Term
| Three Critical Questions for lipids |
|
Definition
• What is the evidence for LDL and non-
HDL goals for secondary prevention of ASCVD?
• What is the evidence for LDL and non-
HDL goals for primary prevention of ASCVD?
• For primary and secondary prevention
of ASCVD, what is the impact on lipid levels, effectiveness, and safety of specific cholesterol-modifying drugs? |
|
|
Term
|
Definition
But in the first part here, we're going to look at what all the tests are and look at how we form some of these lipid deposits. So let's take a closer look here at the pathogenesis of atherosclerosis. As you can see, we ended up with this-- the final thing that we want to do here is we end up building up this fatty streak, and that's the plaque that's inside the artery.
After you get this vascular injury that occurs somewhere along the lines, these monocytes get activated. They bind to the epithelial cells right here. They bind to the epithelial cells, and then they cross over. Once they get into the tissues, they become activated macrophages. They're no longer a monocyte, but they're an activated tissue macrophage.
These macrophages, then-- as you can see right here. Here's the macrophage. These macrophages take up what we call low-density lipoproteins, or LDLs, and these become foam cells. Now, you can see, they're picking up-- here's the LDL particles. They pick those up, and then they become foam cells. That's one part that lays down the atherosclerotic plaque.
T-cells, then, also release-- here's a T-cell-- these cytokines. And these cytokines, which also activate the macrophages, they also cause smooth muscles to proliferate. And so down here at the bottom, all these smooth muscle cells, these are proliferating and dividing. Under the influence of a variety of growth factors, over here, these smooth muscle cells move into the subendothelial space. They should be below this space, but they actually migrate up.
They produce collagen, and they also take up LDL, or this low-density lipoprotein, and also move into the foam cells. So the bottom line here is these foam cells and these activated smooth muscle cells actually form this fatty plaque. |
|
|
Term
|
Definition
- Carbon- and hydrogen-containing compounds, mostly hydrophobic
- Biologically important groups:
• Neutral fats • Fatty acids in form of triglycerides
• Conjugated lipids • Phosphate or sugar group added to lipid molecule • Integral part of cell wall structure
• Sterols • Building blocks in cells and membranes • Constituents of hormones • Cholesterol = sterol of major biologic significance |
|
|
Term
|
Definition
| special transport in blood due to insolubility in water |
|
|
Term
| Major lipid components found in plasma |
|
Definition
• Triglycerides
• Cholesterol
• Phospholipids |
|
|
Term
|
Definition
Transported in blood as lipoproteins
• Lipoprotein = lipid complex + specialized proteins
(apolipoproteins)
• Apolipoproteins help with packaging, solubility, and
metabolism • apoA1 – HDL • apoB – LDL |
|
|
Term
| Lipids in circulation consist of |
|
Definition
different- sized particles that contain different amounts of cholesterol, triglycerides, phospholipids, and protein
• Lipoprotein types based on size
• Two lipid metabolism pathways
• Exogenous
• Endogenous |
|
|
Term
|
Definition
• Chylomicrons—mostly triglycerides (nonfasting)
• VLDL—Very-low-density lipoprotein
- Slightly less triglyceride (TGL), but still high TGL - Slightly more cholesterol (Chol), but still low Chol - Triglyceride here in fasting plasma
• IDL—Intermediate-density lipoprotein • LDL—Low-density lipoprotein
- Little TGL, most of plasma Chol is here
• HDL—High-density lipoprotein
- Very little TGL, more protein, smaller fraction of Chol (15–25%) |
|
|
Term
| Lipid Metabolism—Exogenous |
|
Definition
Dietary pathway
• Absorption of TGL and cholesterol through the
intestine
• Chylomicrons released into the blood
• Chylomicrons release TGL to adipose tissue
• Lipoprotein lipase (LPL) activated
- Cleaves free fatty acids from triglycerides • Reduces chylomicron size • Remnants taken up by liver
- Free fatty acids taken up by muscle and adipose cells |
|
|
Term
| Lipid Metabolism—Endogenous |
|
Definition
• Synthesis of TGL from fatty acids by liver
• Secretion of VLDL particles that contain apolipoprotein B and E
• VLDL particles modified by LPL and converted to IDL
• Removed by liver through apoE or converted to LDL
• LDL taken up by liver (70%) or other tissues (30%) |
|
|
Term
|
Definition
Now, this kind of just is a picture form. We can take a little bit closer look here at what's going on. So, once again, exogenous, we have our dietary fact absorbed in our intestine. The chylomicrons, then, some of them, the free fatty acids, are converted in the adipose tissue and muscle. Some of these remnants go back towards the liver, where they can be recycled through. The low-density lipoproteins come to the liver.
And the bottom line is, once again, as it goes through this cycle with these low- and intermediate-density lipoproteins, free fatty acids are broken off. And once again, those are stored in the adipose tissue and muscle. So we really have two sources to elevated lipids in our body-- our dietary source and our endogenous or internal source within our body. This is why when we want to treat patients with lipid disorders, we tell them to watch their diet for the exogenous source, and we give them medications to help with the endogenous source of increase lipids. |
|
|
Term
|
Definition
These particles modulate synthesis, transport, and deposition of cholesterol
• Can mobilize cholesterol from tissues for metabolism or excretion
• Nascent HDL particles containing apoA1 synthesized and released by liver
• Pick up cholesterol from tissues, become HDL3
• LCAT (lecithin cholesterol acyl transferase) converts particles to HDL2
• Transferred to VLDL
• Taken up by liver and excreted in bile |
|
|
Term
| Characteristics of Hyperlipidemic Serum/Plasma |
|
Definition
- Freshly separated hyperlipemic serum • Uniformly milky or opalescent
- Chilled serum
• Uniform turbidity = ↑ VLDL
• Excessive chylomicrons float to top (layer of cream)
- Patterns
Uniform turbidity ↑ VLDL without chylomicrons,
“Cream” and turbid sample ↑ VLDL, ↑ chylomicrons,
“Cream” and clear sample ↑ chylomicrons, no excess VLDL |
|
|
Term
|
Definition
| Now, we have these lipoprotein phenotypes. There's phenotype one, two, three, and four, and five. And this is just a breakdown of what proteins are elevated, what liquids are elevated, what the plasma total cholesterol will be, what the plasma triglyceride level will be, and how common it is. And this is just FYI. We use electrophoresis, lipoprotein electrophoresis, to determine the presence of chylomicrons, the LDLs, the VLDLs, and the HDLs. These then correlate-- those results from that electrophoresis correlate to the different phenotypes. |
|
|
Term
| Lipid Profile Interpretation |
|
Definition
- Most relevant measurements of serum lipids: • Total cholesterol
• Triglycerides
• Cholesterol fractionation • HDL fraction measured • LDL fraction calculated (valid for trig levels up to 400) • LDL = (Total Cholesterol) – (HDL) – (Triglycerides/5)
- Apolipoprotein measurements:
• Apo A1—predominantly on HDL
• ApoB—predominantly on LDL
• Two measurements can help estimate the distribution of lipoproteins in plasma |
|
|
Term
|
Definition
assess risk of having coronary artery disease.
- Complete lipid profile (fasting)
• Total cholesterol
• LDL
• HDL
• Triglycerides
- Secondary option (nonfasting):
• Total cholesterol
• HDL
• Do lipid profile if TC >200 mg/dl or HDL <40 mg/dl |
|
|
Term
|
Definition
ATP III: • RISK FACTOR COUNTING
• TREAT TO LDL GOAL
• ADDRESS NON-HDL TARGET
ATP IV: • THERE IS NO TARGET • THE INTENSITY
OF STATIN THERAPY IS THE FOCUS OF TREATMENT |
|
|
Term
| what do the guidelines say for statins? |
|
Definition
| • Identify four major statin benefit groups for whom ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence |
|
|
Term
| The Four Statin Benefit Groups |
|
Definition
• Secondary prevention in those with clinical ASCVD
• Primary prevention in those with LDL ≥190
• Primary prevention in those with DM, age 40–
75, with LDL 70–189
• Primary prevention in those without DM, age 40–75, with LDL 70–189, and a 10-year ASCVD risk ≥7.5% (using a new risk calculator) |
|
|
Term
A 63-yo WM smoker with HTN comes to see you for a posthospital f/u visit 1 week after suffering a STEMI. He was discharged on atorvastatin 80 mg, antiplatelet, BB, and ACEI. He recalls that his last PCP had prescribed simvastatin 80 mg years ago, and he stopped it secondary to leg cramps. He recalls he was on amlodipine for his HTN at that time as well. He is worried he will have leg cramps and wants to stop the atorvastatin or at least decrease the dosage.
What do you tell him? |
|
Definition
Now, the question was, what do you tell him about what to do next? And we gave you four options. Do you let him decrease the statin to 20, since that seems to be what he tolerates? Do you tell him to go consult with his chiropractor and get his advice on lipid management? Do you check his CK, lipid profile, and liver enzymes now and at every other visit and then decide? Or do you, D, explain to him the proven benefit of aggressive secondary prevention with high-dose statin therapy?
And the correct answer here is D. It's very important-- studies have shown time and time again that aggressive therapy with high-dose statins provides secondary prevention in people who already have atherosclerotic coronary disease. |
|
|
Term
| CQ 1: Is there evidence to treat to specific LDL or non-HDL targets in secondary prevention? |
|
Definition
• There was NO DATA identified to treat to a specific LDL goal in those with clinical ASCVD
• 19 RCTs used FIXED DOSE statin therapy
• In patients with clinical ASCVD, even if moderate or low- intensity statin therapy results in an LDL <100, the evidence suggests that higher intensity statin therapy provides a greater risk reduction in ASCVD events
• There was NO DATA to support treating to specific non- HDL targets either |
|
|
Term
|
Definition
This is the heart-healthy lifestyle habits and prevention of atherosclerotic cardiovascular disease. And these are the lifestyle management guidelines. And it's a protocol you'll use when you're treating-- taking care of patients.
So you can see, as long as they're over 21 and they're a qualified candidate for statins-- they're not allergic to anything-- if they have a known history of atherosclerotic vascular disease, you check their LDLs and HDLs. If they have had disease before, OK, you automatically put them on high-dose statins if they're under 75. If they're over 75, you put them on moderate-intensity statins. So no matter what the results are, if they've had a known-- or they have known clinical atherosclerotic cardiovascular disease, you start them on either high-intensity, if they're under 75, or moderate-intensity statins if they're over 75. We don't care what the LDLs and HDLs are. We just start them.
If we check them, they don't have known disease, we check their LDL cholesterol. If it's greater than 190, then we'll put them on high-intensity statins. So now we're talking about the people who don't have any known atherosclerotic disease. So our case and our gentleman fit in this category, right here. And since he was under 75, he really should be on high-dose statins.
Now, when you keep going down the chart here, the high-dose statins for the people with elevated LDL cholesterols. If they don't but they're diabetic, between the ages of 40 and 75, you add a moderate dose intensity statin. If they have an elevated risk for atherosclerotic disease-- and we'll talk about the risk calculator in a little bit-- you'd put them on high-intensity statins. |
|
|
Term
|
Definition
For primary prevention now, also, looking at no diabetics, LDL cholesterol is between 70 and 89, and those not receiving statins, you really have to look at their estimated risk for atherosclerotic heart disease. And you re-evaluate this every four to six years. And once again, as I said, we'll go through the evaluation tool.
If it's less than 5% risk, really, then you discuss it with the patients and determine-- you talk about healthy heart lifestyle. You talk about management of other risk factors. And you consider family history and talking to the patient about whether you want to start on a medication.
If they're less than 40 but greater than 75, and their LDLc is less than 190, once again, you can educate these people and select which ones you want to treat. If their 10-year risk is greater than 7.5%, you still educate. But now, you also want to determine if you're going to put them on a statin or not. And if you do put them on a statin, you put them on the appropriate intensity. And we'll talk about that in a little bit. And If their risk factor is between 5% and 7.5%-- 10-year risk-- once again, it's always about education and discussion. But then you decide, based on lifestyle and other factors, whether you're going to put them on a statin or not. |
|
|
Term
| MODERATE INTENSITY STATIN THERAPY |
|
Definition
MODERATE intensity lowers LDL by 30–49%
• Atorvastatin 10 or 20 mg • Rosuvastatin 5 or 10 mg
• Simvastatin 20 or 40 mg • Pravastatin 40 or 80 mg • Lovastatin 40 mg
• Fluvastatin 40 mg BID |
|
|
Term
| HIGH-INTENSITY STATIN THERAPY |
|
Definition
HIGH-intensity lowers LDL by ≥50%
• Atorvastatin 40* or 80 mg • Rosuvastatin 20 or 40 mg
*IDEAL down- titrated to 40 mg when 80 was not tolerated |
|
|
Term
| Even Though We Don’t Treat to Target... |
|
Definition
| Most RCTs showed that HIGH-intensity statin therapy brings most individuals to an LDL < 100 |
|
|
Term
| In patients >75 years old |
|
Definition
MODERATE intensity statin therapy showed a better RR in secondary prevention
• The evidence supports continuation of statins in persons >75 already on them and tolerating them well
• Routine CK and ALT monitoring not necessary |
|
|
Term
|
Definition
• Use it to calculate a 10-year risk of first ASCVD event in those without ASCVD, ages 40–75, with an LDL 70–189. Can be used in those WITH DM or those WITHOUT DM
• If the 10-year risk is >7.5%, the benefit of statin therapy clearly outweighs the risk
• Those with a 10-year risk of 5–7.5% showed a similar RR; however, the potential for AE > RR
• Based on pooled cohort equations for RCTs
- ARIC, CHS, CARDIA, Framingham & Offspring
Cohorts
• Variables that met inclusion criteria:
- Age, TC, HDL, systolic BP, DM smoking status
• Applicable to non-Hispanic whites and AA
• Admittedly OVERestimates for Hispanic and AsianAmerican populations
• Admittedly UNDERestimates for American Indian populations
• Recommendation for use of the risk calculator in AA and whites:
- NHLBI: Grade = B recommendation (moderate)
- ACC/AHA COR: Class = I (benefit > risk)
- Levelofevidence=B(limitedpopulations)
• Recommendation for use of the risk calculator in other populations:
- NHLBI: Grade = E recommendation
- ACC/AHA COR: Class = IIb (benefit ≥ risk)
- Level of evidence = C (expert opinion) |
|
|
Term
| The ASCVD Risk Discussion |
|
Definition
• Shared decision-making
• A time to revisit LSM and address other RF
• Discuss potential for ASCVD risk reduction
• Discuss adverse effects
- New onset DM (dose dependent) • 1 per 1000 in moderate intensity (prevention of 5.4 ASCVD events) • 3 per 1000 in high intensity (5.9 ASCVD events)
- Myopathy and hemorrhagic CVA
• Discuss drug-drug interactions
• Discuss patient preferences |
|
|
Term
| ATP IV Strengths to Consider |
|
Definition
• Encourages a “risk discussion” with patients in regards to primary prevention
• Strictly evidence based
• The bulk of the content is undisputed
• 10-year risk of ASCVD includes CHD and stroke
• More relevant for women and AA populations |
|
|
Term
| ATP IV Weaknesses to Consider |
|
Definition
• Strictly evidence based
- Limited or NO DATA for >75 and <40
• The risk calculator is controversial* and may significantly overestimate risk
• Forgotten populations: diabetics < 40 y/o and other high-risk groups
• Younger patients often have a high lifetime risk and a low short-term (10-year) risk |
|
|
