Module 27 Flashcards
What lipids are associated with the risk of cardiovascular risk?
- The major lipid associated with an increase in cardiovascular risk is cholesterol, but there are different forms. Elevated low-density lipoprotein (LDL) is associated with an increased risk of cardiovascular events. In contrast high-density lipoprotein (HDL) is associated with a decreased risk. This is presumably because HDL can take up more cholesterol and remove it from cells
- Elevated triglycerides is also associated with an increase risk in cardiovascular events, but the association is not as strong as with LDL.
There has been a focus on cholesterol as a major risk factor for heart disease, and there is a recent study providing evidence that lowering cholesterol decreases the risk of a second MI (heart attack) even in patients with “normal” cholesterol. What other common risk factors have been more recently proposed for heart disease that can be revealed by a blood test
- Elevated C-reactive protein, an acute phase protein that correlates with inflammation, is a significant indicator of MI risk.
○ Elevated fibrinogen levels are also associated with an increase risk of cardiovascular disease. It is not clear whether this is because this increases the risk of blood clotting or because it is an acute phase protein, and increases in fibrinogen are an indication of inflammation similar to C-reactive protein (association but not causation). However, other markers of clotting such as thrombin levels also appear to correlate with risk. Specific naturiuretic peptides appear to be important biomarkers of risk. In addition, plasma choline levels and other inflammation markers such as CD40 ligand, IL-6, and serum myeloperoxidase also appear to correlate with risk. It is complicated. I don’t expect you to remember the details, but certainly know that inflammation and clotting propensity appear to be important in the risk of cardiovascular events.
Niacin is used for the treatment of hypercholesterolemia, and since it is a vitamin (vitamin B3), many “herbalists” ask about its use and dosage. What should be considered in the use of this agent with regard to cost, dose, effectiveness, and side effects? What is the rationale for the concomitant use of aspirin?
- The major effect of niacin is on triglycerides, and it can lead to a 20-50% decrease in triglycerides. It can also lower LDL by 5-25% and increase HDL by 15-35%. It is cheap and relatively safe. A few years ago I would have said it was a reasonable alternative to statins for decreasing the risk of cardiovascular-associated mortality in patients who do not tolerate statins.
- However, recent studies did not find that niacin treatment significantly decreased cardiovascular-related mortality, despite its effects on lipids. High doses of niacin cause flushing, which is mediated mostly by prostaglandins; therefore, aspirin decreases this side-effect.
What is the mechanism of action of the statins and what lipids do they modify? How effective are statins at decreasing the risk of cardiovascular effects? What is the optimal timing of their administration and why? What interaction appears to occur with vitamins?
- The statins mimic mevalonic acid and competitively inhibit HMG CO-A reductase, an important step in the synthesis of cholesterol. However, that leads to the increase in the production of HMG CO-A, which essentially negates this inhibition. The major mechanism of action is that inhibition of this pathway leads to an increase in low density lipoprotein (LDL) receptors and an increase in the uptake of LDL by hepatocytes and a decrease in serum LDL.
- Statins also decrease triglycerides and increase HDL. Although statins are the most effective agents to date to decrease cardiovascular events, their effectiveness is somewhat modest; about 15-50%. Most cholesterol synthesis occurs at night, and so for statins with a short half-life, and evening dose is most effective. However, for statins with a longer half-life this is not very important.
For some reason, co-administration of multiple vitamins including the antioxidants vitamin C and vitamin E was found to significantly blunt the effect of statins on LDL, but I have not seen that study repeated so I am not sure that it is real. It does highlight the possible negative effects of taking megavitamins.
- Statins also decrease triglycerides and increase HDL. Although statins are the most effective agents to date to decrease cardiovascular events, their effectiveness is somewhat modest; about 15-50%. Most cholesterol synthesis occurs at night, and so for statins with a short half-life, and evening dose is most effective. However, for statins with a longer half-life this is not very important.
What other effect of HMG CO-A reductase inhibitors may contribute to their apparent ability to decrease the risk of MIs?
- HMG CO-A reductase inhibitors inhibit the synthesis of IL-2, much like cyclosporin. Their antiinflammatory effects may be as important as their effects on cholesterol in decreasing the risk of cardiovascular events.
Studies have shown that statins also decrease the risk of cardiovascular events in patients with normal LDLs but increased C-reactive protein, a measure of inflammation.
As a class, HMG CO-A reductase inhibitors can cause significant myopathy. Rhabdomyolysis is rare, but muscle pain and weakness leading to discontinuation of the drug are very common. The mechanism of this muscle damage is not known; many hypotheses have been proposed, but none demonstrated. What are the risk factors that you should know about in helping a patient decrease the risk of muscle injury?
- The major factor that determines risk appears to be the concentration of the drug in muscle. Factors that affect statin concentrations are metabolism and transporters.
- Metabolism is the easiest to deal with. For most statins, including atorvastatin, one of the most commonly prescribed statins, the major enzyme involved in clearance is CYP3A4. Therefore variability, either genetic variability or due to drug interactions, can be important. However, with some statins, variation in CYP3A4 activity is not important.
○ For example, rosuvastatin, another widely used statin, is metabolized mostly by CYP2C9, but most of the drug is not metabolized at all, but rather excreted unchanged in feces.
○ Some statins are also metabolized by CYP2D6 and are glucuronidated. - Transporters are also very important. The major transporter involved is OATP1B1 (which is encoded by SLCO1B1). Statins are also substrates for efflux transporters ABCB1 and ABCG2. The only gene polymorphism that has been clearly shown to be a risk factor for muscle damage is one resulting in low activity of OATP1B1, but its effect is different for different statins; it is most important for simvastatin.
- Coadministration of other lipid lowering drugs such as fibrates, niacin, and ezetimibe also appears to increase the risk of myopathy. If a patient has significant muscle symptoms it is often possible to successfully treat them by changing the statin and adjusting the dose. I don’t expect you to memorize the transporters involved, but you should know that they are important
- Metabolism is the easiest to deal with. For most statins, including atorvastatin, one of the most commonly prescribed statins, the major enzyme involved in clearance is CYP3A4. Therefore variability, either genetic variability or due to drug interactions, can be important. However, with some statins, variation in CYP3A4 activity is not important.
Statins appear to increase the risk of what chronic disease?
T2DM
Why might it be advisable to start low when beginning rosuvastatin in patients of Asian descent?
on average, the blood levels of rosuvastatin are likely to be higher in patients of Asian decent.
What blood test was recommended for patients taking statins, and what warning is recommended for patients taking statins? What is the evidence in support of this blood test and warning? (That recommendation has been rescinded.)
- In the early clinical trials, the statins were associated with an increase in serum ALT (alanine transaminase), a measure of liver injury hepatocytes undergo necrosis. (Don’t call ALT a liver function test; it does not measure liver function, it is a measure of liver injury. Bilirubin levels and INR are liver function tests because functions of the liver include elimination of bilirubin and the production of clotting factors.)
- Specifically, about 1% of treated patients had a significant increase in ALT. Drugs that cause serious liver injury and liver failure always cause a much higher incidence of mild liver injury. Therefore, it was anticipated that the statins would cause serious liver injury.
- Based on this it was recommended that patients started on statins should have a baseline ALT measurement and then monthly ALT tests so that the drug could be stopped before serious liver injury occurred.
- However, not all drugs that cause mild liver injury cause severe liver injury, e.g. heparin is associated with a very high incidence of ALT increases but never causes severe liver injury. In the case of statins, although there have been very rare cases of severe liver injury, the risk is so low as to be insignificant.
- Therefore, ALT measurements are irrational. If you stopped the statin because of an increase in ALT there would be a much greater risk of cardiovascular mortality than the risk of liver-related mortality if the patient continued to take the statin.
What are omega-3 fatty acids, and what is the designation for arachidonic acid; for a-linolenic acid?
- Fatty acids are named by how far the “first” double bound is from the opposite end of the molecule from the carboxylic acid. Omega is the last letter in the Greek alphabet, and an omega 3 fatty acid such as alpha-linolenic acid has the first double bond 3 carbon-carbon atoms from the end; therefore, it is an omega-3 fatty acid. Arachidonic acid has the carbon-carbon bond 6 carbons from the end so it is an omega-6 fatty acid.
How are fats classified and what are the merits/disadvantages of different types of fats?
- Fats are classified as saturated, monounsaturated, and polyunsaturated. In addition there are trans fats.
- In general the double bonds in natural fats are in the cis configuration. However, when fats are hydrogenated to decrease smoking at high temperatures and to decrease air oxidation that produces rancid fats, the catalyst that is used to add hydrogen across the double bond will also convert much of the cis double bonds to the more stable trans double bonds.
- Saturated fats, and even more so, trans fats, are associated with an increase in cardiovascular disease. A small amount of trans fat is also present in milk products and it is controversial whether this is harmful.
- Monounsaturated fats such as the oleic acid present in olive oil are associated with a decrease in cardiovascular disease, and this appears to be an important component of the Mediterranean diet.
- Polyunsaturated fats are also associated with a decrease in cardiovascular disease; however, they are prone to free radical oxidation to produce toxic products. Most fats, especially in grain fed animals contain mostly omega-6 fatty acids, and there is evidence that a diet with a greater proportion of omega-3 fatty acids is beneficial
Is eating salmon good for you?
There was a study that examined the amount of various toxins such as PCBs and mercury in salmon, especially farmed salmon. In fact, among fish, salmon has one of the lowest concentrations of mercury. there is no evidence that the levels of toxins that were detected present a significant risk, and there is good evidence that eating fish, especially fatty fish such as salmon is beneficial. Therefore, overall, I think the evidence favors eating salmon.
Are eggs bad for you?
- Obviously there is a correlation between serum cholesterol levels and the risk of cardiovascular disease, although it also depends on whether the cholesterol is part of LDL or HDL. Therefore, it was believed that eating eggs, which contain significant concentrations of cholesterol, was bad.
- However, most of the cholesterol in the body is synthesized in the liver (about 90%, although it depends on the diet), and there is feedback inhibition of cholesterol synthesis if there is more cholesterol in the diet.
- Within limits, eating eggs does not change cholesterol levels in the blood. There is one possible caveat: there is one Canadian study that found that frequent egg consumption was associated with more intimal thickness of the carotid arteries. The hypothesis is that even though the fasting level of cholesterol was not changed by eating eggs, there were peak levels of cholesterol after eating the eggs that contributed to atherosclerosis.
- This study was not prospective, and involved a small number of patients, so I was skeptical. However, a more recent study involving 29,615 patients also found a significant association between cholesterol intake and cardiovascular disease. Even though association does not prove causation, I may have to rethink this.
What is ezetimibe, what is the mechanism of action, and how well does it work?
- Ezetimibe decreases absorption of cholesterol from the intestine by inhibiting Niemann-Pick C1-like 1 (NPC1L1) protein that controls cholesterol absorption.
- You might argue that since dietary cholesterol does not affect cholesterol levels in the blood, this drug would not lower cholesterol. However, most of the cholesterol in the intestine is not from the diet, but from enterohepatic circulation of cholesterol and bile salts in bile. In fact ezetimibe does lower serum cholesterol; however, its efficacy is decreasing cardiovascular disease is marginal at best, especially compared to statins. However, there is evidence that its combination with statins may be beneficial.
