Title : Lipid management for ASCVD: Flash back and vision ahead
Abstract:
Dyslipidemia is the most common major modifiable risk factor for ASCVD.
Low-density lipoprotein cholesterol
There is unequivocal evidence that LDL-C is causally related to atherosclerosis. The era has come when we are able to stabilise the plaque, arrest the progression of atherosclerosis, and even achieve regression of atherosclerosis. Due to this, LDL-C targets are being slashed again and again by various guidelines.
Statins are the foundational therapy for lowering LDL-C, and HI statins decrease LDL-C by approximately 40 mg/dL. If the LDL-C goals are not achieved with statins, ezetimibe (10 mg per day) is added, which will further decrease LDL-C by 15-20%. If further lowering of LDL-C is required, a triple combo of high-intensity statins, ezetimibe, and bempedoic acid (180 mg/day) is very useful and decreases LDL-C by 70–80%. For those patients who do not tolerate statins or have FH, PCSK9 MoAbs like evolocumab and alirocumab can be used. Both of these molecules decrease LDL-C by 50–60%, irrespective of baseline therapy. Inclisiran acts by inhibiting the synthesis of PCSK9 in the liver. After an injection of 300 mg every six months, it decreases LDL-C by 50%, and this remains so for a period of six months. Therefore, two injections per year are emerging as a new way to target ASCVD, but this is also a very costly molecule.
Familial hypercholesterolemia
For patients with FH, in addition to the usual drugs, lomitapide and mipomersen can also be used. Evinacumab, a monoclonal antibody against ANGPTL3, is a boon for HoFH because its action is independent of the density of the LDL-C receptor.
The PCSK9 vaccine is being evaluated, and a single dose of the vaccine decreased LDL-C by 50%, which remained there for a period of one year. High-density lipoprotein cholesterol (HDL-C)
HDL Cholesterol
HDL-C is a fallen angel, and all trials of HDL-C elevation on top of statins have been flop trials.
Triglycerides
The role of TG as a causal factor in ASCVD is still evolving. All trials of triglyceride lowering on top of statins, including the ACCORD, STRENGTH, and recently completed PROMINENT trials with pemafibrate, have been negative. Subgroup analysis in the ACCORD LLA with TG > 204 mg/dl and HDL-C < 34 mg/dl showed positive results, but subgroup analysis is only hypothesis-generating. The REDUCE IT trial with icospent ethyl has shown a reduction in ischemic CV events in patients with established CVD or diabetics with other RF on statins and elevated TG between 135 and 499 mg/dL, but the mechanism of benefit does not seem to be related to lowering TG because the benefit was similar in subgroups of patients with TG > 150 and <150 mg/dL. Saroglitazar, which is a dual PPAR agonist, is only available in India. It lowers TG by 45–62% and has been approved in India for the treatment of diabetic dyslipidemia and nonalcoholic steatohepatitis.
Remnant Cholesterol
The Remnant cholesterol = total cholesterol - HDL-C - LDL-C. The RC has not been incorporated into any of the lipid guidelines as yet.
Lipoprotein (a)
Pelacarsen, an antisense to apo A, is undergoing evaluation in a phase 3 HORIZON trial.
Gene editing
Gene editing could stop the biggest killer on earth. A volunteer in New Zealand has become the first person to undergo DNA editing in order to lower his blood cholesterol. The HEART-1 trial with Verve 101 has been planned to treat 40 people with FH with this technology.Thus, the future of lipid management for ASCVD seems very bright.
Audience Take Away:
- The audience will be able to learn about the treatment of dyslipidemia in different subsets of patients. They will also utilise the knowledge from the presentation regarding the selection of drugs to reach the LDL-C goal in their patients, and this will impact the CV outcome of the patients. The talk will also provide information regarding newer developments in dyslipidemia like Inclisiran, Pelacarsen, Evinacumab, the PCSK9 vaccine, gene editing, etc. The presentation will also provide some information on familial hypercholesterolemia
