More research on these topics would be useful: What is the optimal combination of lipid-lowering treatments or achieved LDL-C level that will result in the largest reduction in CV events (e.g., whether adding a PCSK9 inhibitor to maximum- dose statins plus ezetimibe versus moderate-dose statins plus ezetimibe results in an incremental benefit in CV risk)? What is the comparative effectiveness of a high-dose statin plus ezetimibe, a high-dose statin plus PCSK9 inhibitor, and a high-dose statin plus ezetimibe plus PCSK9 inhibitor (triple therapy) on important CV outcomes in higher risk patients? What is the optimal duration of more aggressive treatment in higher risk patients? For example, in a patient with ACS placed on high-dose statins, is the more aggressive treatment continued indefinitely or can some patients have their treatment titrated downward after a period of time? c. Other Medications, Supplements, and Nutraceuticals Recommendation 15. For primary or secondary prevention, we recommend against using niacin (i.e., supplements or prescriptions). (Strong against | Reviewed, New-replaced) Discussion Primary Prevention In a fair quality SR of five RCTs that evaluated niacin in primary prevention (n=30,310), Keene et al. (2014) noted no patient benefit from niacin. There was no difference in all-cause mortality, non-fatal MI, or stroke.[90] There was evidence of harm, manifested by an increase in infections, gastrointestinal (GI) complications, bleeding, new-onset DM, and DM complications. Primary and Secondary Prevention In a fair quality SR of five RCTs in a mix of primary and secondary prevention patients (n=32,966) who used supplements containing therapeutic doses of niacin (2 3 grams/day), Schandelmaier et al. (2017) noted no benefits and increased harms.[91] This systematic review noted no difference in CV mortality, all-cause mortality, non-fatal MI, or stroke. However, side effects resulted in significant flushing, pruritus, GI symptoms, new-onset DM, and more discontinuations. 