Now, I'm going to briefly discuss the 2018 guidelines and also individual evidence for non-statin therapy for high-risk patients. So if patients with established atherosclerotic cardiovascular disease, but not at high risk, if patients are less than 75 years old, start high-intensity starting to lower LDL cholesterol by 50% is a class-one recommendation. However, if they cannot tolerate the high-intensity statin, using the moderate-intensity statin is also a class-one indication in this age group. But if patients are more than 75 years old, if they are already taking high-intensity or moderate-intensity statin, continuation of high-intensity statin or moderate-intensity statin is reasonable. But patients with SCVD and at very high risk, regardless of their age, they should be on high-intensity statin or maximally tolerated statin, and these are class-one indications. So how do we follow up and monitor statin therapy? So when we start the statin therapy, we always get the baseline, and then for every dose adjustment, we should check the lipid panel and also the liver function test 4 to 12 weeks after to assess the safety, and also every 3 to 12 months thereafter, if we need to assess their adherence and also safety. In patients with chronic liver disease, if they are stable, including the non-alcoholic fatty liver disease, using the statin is reasonable after assessing the baseline measurements and also continued follow-up as indicated before. So in patients with severe statin-related muscle symptoms, muscle pains, even after adjustment of the statin therapy, it is reasonable to use non-statin therapy to reduce their LDL up to the goal and to get the net clinical benefit. So there are multiple non-statin therapies that we'll be discussing in the next few slides if they are statin intolerant. However, if they have side effects from the statin use, coenzyme Q is not recommended, it's a class 3. At the same token, routine measurement of the creatine kinase or liver function test is not useful. Next. Women who are at childbearing age or who have a history of premature menopause or pregnancy-associated hypertension, gestational diabetes, or if they have preterm deliveries or preeclampsia, those are the patients are high risk for subsequent atherosclerotic cardiovascular disease and events. So when you discuss about the lifestyle intervention with those patients and family, we should always talk about the benefit of the statin and likely start the statin as indicated by guidelines. For statin, it's contraindicated during pregnancy. So if someone got pregnant and if we know that they're on statin, we should stop the statin as soon as we know. Also if someone wants to get pregnant, we should stop the statin one to two months before the pregnancy starts. Next slide. So ezetimibe has been approved for many years for lowering cholesterol, especially the LDL cholesterol. In 2015, they improved a trial that included 18,000 patients with ACS. They compared ezetimibe plus statin versus ezetimibe, and they looked for seven-year cardiovascular events, and it showed that significant reduction of cardiovascular events. Ezetimibe decreased LDL by an additional 18% either as monotherapy or if we start on top of statin. So the patients who cannot take the statin, ezetimibe is a reasonable good option. Next. Bempudoic acid has been approved since early 2020. It's easy to use the drug as oral medication, 180 milligrams once a day, and it should be used as an add-on therapy if their LDL is not on goal, if they're intolerant or if they're already on maximally tolerated doses, either alone with statin with or without ezetimibe too. And it decreased the LDL almost identical that ezetimibe decreased if we use on top of statin. Interestingly, if we have patients not on statin and if they are on ezetimibe, if they are statin intolerant, if we use the Bempudoic acid with the ezetimibe, there's an additional 67% decrease of LDL cholesterol. So Bempudoic acid has been studied in a large randomized trial, a clear trial that was published this year, and this study showed that there is significant reduction of composite of cardiovascular death, nonfatal MI, nonfatal stroke, and coronary vasculation. So a statin intolerant patient, Bempudoic acid is a reasonable option. There are some common side effects associated with Bempudoic acid, such as hyperuricemia, gout, cholerithiasis, and tendon rupture. Next. PCSK9 inhibitor, there are two currently injectable forms of PCSK9 inhibitors. One is small interfering RNA that Dr. Mukherjee will discuss, but there are monoclonal antibodies. So ivolecumab and elirocumab, those are monoclonal antibodies, and PCSK9 inhibitors have been studied in randomized clinical trials with statin and or ezetimibe therapy. Next. These are the two landmark trials. So in a four-year trial, more than 27,000 patients tested ivolecumab, including patients whose LDL was more than 70 or non-HDL cholesterol more than 100. Those patients who are already on statin without ezetimibe follow for 2.2 years, and it showed there is a significant reduction in composite of cardiovascular death, MI, stroke, hospitalization for anisotropal angina, or coronary vascularization. On the other hand, elirocumab has been tested in ODYSSEY trial, almost 19,000 patients. They included patients with acute coronary syndrome within four weeks, and they are also on maximally tolerated statin with or without ezetimibe, and they followed as a mean almost three years, and it showed exactly similar reduction of composite cardiovascular events and mass. And you can see both the trials, the relative, sorry, absolute risk reduction is approximately 1.5%. Next. So, the addition of PCSK9 inhibitor to a statin therapy further reduced the LDL cholesterol anyhow between 43% to 64%. The FOURIER trial showed that the additional reduction of LDL was 59%, and ODYSSEY trial showed that additional LDL reduction was 61%. So basically, mean reduction of extra LDL is around 60% if you use the PCSK9 inhibitor. So it's a very strong PCSK, very strong LDL reductor. And PCSK9 inhibitors, as I mentioned, is associated with significant reduction of cardiovascular events, especially in very high-risk patients. Next. Patients with PAD, we know, as Dr. Lothik mentioned, is a very high-risk patient and are associated with very high cardiovascular events. So, overall reduction of LDL get at the benefit we get even in PAD patients. Unfortunately, in PAD patients, three quarters of the patients failed to achieve their guideline-directed LDL goal below 70, not even 55, below 70. And half of them had LDL goal more than 100. The pre-specified subgroup analysis in ODYSSEY trial and FOURIER trial had shown significant reduction of MERS events. Next. So the FOURIER trial in a pre-specified analysis showed that Ivolucuma reduced composite of cardiovascular death, MI, stroke, and other outcomes by 21% in PAD patients, even if they don't have PAD symptoms. And they also reduced major adverse limb effect by 42% in all patients and 37% in PAD patients. So basically, PCOSK9 inhibitors is very useful in high-risk patients, including the PAD patients. Next. And the ODYSSEY outcome trial also showed that Ivolucuma reduced the risk of both PAD events and PAD plus venous thrombomelic events by 31%. And they also reduced the baseline lipoprotein cholesterol. And lipoprotein cholesterol was the indicator, not the LDL reduction in some of these PAD patients with Ivolucuma. Now Dr. Mukherjee will carry on, and he will discuss some of the other aspects of our cholesterol management.

2018 guidelines

non-statin therapy

LDL cholesterol

statin therapy

cardiovascular events