B P4 C27 Lipoprotein Disorders and Cardiovascular Disease Flashcards
A young patient with eruptive xanthomas and a plasma triglyceride level of 22 mmol/L (2000 mg/dL) probably has _____ as a result of LPL deficiency or other monogenic defects
Familial hyperchylomicronemia
A 38-year-old woman with a strong family history of ASCVD, tendinous xanthomas, and an untreated LDL-C of 240 mg/dL (6.4 mmol/L) likely has _____.
Heterozygous familial hypercholesterolemia (HeFH)
An obese,hypertensive middle-aged man with a cholesterol level of 6.4 mmol/L (245 mg/dL), a triglyceride level of 3.1 mmol/L (274 mg/dL), an HDL-C level of 0.8 mmol/L (31 mg/dL), and a calculated LDL-C level of 4.2 mmol/L (162 mg/dL) probably has _____.
Metabolic syndrome
Affected subjects with FH have an elevated LDL-C level greater than the 95th percentile for age and sex, approximately ____ mg/dL (5.0 mmol/L) in adults.
In adulthood, clinical manifestations include tendinous xanthomas over the _____; corneal arcus and xanthelasma are less specific signs of FH.
190 mg/dL
Extensor tendons (MCP joints, patellar, triceps, and Achilles tendons)
- Transmission: Autosomal codominant
- High risk for the development of CAD by the third to fourth decade in men and approximately 8 to 10 years later in women
- Remarkably, prompt recognition in childhood or early adulthood and treatment (statins) can normalize life expectancy.
Gain-of- function mutations in the _____ gene decrease surface availability of the LDL-R protein and cause accumulation of LDL-C in plasma
PCSK9
- A loss-of-function mutation in PCSK9 confers lower LDL-C than in individuals without the mutation
- Black Americans had a higher prevalence of this protective mutation than did whites in the ARIC (Athero- sclerosis Risk in Communities) study, and subjects with life-long low LDL-C because of a mutation at the PCSK9 gene locus had a marked reduction in coronary events, thus confirming that genetically low LDL-C states lower cardiovascular risk.
A rare condition of increased intestinal absorption and decreased excretion of plant sterols (sitosterol and campesterol) can mimic severe FH with extensive xanthoma formation.
Sitosterolemia
- Premature atherosclerosis, often apparent clinically well before adulthood, occurs in patients with sitosterolemia.
- Diagnosis requires specialized analysis of plasma sterols documenting an elevation in sitosterol, campesterol, cholestanol, sitostanol, and campestanol.
- Patients with sitosterolemia have normal or reduced plasma cholesterol levels, and normal triglyceride concentrations.
- Patients with sitosterolemia have rare homozygous (or compound heterozygous) mutations in the ABCG5 and ABCG8 genes.
Conversely, an obese middle- aged man with a plasma triglyceride level of 7 mmol/L (620 mg/dL) probably has mutations in several genes associated with _____ levels.
Plasma triglyceride levels
Disorders of LDL
Familial hypercholesterolemia
LDLR gene defect
Familial defective ApoB
G-O-F of PCSK9
Polygenic hypercholesterolemia
Nonfasting triglycerides are higher than fasting levels (by approximately 0.3 mmol/L or 27 mg/dL), and guidelines consider nonfasting triglycerides _____ mmol/L (_____ mg/dL) as abnormal, while for fasting triglycerides the corresponding level is _____ mmol/L (_____ mg/dL).
Nonfasting:
> 2 mmol/L
> 175 mg/dL
Fasting:
> 1.7 mmol/L
>150 mg/dL
The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline and the 2019 AHA/ACC prevention guideline consider fasting or nonfasting triglycerides greater than ____ mg/dL as a risk enhancing factor that could prompt consideration for initiating or intensifying statin therapy.
175 mg/dL
There are some differences in the guideline cutpoints for severe hypertriglyceridemia, defined as fasting triglycerides greater than _____ mmol/L (_____ mg/dL) in European guidelines or _____mg/dL (_____mmol/L) in US guidelines
EU: >10 mmol/L or 885 mg/dL
US: > 5.7 mmol/L or 500mg/dL
Because the triglyceride to cholesterol ratio in TRLs progressively increases as the hypertriglyceridemia becomes more severe, the Friedewald equation (which assumes a fixed triglyceride to cholesterol ratio of triglycerides/5 [mg/dL] or triglycerides/2.2 [mmol/L]) to calculate LDL-C is inaccurate when triglycerides are greater than 4.5 mmol/L (400 mg/dL), as it underestimates the true LDL-C at high triglyceride levels. Instead, it is preferable to use _____ instead of calculated LDL-C for LDL-related treatment decisions in patients with hypertriglyceridemia, as direct LDL-C assays may also be inaccurate
Non-HDL-C or apo B
Primary causes of hypertriglyceridemia: Mild-to-moderate HTG (TG 2.0–9.9mmol/L)
Multifactorial or polygenic HTG (formerly HLP Type 4 or familial HTG)
Complex genetic susceptibility (see above)
Dysbetalipoproteinemia (formerly HLP Type 3 or dysbetalipoproteinemia)
Complex genetic susceptibility (see above), plus
APOE E2/E2 homozygosity or
APOE dominant rare variant heterozygosity
Combined hyperlipoproteinemia (formerly HLP Type 2B or familial combined hyperlipidemia)
Complex genetic susceptibility (see above), plus
Accumulation of common small effect LDL-C-raising polymorphisms
Primary causes of hypertriglyceridemia: Severe HTG (TG >10 mmol/L)
Monogenic chylomicronemia (formerly HLP Type 1 or familial chylomicronemia syndrome)
Lipoprotein lipase deficiency (Bi-allelic LPL gene mutations)
Apo C-II deficiency (Bi-allelic APOC2 gene mutations)
Apo A-V deficiency (Bi-allelic APOA5 gene mutations)
Lipase maturation factor 1 deficiency (Bi-allelic LMF1 gene mutations)
GPIHBP1 deficiency (Bi-allelic GPIHBP1 gene mutations)
Multifactorial or polygenic chylomicronemia (formerly HLP Type 5 or mixed hyperlipidemia)
Complex genetic susceptibility, including
Heterozygous rare large-effect gene variants for monogenic chylomicronemia (see above); and/or
Accumulated common small-effect TG-raising polymorphisms (e.g., numerous GWAS loci including APOA1-C3-A4-A5; TRIB1, LPL, MLXIPL, GCKR, FADS1-2-3, NCAN, APOB, PLTP, ANGPTL3)
Other
Transient infantile HTG (glycerol-3-phosphate dehydrogenase 1 deficiency) from bi-allelic GPD1 gene mutations
______ results from both common and rare genetic variants that result in increased VLDL particles.
Polygenic hypertriglyceridemia (formerly Type IV hyperlipidemia)
- Fasting plasma concentrations of tri- glycerides range between 2.3 to 5.7 mmol/L (200 to 500 mg/dL).
- After a meal, plasma triglycerides may exceed 11.3 mmol/L (1000 mg/dL).
- Polygenic hypertriglyceridemia does not associate with clinical signs such as corneal arcus, xanthoma, and xanthelasmas.
Polygenic hypertriglyceridemia does not associate with clinical signs such as ______.
Corneal arcus, xanthoma, and xanthelasmas
Polygenic hypertriglyceridemia has a weaker relationship with _____ than combined hyperlipoproteinemia (familial combined hyperlipidemia), and not all studies support this association
CAD
Lifestyle modifications should be the first step in treatment of Polygenic hypertriglyceridemia, including:
(1) Weight reduction in overweight individuals
(2) Limiting alcohol intake
(3) Reducing caloric intake
(4) Increasing exercise
(5) Withdrawal of hormones (estrogens and progesterone or anabolic steroids)
An unrelated X–linked genetic disorder,_____, may mimic familial hypertriglyceridemia because most measurement techniques for triglycerides use the measurement of glycerol after enzymatic hydrolysis of triglycerides.
Diagnosis of of this disease requires ultracentrifugation of plasma and analysis of glycerol.
Familial glycerolemia
A less common subset of patients have more severe hypertriglyceridemia which is characterized by a more severe elevation in both VLDL and chylomicrons and are classified as having _____.
Polygenic chylomicronemia (formerly Type V hyperlipidemia)
A rare disorder of HDL deficiency, identified in a proband from Tangier Island in Virginia, Tangier disease and familial HDL deficiency result from mutations in the _____ gene
ABCA1 gene
Reduced plasma levels of _____ consistently correlate with the development or presence of ASCVD
HDL-C
_____ all associate with reduced HDL-C levels.
Monogenic hyperchylomicronemia
Polygenic hypertriglyceridemia
Combined hyperlipoproteinemia
C-H-oMP
Plasma triglyceride and HDL-C levels vary inversely. Several mechanisms contribute to this association:
(1) Decreased lipolysis of TRLs decreases the availability of substrate (phospholipids) for HDL maturation
(2) HDL enriched with triglyceride has an increased catabolic rate and hence reduced plasma concentration
(3) The augmented pool of TRLs saps cholesterol from the HDL compartment by CETP-mediated exchange.
Hypothyroidism often elevates ____ or both.
An increased _____ provides the key to the diagnosis, and the lipoprotein abnormalities often revert to normal after correction of thyroid status.
LDL-C, triglycerides, or both
TSH
Estrogens can elevate plasma _____, because of increases in both hepatic VLDL and apoA-I production.
Triglyceride and HDL-C levels
Oral contraceptives should be avoided in premenopausal women with _____.
In postmenopausal women, estrogens may reduce LDL-C by up to ___%. Use of estrogens for the treatment of lipoprotein disorders is no longer recommended
Premenopausal women with:
* Hypercholesterolemia (LDL-C >4 mmol/L, 160 mg/dL)
* Multiple risk factors
* High thrombotic risk
Postmenopausal women:
15% reduction in LDL-C
Both ____ increase during pregnancy.
Cholesterol and triglycerides
Rarely, pregnancy (particularly in the third trimester) causes severe increases in triglycerides on a background of LPL deficiency or other genetic defects, even if such mutations do not result in dyslipidemia in the non-pregnant state
Male sex hormones and anabolic steroids can increase ______ activity and have been used for the treatment of hypertriglyceridemia in men; however, these agents can also contribute to an elevated triglyceride level, reduced HDL-C, increased blood pressure, and other features of metabolic syndrome.
Hepatic lipase activity
Growth hormone can reduce _____ and increase _____ but is not recommended for the treatment of lipoprotein disorders.
Reduce: LDL-C
Increase: HDL-C
The most frequent secondary cause of dyslipoproteinemia is the constellation of metabolic abnormalities seen in patients with metabolic syndrome.
The finding of _____ and represents the major components of metabolic syndrome
Increased visceral fat (abdominal obesity)
Elevated blood pressure
Impaired glucose tolerance
Increased plasma triglycerides
Reduced HDL-C level
The main cause of dyslipoproteinemia in patients with metabolic syndrome is _____, the substrates for TRL synthesis.
Insulin resistance
Associated increase in FFAs
Overt diabetes, especially type 2 diabetes, frequently elevates plasma _____ and reduces _____.
While LDL-C may be normal or nonelevated due to the excess of small dense LDL particles, increased concentrations of apo B or non-HDL-C are often present and result in a “discordant” lipid profile.
Elevated: TG
Reduced: HDL-C
____ lipodystrophy, a genetic disorder with features of metabolic syndrome, results from mutations within the lamin A/C gene and is associated with limb-girdle fat atrophy. Excess plasma triglycerides often accompany glycogen storage disorders.
Dunnigan lipodystrophy
In patients with glomerulonephritis and protein-losing nephropathies, a marked increase in secretion of hepatic lipoproteins can raise _____, which may approach the levels seen in those with FH.
LDL-C
By contrast, patients with chronic renal failure have a pattern of ______.
Hypertriglyceridemia
Increased small dense LDL particles
Lp(a) - may also be elevated
Reduced:
HDL-C
In the Cholesterol Treatment Trialists meta-analysis of 28 trials of patients with varying degrees of renal impairment, statins reduced cardiovascular risk among patients with _____ chronic kidney disease (estimated glomerular filtration rate >/=30 mL/min/1.73 m2) with smaller benefit among patients with more _____ renal failure, and there was no benefit for patients with _____.
Reduceed CV risk: mild to moderate CKD
Small benefit: advanced renal failure
No benefit: ESRD undergoing dialysis
After organ transplantation, the immunosuppressive regimen (glucocorticoids and cyclosporine) typically elevates _____, reduces ____, and increases _____. Because transplant recipients generally have an increase in cardiovascular risk, this secondary hyperlipidemia may warrant treatment.
Increased:
Triglycerides
VLDL
small dense LDL
Reduced: HDL-C
The Kidney Disease International Improving Outcomes (KDIGO) recommends _____ treatment for patients with chronic kidney disease but does not recommend lipid lowering treatment initiation in patients undergoing long-term dialysis.
Statin or statin plus ezetimibe
Obstructive liver disease, especially primary biliary cirrhosis, may lead to the formation of an abnormal lipoprotein termed _____.
This type of lipoprotein, also associated with LCAT deficiency, consists of an LDL-like particle with a marked reduction in cholesteryl esters.
Extensive xanthoma formation on the ____ areas can result from accumulation of lipoprotein-x.
Lipoprotein-x
Xanthomas of face and palmar areas
Factors contributing to _____, such as an imbalance between caloric intake and energy expenditure, lack of physical activity, and a diet rich in saturated fats and refined sugars, contribute in large part to the lipid and lipoprotein lipid levels within a population.
Obesity
Excessive alcohol intake stimulates _____ and decreased _____.This results in TRL accumulation in the plasma and the liver, and increases hepatic fat accumulation and insulin resistance.
Stimulation of:
Chylomicron and VLDL secretion
VLDL overproduction
Decreased:
LPL activity, and fatty acid oxidation
Several medications can alter lipoproteins:
Thiazide diuretics - increase TG
Beta-blockers (non–beta1-selective agents): increase TG, lower HDL-C
Retinoic acid and estrogens - increase TG.
Corticosteroids and immunosuppressives - increase TG , lower HDL-C.
Estrogens - increase HDL-C and TG.
Anabolic steroids (by endurance or body-building athletes) - hypertriglyceridemia and very low HDL-C.
Atypical antipsychotics -lipoprotein abnormalities, metabolic disorders, and weight gain.
Highly active antiretrovirals - severe lipoprotein disorders and an increase in CAD in patients with chronic human immunodeficiency virus infection
Statins inhibit cholesterol synthesis by inhibiting the enzyme _____ and preventing the formation of mevalonate, the rate-limiting step of sterol synthesis.
HMG- CoA reductase
Atherosclerosis involves inflammation and statins have anti-inflammatory effects. The effect of statins include ____.
(1) Decrease the inflammatory biomarker CRP independent of LDL-C lowering
(2) Augment the collagen content of atherosclerotic plaque
(3) Alter endothelial function
(4) Decrease the inflammatory component of plaque
Statins lower LDL-C in a dose-response manner which is nonlinear: for every doubling of the statin dose, LDL-C drops by about an additional _____%.
6%
Statins vary in intensity from high-intensity (_____) to moderate-intensity (_____) and low-intensity (_____).
High: average lowering of LDL-C by 50%
Atorvastatin 40 to 80 mg/day
Rosuvastatin 20 to 40 mg/day;
Moderate: 30% to 49%
Low: <30%
Statins reduce LDL-C and non-HDL-C more than reducing apo B (by ___<%), triglycerides (by ___%, depending on baseline levels), and may increase HDL-C (by ___%). Statins do not reduce Lp(a)
Reduction:
apo B: 30%
TG: 10-20%
Increase:
HDLC: 1-10%
No reduction: Lp(a)
Statins differ in several aspects including their lipophilicity, plasma protein binding, and absorption, and many statins (except for _____) undergo hepatic metabolism via cytochrome P450 isoenzymes.
Pravastatin
Rosuvastatin
Pitavastatin
PRP - No care sa Liver
Concomitant drugs that interfere with the metabolism of statins by inhibiting the cytochrome P-450 3A4 (which metabolizes ______) and 2C9 can increase plasma concentrations of statins.
Lovastatin
Simvastatin
Atorvastatin
LSA 3A4
Common substances that may interact with statins include:
Amiodarone
Antibiotics (e.g., erythromycin, clarithromycin, rifampin)
Antifungal medications (e.g., azoles)
Antiviral drugs (e.g., lopinavir and ritonavir)
Grapefruit juice
Calcium channel blockers
Colchicine
Cyclosporine
Warfarin
For patients who cannot tolerate daily statin, switching to an alternative appropriate statin with daily dosing (_____ may have less muscle toxicity), or lowering the dose to a small dose of a high-intensity statin every other day or less frequently is usually tolerated and results in considerable LDL-C lowering although outcomes trials have not evaluated this alternate dosing approach.
Pravastatin
Pitavastatin
Fluvastatin
Less muscle/leg work - less P2F
The 2013 ACC/AHA cholesterol guidelines recommended against routine measurement of ___ in all
CK
After initiation of statin therapy, the response should be checked with a repeat lipid panel (fasting or nonfasting) within the first _____ months to determine the patient’s adherence and response.
1-3 months
The unwanted effects of statins are muscle symptoms (statin-associated muscle symptoms [SAMS]) ranging from diffuse myalgias (normal CK without functional loss), seen in up to _____% of statin users, to myositis, defined as diffuse muscle pain with evidence of muscle inflammation and elevated CK levels, which necessitate discontinuation of use of these drugs in less than ___% of cases
Routine CK or transaminase measurements are not recommended in follow-up, unless the patient has _____.
Muscle symptoms:
* Diffuse myalgias: 10-15%
* Myositis: <1%
CK/Transaminase on ff-up if:
* Muscle symptoms
* Fatigue
* Symptoms of hepatotoxicity
Mildly elevated ALT occurs in less than _____% of patients on statins and is not associated with hepatotoxicity.
<2%
Clinically relevant ALT elevation is defined as greater than _____ times upper limit of normal on two consecutive occasions, and progression to liver failure is very rare.
> 3x ULN on 2 consecutive occasions
Rarely, statin use associates with rhabdomyolysis.This life-threatening situation often associates with predisposing factors:
Advanced age
Frailty
Renal failure
Shock
Concomitant use of antifungal agents, antibiotics, gemfibrozil
Hypothyroidism
The _____ trial was a parallel- group trial conducted among patients with recent ischemic stroke or transient ischemic attack (N = 2860) from France and South Korea assessing a target LDL-C of less than 70 mg/dL versus 90 to 110 mg/ dL using statins and/or ezetimibe.The trial was stopped prematurely after 3.5 years due to lack of funding but showed a significant 22% risk reduction in cardiovascular events with the lower LDL-C target, with no increased risk of intracranial hemorrhage.
Treating Stroke to Target Trial
Statins do not adversely affect cognitive function.
On average, lowering of LDL-C by 1% corresponds to approximately ____% lower risk of cardiovascular events.
1% LDL decrease = 1% CV event decrease
The ______ meta-analysis included 27 randomized statin trials (N = 174,149 individuals,27% women). It found for a 1 mmol/L (39 mg/ dL) in LDL-C with statin versus placebo (22 trials), or more versus less intensive statin (5 trials),a 21% reduction in major vascular events over median follow-up of 4.9 years.There were significant risk reductions in all-cause mortality (10%) driven by reduction in vascular mortality (12%),major coronary events (23%),coronary revascularization (24%), and stroke (15%), with no effect on incident cancer or cancer mortality. During the first year of statin treatment, the relative benefit was half as large as subsequent years.
Cholesterol Treatment Trialists
A ______ meta-analysis of 18 randomized trials of statin versus placebo on 56,934 individuals from primary prevention, yielded similar results, with 14% relative risk reduction in all-cause mortality and 25% reduction in vascular events
Cochrane
Cardiovascular disease is the leading cause of the increased morbidity and mortality in patients with diabetes, and ______ therapy is first-line treatment for reducing cardiovascular risk.
Statin
The 2019 ACC/AHA guidelines recommend moderate-intensity statin for adults with _____, and high intensity statin for adults with _____.
Moderate: diabetes age 40 to 75 years
High:
Diabetes and multiple cardiovascular risk factors or with diabetes-specific risk enhancers (long diabetes duration, albuminuria, eGFR <60 mL/min/1.73 m2, retinopathy, neuropathy, or ankle-brachial index <0.9).
In the ______ meta-analysis of 186,854 individuals from 28 trials, a total of 14,483 individuals were older than 75 years at randomization. Over a median follow-up of 4.9 years, statin or more intensive statin reduced vascular events by 21% per 1 mmol/L reduction in LDL-C, with significant reductions in all age groups. Among individuals 70 to 75 years or older at base- line with no prior vascular disease, the relative risk reduction was smaller than those with manifest disease
Cholesterol Treatment Trialists
The _____ study randomized 12,705 participants in 21 countries at intermediate risk of ASCVD to rosuvastatin 10 mg per day or placebo, resulting in 24% relative risk reductions in vascular events, with similar results by race and ethnicity.
Health Outcomes and Population Evaluation-3 (HOPE-3)
Statin therapy does not reduce cardiovascular morbidity or mortality in patients with advanced heart failure of ischemic or nonischemic cause’
Statins reduced cardiovascular risk among patients with __________
There was no benefit for patients with end-stage renal disease undergoing dialysis, despite these patients having very high risk for cardiovascular events and mortality
Renal disease is a risk factor for statin-related ________, in particular with high statin doses, and clinical judgment must care- fully weigh the benefits of such preventive measures in these patients.
Mild to moderate chronic kidney disease (estimated glomerular filtration rate ≥30 mL/min per 1.73 m2)
Myopathy
_____ is a protein that regulates the surface expression of the LDL-R on the hepatocyte
PCSK9
Elevated concentration or function of PCSK9 reduces LDL-R expression by binding to it and promoting lysosomal degradation of the LDL-R, resulting in higher circulating LDL.
Lower PCSK9 concentration or function increases the LDL-R expression and results in lower circulating LDL. PCSK9 also inhibits intracellular degradation of apo B, the main apolipoprotein on LDL and VLDL particles
A liver-targeted small interfering (si) RNA _____ inhibits synthesis of PCSK9 by inhibiting the messenger RNA for PCSK9. This RNA interference approach is appealing from a clinical standpoint as it requires infrequent dosing (twice a year), a strategy that is being evaluated in an outcomes trial ____ of 15,000 patients with known cardiovascular disease.
Inclisiran
ORION-4 trial
Lower PCSK9 concentration or function ______ the LDL-R expression and results in lower circulating LDL.
Increases
The monoclonal antibodies (evolocumab [Repatha], and alirocumab [Praluent]) have demonstrated potent LDL-C-lowering capacity _____%), regardless of background therapy, in a wide variety of patients, including those on statins and statin-intolerant patients, as long as patients express LDL-R in the liver (including heterozygous FH), with less LDL-C lowering among homozygote FH with residual LDL-R expression. They also moderately lower triglycerides (by approximately ___%) and may increase HDL-C. Unlike statins, they reduce Lp(a) levels by ___% through unclear mechanisms that may be contributing in part to their cardiovascular benefit.
MAb: (Evolocumab, Alirocumab)
LDL-C: Dec 50-60%
TG: 25%
HDL: increase
Lp(a): DECREASE by 25-30%
The siRNA inclisiran also lowered LDL-C and non-HDL-C in a dose-response manner by up to ___%, apo B (by ___%), with variable effects on lowering triglycerides and Lp(a).
siRNA: Inclisiran
LDL-C: 50%
apo B:20-40%
TG: Variable
_____ trial examined the effect of evolocumab on cognitive function, tested formally in 1204 patients enrolled in FOURIER. After a mean follow-up of 20 months, there was no evidence of increased risk of cognitive events in patients treated with evolocumab, compared with placebo, including those who reached a very low LDL-C (<25 mg/dL, 0.7 mmol/L).
EBBINGHAUS Trial
_____-of- function mutations within the PCSK9 gene associate with normal health and a marked reduction in life-long cardiovascular events.
Loss-of-function
Two trials evaluating fully human antibodies (FOURIER: ______, and ODYSSEY Outcomes: _____) both showed similar 15% relative reductions in risk of cardiovascular events when added to statins ± ezetimibe, while the two other trials (SPIRE I and II, evaluating _____, a monoclonal antibody that is not fully human) were stopped early due to development of high rates of antidrug neutralizing antibodies and attenuated LDL-C lowering.
FOURIER: Evolocumab
ODYSSEY: Alirocumab
SPIRE I and II: Bococizumab
The _____________ trial
Tested evolocumab (140 mg every 2 weeks or 420 mg monthly subcutaneously) versus placebo in 27,564 patients with cardiovascular disease plus additional risk factors on maximal statin ± ezetimibe with starting LDL-C 70 mg/dL 1.8 mmol/L), or non-HDL-C 100 mg/ dL (2.6 mmol/L)
Trial showed that evolocumab was superior to placebo at reducing adverse cardiovascular events.
FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)
The primary outcome, incidence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group versus 14.6% of the placebo group (p < 0.0001). This finding was consistent among all tested subgroups. Benefit was enhanced among higher-risk subgroups (those with recent MI, multiple prior MIs, and residual multivessel coronary artery disease) compared to those without such characteristics.
Evolocumab reduced total cardiovascular events (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75-0.90, p < 0.001), first cardiovascular events (HR 0.85, 95% CI 0.79-0.92, p < 0.001), and subsequent events (HR 0.74, 95% CI 0.65-0.85).
The ____________ examined cardiovascular outcomes in 18,924 patients post–acute coronary syndrome treated with alirocumab versus placebo on top of baseline statin and LDL-C 70 mg/dL (1.8 mmol/L), non-HDL-C 100 mg/dL (2.6 mmol/L) or apoB 80 mg/dL.
This showed that use of alirocumab, taken every other week, significantly reduces ischemic events, including all-cause mortality and MI, compared with placebo among patients with an ACS event within the preceding 1-12 months.
In an exploratory analysis, this showed reduction in all-cause death (without reduction in cardiovascular death),while FOURIER did not find reduction in all-cause or cardiovascular death.
ODYSSEY Outcomes trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab)
This is one of the first trials to show a therapeutic benefit with reduction in Lp(a) that is independent of LDL-C. This
In a meta-analysis of 66,478 patients from randomized trials (mean follow-up 2.3 years) evaluating alirocumab or evolocumab versus placebo or other lipid-lowering therapies, there was about __% risk reduction in myocardial infarction and ischemic stroke with no significant reduction in all-cause or cardiovascular mortality and no significant increase in neurocognitive events, liver enzymes or new-onset diabetes
20%
Ezetimibe inhibits cholesterol absorption via the _____. By reducing the amount of cholesterol that is delivered to the liver, the liver upregulates LDLR expression result- ing in increased clearance of LDL from the circulation.
Niemann-Pick C1- like protein 1 (NPC1L1)
Ezetimibe monotherapy lowers LDL-C up to ___%,while ezetimibe added to statin reduces LDL-C by an additional _____%.Adding ezetimibe to statin did not result in increased elevations of CK levels or muscle adverse events compared with statin alone, and life-threatening liver failure is very rare
Monotherapy: 20%
Combination: 15 - 20%
In the _____ Trial of 18,144 patients after a recent acute coronary syndrome with baseline LDL-C levels of 50 to 125 mg/dL (1.3 to 3.2 mmol/L), adding ezetimibe 10 mg/day to statin therapy.
Patients with recent ACS were randomized in a 1:1 fashion to either ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg.
This resulted in additional benefit of 6.4% relative risk reduction in ASCVD events (including coronary and stroke events) during a 7-year follow-up period.
The median on-treatment LDL-C levels during the study was 54 mg/dL (1.4 mmol/L) in the combination group and 70 mg/dL (1.8 mmol/L) in the statin-only group.
IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)
The results of the landmark IMPROVE-IT trial indicate that in patients post high-risk ACS, ezetimibe 10 mg/simvastatin 40 mg is superior to simvastatin 40 mg alone in reducing CV events. A reduction was observed in first as well as recurrent events. Patients with DM, prior stroke, and prior CABG appeared to have a greater treatment effect than patients without DM. Benefit was noted irrespective of baseline LDL-C levels, including among those with LDL-C <70 mg/dl at baseline. Interestingly, there was no increase in the incidence of new-onset DM, as observed with statin therapy. This is the first study powered for clinical outcomes to show a benefit with a nonstatin agent when added to a statin.
_____ lowers triglycerides but cannot be combined safely with statins due to a drug-drug interaction and has limited utility in current practice.
Gemfibrozil (Lopid)
Fibrates interact with the nuclear transcription factor _____,which regulates transcription of the LPL, apo C-III, and apoA-I genes.
Side effects of fibrates include cutaneous manifestations, gastrointestinal effects (abdominal discomfort, increased bile lithogenicity), erectile dysfunction, elevated transaminase levels, interaction with oral anti- coagulants, and elevated plasma homocysteine, especially with fenofibrate and,to a lesser extent, with bezafibrate.
Because fibrates increase LPL activity, _____ levels may rise in patients with hypertriglyceridemia treated with this class of medications.
PPAR-a
LDL-C
Another consideration with the use of fibrates is the theoretical prevention of pancreatitis in patients with severe hypertriglyceridemia (>____ mmol/L; ____mg/dL).
> 11 mmol/L; 1000 mg/dL
Niacin increases _____ and lowers _____ levels but has more modest effects on ____ levels.
Niacin requires doses in the range of _____ mg/day in three separate doses to maximize effects on lipid levels
Increases: HDL-C
Lowers: Triglyceride
Modest effect: LDL
2000 to 3000 mg/d
An escalating dose schedule to reach the full dose in 2 to 3 weeks rather than starting with the full dose can help manage the adverse effects of this agent.
Slow-release forms of niacin, including Niaspan (1 to 2 g/day), decrease the side effect profile of the drug.
Daily _____ intake can attenuate skin flushing, as does the prostaglandin D2 receptor (DP1) antagonist _____.
Aspirin
Laropiprant
Side effects of niacin include flushing, hyperuricemia, hyperglycemia, hepatotoxicity, dysglycemia, bleeding, acanthosis nigricans, and gastritis
Clinical trials do not support the ability of niacin therapy to improve cardiovascular outcomes in patients receiving statin
Cholestyramine (Questran) is used in 4-g unit doses as a powder, and colestipol (Colestid) is used in 5-g unit doses.
Effective doses range from 2 to 6-unit doses/day,always taken with meals.
The most important side effects are predominantly _____.
These drugs can cause _____.
Gastrointestinal: constipation, a sensation of fullness, and gastrointestinal discomfort
Hypertriglyceridemia
Because bile acid–binding resins are not absorbed systemically (they remain in the intestine and are eliminated in stool), they are considered safe in _____.
Children and in pregnant women
Decreased absorption of concomitantly administered drugs dictates careful scheduling of other medications 1 hour before or 4 hours after the patient takes bile acid–binding resins.
Bile acid binding resins can be used in combination with statins and/or cholesterol absorption inhibitors in cases of severe hypercholesterolemia
Bile acid–binding resins interrupt the enterohepatic circulation of bile acids by inhibiting their _____ in the intestine (the site of reabsorption of more than 90% of bile acids).
Currently, their main use is adjunctive therapy in patients with severe hypercholesterolemia secondary to increased LDL-C.
Reabsorption
_____ is a bioengineered bile acid–binding resin that has roughly twice the capacity to bind cholesterol as cholestyramine does.
In doses of 1.875 to 3.75 g/day, it can be a useful third-line therapy for patients not meeting their LDL-C targets or in whom the side effects of statins preclude their optimal use.
Colesevelam can also decrease _____ thus making this drug a potentially useful adjunct in the treatment of complicated diabetic patients.
Even though relatively few drug- drug interactions have been reported with colesevelam, prudence still warrants a careful dosage schedule (4 hours), which makes the use of all bile acid–binding resins cumbersome in patients taking multiple medications.
Colesevelam
Decrease: HBA1c
The triglyceride-lowering response to fish oils depends on the dose, with up 10 g/day of EPA or DHA being required for maxi- mal reduction of plasma triglycerides. Fish oils may raise _____ levels and have variable effects on _____.
Increase: LDL-C
Variable effects: HDL-C
The dose-response curve for many favorable nonlipid n-3 fatty acid effects appears to plateau at n-3 doses of _____ g/day, including lowering heart rate, blood pressure, and arrhythmias, while other clinical effects such as triglyceride lowering or antithrombotic effects may require higher doses.
0.5 to 1g/day
For over the counter fish oil supplements, the typical pill content is _____ mg for EPA and ___ mg for DHA, and the analytical content of EPA and DHA was found to be mostly consistent with the labeled amounts.
EPA 180 mg
DHA 120 mg
Of the subsequent placebo-controlled secondary prevention trials, only two trials found significant cardiovascular benefit, namely the _____ of EPA+DHA (1 g/day) in chronic heart failure (NYHA II-IV,most with reduced ejection fraction), and _____ trial which tested another highly purified EPA, icosapent ethyl (4 g/day) in 8,179 statin-treated patients with hypertriglyceridemia and either prior cardiovascular dis- ease (approximately 70%) or diabetes plus other risk factors.72 With the exception of REDUCE-IT which found benefit for both coronary and ischemic stroke events, none of the other trials found reduction inischemic stroke, and benefit, if any, was mostly due to reductions in fatal coronary events.
GISSI-Heart Failure
REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial)
Two early open-label trials found significant reductions in coronary events, specifically the Italian ______ which tested 3.5 years of EPA+DHA (1 g/day) in 11,324 post recent myocardial infarction patients,and the Japanese_____, which tested 4.6 years of a purified EPA (1.8 g/day; containing 900 mg highly purified EPA ethyl ester) in 18,645 patients with hypercholesterolemia (approximately 20% secondary prevention) on top of statin treatment versus statin alone
GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto)
JELIS (the Japan EPA Lipid Intervention Study)
A 2018 metaanalysis from the Omega-3 Treatment Trialists’ Collaboration from 10 n-3 fatty acid randomized trials (EPA dose ranged from 226 to 1800 mg/ day; 9 trials tested combined EPA+DHA) conducted in high-risk populations (n = 77,917 individuals; 12,001 vascular events) and found _____reduction in major cardiovascular or coronary events, with a trend toward ____% relative risk reduction in coronary deaths
No significant reduction: Major cardiovascular or coronary events
7% Trend toward RRR in coronary deaths
_____ are derivatives of cholesterol from plants and trees.They interfere with the formation of micelles in the intestine and prevent intestinal absorption of cholesterol.They are available as “nutraceuticals” and are incorporated in soft margarines.Sterols may prove useful for the adjunctive management of lipoprotein disorders.The safety of plant sterols has not been established.
Phytosterols
A novel compound, _____, inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Bempedoic acid (Nexletol)
A randomized, double-blind, placebo-controlled clinical trial involving 779 patients with ASCVD, HeFH, or both and an LDL-C level greater than 70 mg/dL (1.8 mmol/L) despite maximally tolerated lipid-lowering therapy were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and bio- markers. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (−_____% vs. 2.4%, respectively; difference, −17.4% [95% CI, −21.0% to −13.9%]; P < 0.001). Side effects included a higher incidence of urinary tract infection (5.0% vs.1.9%), and hyperuricemia (4.2% vs.1.9%)
15.1%
___ was the leading risk factor for causes of death in the United States and has important impact on risk of coronary heart disease, stroke, neurocognitive health, hypertensive disorders, diabetes, lipids, obesity, and many cancers.3
Diet
While older guidelines had limits on dietary cholesterol (usually to <300 mg/day),recent guidelines do not recommend specific limits and avoid explicit guidance on dietary cholesterol, instead recommending one of a number of heart-healthy dietary patterns:
Mediterranean-style pattern
DASH diet
Healthy vegetarian diet
Individuals with dyslipoproteinemias, particularly those with diabetes or heart failure, should always adopt a healthful diet. For individuals with hypercholesterolemia, the National Lipid Association (NLA) recommends limiting dietary cholesterol intake to less than _____mg/ day to lower LDL-C and non-HDL-C, recognizing that there may be hypo- and hyper-responder
<200 mg/day
The 2013 AHA/ACC Lifestyle guidelines recommends that saturated fat intake should be less than _____% of energy intake.
<6%
The 2019 AHA/ACC Prevention guideline recommends replacing dietary saturated fat with _____.
Polyunsaturated or monounsaturated fat (but not with carbohydrates)
High-risk subjects should have medications started concomitantly with a diet because in many cases, diet may not suffice to reach target levels.The diet should have three objectives. ____. Dietary counseling should involve a professional dietitian. Frequently, the help of dietitians, weight loss programs, or diabetic outpatient centers can aid in achieving sustained weight loss.
First, it should allow the patient to reach and maintain ideal body weight.
Second, it should provide a well-balanced diet with fruits, vegetables, and whole grains
Tthird, it should be restricted in sodium, saturated fats, and refined carbohydrates.
Combined lipoprotein disorders, characterized by an increase in _____, frequently occur in clinical practice and present difficult challenges.
Plasma TC and TG
Treatment of patients with combined lipoprotein disorders should begin with _____, which is the cornerstone of treatment, as it can improve about half of the deviation in lipid parameters.
Lifestyle modification
Dietary _____ in particular increases triglycerides in a dose-dependent manner and should be avoided (e.g., sucrose).
Fructose
In individuals with hypertriglyceridemia, abstinence from alcohol could reduce triglycerides by up to ___%. Weight loss reduces triglycerides by approximately ___ mmol/L (___ mg/dL) per kg of weight loss, while regular aerobic exercise and n-3 supplements reduce triglycerides by _____% (higher with higher doses of n-3). Often, the help of dietitians, weight loss programs, or diabetic outpatient centers considerably aid management.
Alcohol abstinence: 80%
Weight loss: 0.1 mmol/L or 8 mg/dL
Regular aerobic exercise, n3 supplements: 10-20%
Fibrates can reduce triglycerides by up to __% and may change the composition of LDL to larger and less dense particles.
70%
Patients with uncontrolled cardiometabolic risk factors or known ASCVD are at high risk of suffering from future cardiovascular events despite contemporary preventive therapies; this has been termed _____.
Residual Risk
Even with recent advances in cardiovascular interventions including statins, dual antiplatelet therapies, revascularization, and other therapies,c ardiovascular event rates among patients with known cardiovascular disease remain high, ranging from ____% per year in recent clinical trials and higher in real-world contemporary patient populations.
3 - 3.5%/year
Residual risk is multifactorial. Determinants of increased risk include:
Traditional risk factors (older age, male gender, hypertension, diabetes, smoking, dyslipidemia, greater burden of clinical cardiovascular disease)
Nontraditional cardiovascular risk factors (systemic inflammation, elevated Lp(a), remnant cholesterol, thrombosis).
Autosomal codominant; defects in LDL R
Elevated LDL-C level greater than the 95th percentile for age and sex, approximately 190 mg/dL (5.0 mmol/L) in adults
Tendinous xanthomas over the extensor tendons (metacarpophalangeal joints, patellar, triceps, and Achilles tendons); corneal arcus and xanthelasma
High risk for the development of CAD by the third to fourth decade in men and approximately 8 to 10 years later in women.
Familial Hypercholesterolemia (formerly Type 2A)
Heterozygous - tendinous xanthomas, corneal arcus and xanthelasma
Homozygous - planar xanthoma (areas of trauma, interdigital webs between thumb/index fingerz0
Autosomal dominant hypercholesterolemia clinically indistinguishable from FH
Defective apo B has reduced affinity (20% to 30% of control) for LDL-R.
LDL particles with defective apo B have a plasma half-life threefold to fourfold greater than the halflife of normal LDL.
These LDL particles can more readily undergo oxidative modifications that can enhance their atherogenicity. A
Familial Defective Apolipoprotein B
_______ decrease surface availability of the LDL-R protein and cause accumulation of LDL-C in plasma
Gain-offunction mutations in the PCSK9 gene
________ mutation in PCSK9 confers lower LDL-C
Loss-of-function
Mutations within the APOB gene can lead to truncations of the mature apo B100 peptide.
reduced LDL-C and VLDL-C but few if any clinical manifestations and no known risk for ASCVD
Hypobetalipoproteinemia
Mutation in the gene coding for the microsomal triglyceride transfer protein (MTTP), which is required for assembly of apo B containing lipoproteins in the liver and the intestine.
The resulting lack of apo B–containing lipoproteins in plasma causes a lack of fat-soluble vitamins (A, D, E, and K) that circulate in lipoproteins.
In turn, this deficiency result in mental and developmental retardation in affected children.
Abetalipoproteinemia
Increased intestinal absorption and decreased excretion of plant sterols (sitosterol and campesterol) can mimic severe FH with extensive xanthoma formation
Premature atherosclerosis, often apparent clinically well before adulthood, occurs in patients with sitosterolemia
Documenting an elevation in sitosterol, campesterol, cholestanol, sitostanol, and campestanol is required for the diagnosis
Normal or reduced plasma cholesterol levels, and normal triglyceride concentrations
Sitosterolemia
________ consists of an LDL particle linked covalently with one molecule of apo (a)
High degree of homology with plasminogen
Statins do not decrease Lp(a) levels, in contrast to _________ which reduce Lp(a) levels modestly.
Lipoprotein(a)
PCSK9 inhibitors
The gene for apo (a) appears to have arisen from the plasminogen gene. The apo (a) gene has multiple repeats of one of the kringle motifs (kringle IV), which vary in number from 12 to more than 40
The pathogenesis of Lp(a) may result from an antifibrinolytic potential and/or ability to bind oxidized lipoproteins
Results from both common and rare genetic variants that result in increased VLDL particles
Hepatic overproduction of VLDL causes this condition
Plasma triglycerides, VLDL-C, and VLDL triglycerides rise moderately to markedly
The LDL-C level is usually low, as is HDL-C
Total cholesterol is normal or elevated
Fasting plasma concentrations of triglycerides range between 2.3 to 5.7 mmol/L (200 to 500 mg/dL).
After a meal, plasma triglycerides may exceed 11.3 mmol/L (1000 mg/dL).
Does not associate with clinical signs such as corneal arcus, xanthoma, and xanthelasmas.
Weaker relationship with CAD
Polygenic hypertriglyceridemia (formerly Type IV hyperlipidemia)
Common, with a prevalence of approximately 1 in 50 to 100, and accounts for 10% to 20% of patients with premature CAD
Characterized by the presence of elevated total cholesterol and/or triglyceride levels
The condition has few clinical signs; corneal arcus, xanthomas, and xanthelasmas occur infrequently.
Biochemical abnormalities include elevation of plasma total cholesterol and LDL-C levels and/or elevation of plasma triglycerides —a type IIb lipoprotein phenotype, often associated with low HDL-C and elevated apo B levels; small, dense LDL particles occur frequently.
Combined hyperlipoproteinemia (formerly familial combined hyperlipidemia, 2B)
The combination of apo B greater than 120 mg/dL and elevated triglycerides together with a family history of premature cardiovascular disease identifies patients who may have this condition
Combined hyperlipoproteinemia (formerly familial combined hyperlipidemia
Rare (approximately 1 to 10 in a million) monogenic autosomal recessive disorder of severe hypertriglyceridemia elevates fasting plasma triglycerides (often to greater than 11.3 mmol/L, >1000 mg/ dL) and VLDL cholesterol due to increased levels of chylomicrons, but usually with lower apo B concentrations (<75 mg/dL) than polygenic or multifactorial chylomicronemia
Extreme elevations of plasma triglycerides (>113 mmol/L; >10,000 mg/dL) can result
Recurrent bouts of pancreatitis and eruptive xanthomas; can also associate with lipemia retinalis, xerostomia, xerophthalmia, and behavioral abnormalities.
Monogenic Chylomicronemia Syndrome (Formerly Familial Hyperchylomicronemia Syndrome or Type I Hyperlipidemia)
Primary defects affecting the production of HDL particles may be caused by mutations in the apo AI-CIII-AIV-AV gene complex
Clinical findings can vary from extensive atypical xanthomatosis and corneal infiltration of lipids to no manifestations at all
Apolipoprotein A-I Gene Defects
Rare disorder of HDL deficiency; mutations in the ABCA1 gene, which encodes the ABCA1 transporter.
Have an increased risk for CAD, counterbalanced by their very low levels of LDL-C.
Tangier Disease and Familial High-Density Lipoprotein Deficiency
Disorder of lysosomal cholesterol transport; markedly decreased cholesterol esterification and a defect in the cellular transport of cholesterol to the Golgi apparatus.
Mental retardation and neurologic manifestations occur frequently.
Niemann-Pick type C disease
Deficiencies of the enzyme that catalyzes the formation of cholesteryl esters in plasma, cause corneal infiltration of neutral lipids and hematologic abnormalities as a result of the abnormal constitution of red blood cell membranes
“fish eye disease”
Does not appear to increase risk for CAD.
Lecithin-Cholesterol Acyltransferase Deficiency
Facilitates the transfer of HDL cholesteryl esters into TRLs, a deficiency of this enzyme causes accumulation of cholesteryl esters within HDL particles
Have very elevated levels of HDL-C, which is enriched in cholesteryl esters.
Does not associate with premature CAD but may not afford protection against CAD.
Cholesteryl Ester Transfer Protein Deficiency
Rare genetic lipoprotein disorder that is characterized by accumulation of remnant lipoprotein particles in plasma
Defect results from abnormal apo E, which does not bind to hepatic receptors that recognize apo E as a ligand. The apo E2 allele has markedly decreased binding to the apo B/E receptor
Pathognomonic tuberous xanthomas and palmar striated xanthomas
Patients with this disease have increased cardiovascular risk and are prone to premature coronary disease and peripheral arterial disease.
The lipoprotein profile shows increased cholesterol and triglyceride levels and reduced HDL-C.
Dysbetalipoproteinemia (Formerly Type III Hyperlipoproteinemia)
The use of statins is associated with a small but significant dosedependent increase in _______ of approximately 1 per thousand person-years.
New-onset diabetes
Statins hasten the diagnosis almost exclusively in subjects with preexisting risk factors for the development of diabetes, such as baseline elevation of plasma glucose levels, metabolic syndrome/prediabetes, obesity, or family history of diabetes, and the risk is greater with high doses of potent statins
_______ are contraindicated in pregnant or nursing women.
Statins
