Know basic principles of lipid metabolism and how this can lead to biochemical derangement and disease
Understand the relationship between cholesterol level and cardiovascular disease risk
Pretty much the main takeaway from this lecture is that levels of LDL cholesterol is positively associated with increased cardiovascular disease risk. Therefore, it is important to try and manage cholesterol levels so that levels of "good" cholesterol (HDL) prevail over levels of all the "bad" cholesterol (pretty much all of the other types of cholesterol).
Understand the options of drug and non-drug treatments for hyperlipidaemia
Drug treatments
There are various drugs that can lower lipid levels. I will discuss this a bit further down in this post.
Non-drug treatments
There are several non-drug lifestyle treatments that can help with hyperlipidaemia. In short: cessation of smoking, exercise, and a healthy diet are all factors that can help in treating hyperlipidaemia. The Mediterranean diet (see here) is generally considered to be one of the best for overall cardiovascular health. For patients who specifically need to lower cholesterol, a low saturated fat diet may be helpful, and for patients who specifically need to lower triglycerides, simply losing weight may be helpful. (However, please note that I am not a dietician, so do take my words with a pinch of salt ;) )
Know the main classes of lipid lowering drugs
Statins
Statins are the first-line therapy for lowering LDL and reducing the risk of cardiovascular disease. They decrease the synthesis of cholesterol by inhibiting the enzyme HMG-CoA reductase. They can also increase SREBPs (transcription factors that regulate LDL receptors), increasing LDL receptor production, which in turn increases removal of cholesterol from the blood. Common side effects of statins include an increase in diabetes risk and some hepatic side effects (0.5-3% of patients have an increase in an enzyme called transaminase, which to my understanding is a marker of liver damage). Myositis is another side-effect of statins. There has also been concern about memory loss associated with statin use, but only 60 cases of this have been reported since 1997.
Another important thing to know about statins is that while a small dose of statins can reduce LDL levels by a decent amount, increasing the dose has a much smaller effect. Therefore, in some cases, it might be better to add a second drug (e.g. ezetimibe, which I'll talk about next) rather than increase the dose of the statin.
Ezetimibe
Ezetimibe is the second-line therapy for lowering LDL and reducing cardiovascular disease risk. Ezetimibe inhibits NPC1L1 receptors on enterocytes, preventing uptake of cholesterol. It is generally well-tolerated but may have some side-effects such as diarrhoea and fatigue. It is sometimes used as a good alternative to statins in patients with myositis, or used in addition to statins to reach the target LDL level.
PCSK9 inhibitors
PCSK9 inhibitors are relatively new. PCSK9 can bind to LDL particles that have bound to LDL receptors, triggering breakdown of the receptor as well as the LDL. What this means is that the LDL receptor is not recycled and taken to the surface, meaning that the cell cannot remove as much LDL from the circulation. Patients with gain-of-function mutations in the PCSK9 gene may be at a greater risk of familial hypercholesterolaemia (high levels of cholesterol in the blood). Currently-approved PCSK9 inhibitors include alirocumab and evolocumab, which are antibodies against PCSK9. Since they are antibodies, they need to be given by injection every few weeks. Side effects from PCSK9 inhibitors appear to be relatively mild, such as nasopharyngitis and reactions at the injection site.
Mipomersen
Mipomersen is an antisense oligonucleotide against the mRNA of apoB. Therefore, it can stop production of apoB. However, it seems to have a high rate of injection site reactions (~90%) and may increase hepatic fat and transaminase levels.
Lomitapide
Lomitapide is an inhibitor of microsomal transfer protein (MTP) (an enzyme that packages cholesteryl ester and triglycerides together to form chylomicrons). Hence, lomitapide prevents the formation of lipoproteins that contain apoB. Unfortunately, it seems to have a high rate of GI side effects (~93%).
Fibrates
Fibrates activate PPARα, increase beta-oxidation of fatty acids, and down-regulates ApoCIII. As ApoCIII inhibits lipoprotein lipase (contrast with ApoCII which activates lipoprotein lipase), downregulation of ApoCIII allows lipoprotein lipase to become more active and break down lipoproteins.
n3 Polyunsaturated Fatty Acids
n3 polyunsaturated fatty acids (a.k.a. omega-3 fatty acids), such as those found in fish, may help to reduce cardiovascular disease. The actual mechanism is quite complex, but it may help reduce synthesis of lipoproteins. In particular, they seem to reduce levels of basically all non-HDL cholesterols, with the exception of LDL, which they increase.
Niacin
Niacin downregulates hepatic DGAT, reducing the synthesis of triglycerides. However, it has not been seen to improve outcomes in people with cardiovascular disease, and has very limited indications now.
GLP1
DPP-4 inhibitors
While these drugs can be used to manage glucose levels, they are also being trialled to see if they will help with cardiovascular disease as they appear to also affect lipid levels.
Thiazolidinediones
Thiazolidinediones are PPARγ agonists that act on adipose tissue, muscle, and liver. They can stimulate uptake of lipids and reduce fatty acid supply to the liver and muscles. They can also increase glucose uptake and decrease glucose production, so they are often used to treat diabetes. (Cardiovascular disease outcomes, however, are still uncertain.)
No comments:
Post a Comment