptorsIIb and ↑apoB

LDL, VLDL ↑ ↑ 150-500

ASCVD, arcus senilis

III: 0.01%Dysbeta-lipoproteinemia

ApoE2 mutation

IDL, VLDL remnants,chylomicron remnants

↑↑VLDL/TG

↑>500

ASCVD, tubo-eruptive &palmarxanthomas

IV: 5%Primary HTG

Multiple VLDL Normal to ↑

↑300- >1000

ASCVD, Pancreatitis

V: 0.16%Mixed HTG

↓LPL or ↓Apo CII

Chylomicrons, VLDL

↑ ↑>1000

Pancreatitis, eruptive xanthomas, hsm

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Secondary Causes of HTG

• Obesity, insulin resistance, Metabolic Syndrome• Diabetes Mellitus• High carbohydrate diet or High fat diet• Rx: betablockers, hctz, steroids, retinoids, estrogen,

protease inhibitors, antipsychotics, immunosuppressants, rosiglitazone, bileacid seq

• Hypothyroid, Renal failure, Nephrotic syndrome, Liver disease

• Paraproteinemias (macroglobulinemia, myeloma, lymphocytic leukemia)

• Auto-immune (SLE)

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Metabolic Syndrome

• Increased waist circumference– ≥ 40.1 inches (102 cm) in men– ≥ 34.6 inches (88 cm ) in women

• Increased triglycerides– ≥ 175 mg/dL (2.0 mmol/L)– On medications for hypertriglyceridemia

• Decreased HDL-C– < 40 mg/dL (1.0 mmol/L) in men– < 50 mg/dL (1.3 mmol/L) in women

• Hypertension– ≥ 130 mmHg systolic ≥ 85 mmHg diastolic– On medications for hypertension

• Elevated fasting glucose– ≥100 mg/dL 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/

AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

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Metabolic Syndrome and CVD Risk

• 34% of adult US Population (NHANES data)

• RR for CVD mortality: 1.75 (95% CI 1.19-2.58)

• Risk Enhancer for CVD risk estimation in primary prevention

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

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Management of HTG- Case

• 49 y.o man with PMHx: longstanding dyslipidemia, DM on oral agents, overweight BMI 28kg/m2

• Lifetime nonsmoker • Father died of first MI at 50, Paternal uncle first MI at

58 (nonsmoker)• No etoh, No medications except metformin 500 mg bid• Normal exercise tolerance without heart failure or

ischemic symptoms• Normal exam except arcus, bp 110/78• Normal TSH, CMP normal except fasting glucose 240,

HBA1c =8.2, +microalbuminuria

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Data for Evaluation HTG

• Height, Weight, BMI, Waist Circumference

• Fasting lipid panel

• Fasting glucose, HBA1c

• CMP

• Urine protein

• TSH

• Baseline CPK if baseline muscle symptoms

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Lipid Panel

• Total Cholesterol: 281 mg/dL

• TG: 487 mg/dL

• LDL: 152 mg/dL

• Non-HDL: 249 mg/dL

• HDL 32 mg/dL

• Diagnosis: Likely combined hyperlipidemia with moderate hypertriglyceridemia

--Fredrickson- WHO class IIb exacerbated by DM

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2018 AHA Guidelines for Treatment of HTG for Adults

COR LOE Recommendations

1 B-NR

≥ 20 years with fasting or nonfasting triglycerides 175-499 treat lifestylefactors and secondary factors

IIa B-R 40-75 years with severe htg (tg ≥ 500 mg/dL) AND ASCVD risk ≥ 7.5% do above and initiate statin therapy

IIa B-NR

Severe HTG (≥ 500 mg/dL) address behavioral/secondary causesStatin & Below: a. Very low fat dietb. Avoid refined carbs and etohc. Omega-3 Fatty acids*d. Fibrate therapy**

*Omega-3 fatty acids prescription dose**Avoid gemfibrozil if on statin

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

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Behavioral therapiesIntervention Magnitude of Effect Level of

Evidence

Weight loss +++ A

Minimize etoh +++ A

Increase physical activity ++ A

Reduce total amount of carbohydrate ++ A

Omega-3 fatty acids ++ A

Decrease intake of mono and disaccharides ++ B

Replace saturated fat with mono or polyunsaturated fat

+ B

Adapted from htg management acc/aha guidelines

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Case

• In adults age 40-75 yrs with diabetes, regardless of estimated 10 year ASCVD risk, moderate-intensity statin therapy is indicated (Class 1a for 1° prevention: 2018 ACC/AHA Guideline)

• In adults with DM who have other ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C by 50% or more (Class IIa)

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Statin Effect by Dose on Triglycerides

0

5

10

15

20

25

30

10 mg

20 mg

40 mg

80 mg

% ReductionFrom baseline

Adapted from Jones PH. Am J Cardiol 2003; 93: 152-160

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Drug Effect on Dyslipidemia

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Case #1 Plan

• Weight loss• DM control (consider referral to Endocrinologist)• Regular daily exercise 30-45 minutes• Nutritionist consult to help minimize refined

carbohydrate and saturated fat intake• Start with statin

– Rosuvastatin 10 mg – Follow up 6 weeks increase eventually to 40 mg if

needed to get LDL <100 mg/dL – Add omega-3 fatty acid if needed

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Combination Therapy

• If combination therapy or high dose statin recheck lfts

• Do not use gemfibrozil with statin instead use fenofibrate

• Do not use ezetimibe (for LDL lowering) if TG >300 mg/dL

• If combination therapy monitor for muscle symptoms

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EPA and CVD reduction

• REDUCE-IT– Multicenter, randomized, double-blind, placebo controlled trial

• Population (n=8179): Fasting triglycerides 150-499 mg/dL and on statin therapy and LDL-C 41 to 100 mg/dL

• A) Age ≥ 45 and Cardiovascular Disease (70.7%)• B) Age ≥ 50 and DM and 1 additional CVD risk factor (20.3%)• Intervention:• EPA (purified eicosapentaenoic acid ethyl ester) 2 grams bid vs.

Placebo• Primary Outcome: Composite CVD death, nonfatal MI, nonfatal

CVA, coronary revascularization or unstable angina• Secondary Outcome: composite of CVD death, nonfatal MI, nonfatal

CVA– Bhatt et al. NEJM 2019; 380:11-22, DOI: 10.1056/NEJMoa1812792

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EPA and CVD

• Primary Endpoint:– HR 0.75 (95%, CI 0.68 - 0.83)

• Secondary Endpoint– HR 0.74 (95% CI, 0.65- 0.83)

• CVD benefit was not related to the triglyceride level attained

• No difference in major bleeding• Atrial fibrillation was significantly higher in EPA group

vs. placebo (5.3% vs. 3.9%)• GI side effects lower in EPA vs. placebo (33.0% vs.

35.1%)– Bhatt et al. NEJM 2019; 380:11-22, DOI: 10.1056/NEJMoa1812792

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Summary

• HTG very common (30% population)

• Behavioral treatment and treating secondary causes is indicated for all levels of HTG

• Moderate and Severe HTG typically require Rx treatment

• For moderate HTG (175-499 mg/dL) calculate CVD risk and initiate statin when indicated (pooled cohort risk ≥ 7.5%), DM, known atherosclerotic disease

• For severe HTG (≥ 500 mg/dL) lower TG with fibrate and/or omega-3 fatty acids and initiate statin when indicated based on CVD risk

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Extra slides

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Frequency distribution of fasting plasma triglyceride (TG) concentrations.

Christopher T. Johansen et al. J. Lipid Res. 2010;52:189-

206

Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc.

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Mechanism of Action of RX on↓ TG

• Statin– ↑clearance of VLDL, Chylomicrons, Remnants by upregulating

LDL receptor– Inhibit HMGCoA reductase and thus inhibit VLDL production

• Fibrates via PPAR-alpha– Inhibit TG secretion from liver– Stimulate LPL which increases clearance of TG

• Omega-3 fatty acid– ↓ VLDL-TG production– Possibly ↓ nonesterified fatty acid (NEFA)delivery to liver and

block lipolytic release of NEFA from adipose – ↑TG clearance