In high-risk adults, consider combination therapy up front to achieve LDL goals
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High-risk patients with clinical atherosclerotic cardiovascular disease or multiple CV risk factors benefit from more intensive lipid-lowering therapy, and clinicians should initiate combination treatment sooner, according to a speaker.
LDL cholesterol remains a central target for the prevention and management of atherosclerotic CVD (ASCVD), Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, associate professor of medicine and associate director of preventive cardiology at the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Overwhelming genetic, observational and interventional data demonstrate LDL cholesterol is causally related to ASCVD in a proportional fashion, with a low LDL for more life-years associated with greater reduction in coronary heart disease risk, Michos said.
“Lower accumulative exposure to LDL delays the onset of CV events and slows plaque progression,” Michos said. “High-risk patients, such as those with clinical atherosclerotic CVD or multiple atherosclerotic CVD risk factors with a residual burden of atherogenic lipid particles, benefit from more intensive lipid-lowering therapy, and this needs to be onboarded sooner.”
Add-on therapy options
When it comes to pharmacotherapy, statins remain first-line therapy; however, for some, residual risk remains, Michos said.
“We see this in primary prevention and secondary prevention,” Michos said. “In high-risk patients, nearly one-fifth will have a recurrent event within 3 to 5 years.”
Other risk factors, such as hypertension, insulin resistance, diabetes and smoking, can play a role in residual risk; however, much of the risk is due to the residual burden of atherogenic lipid particles, Michos said.
“Now, we had data that show add-on therapy and further LDL lowering can further lower atherosclerotic CVD risk,” Michos said. “We have new options with outcome data for add-on therapy to statins.”
Michos highlighted pivotal trials demonstrating the benefits of add-on therapy to statin therapy:
IMPROVE-IT — The addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with acute coronary syndrome compared with simvastatin alone. In the intention-to-treat population, the simvastatin/ezetimibe group had a 32.7% rate of the primary outcome compared with 34.7% for the simvastatin group, for an HR of 0.936 (95% CI, 0.887-0.988) and a number needed to treat of 50. The trial was the first to demonstrate clinical benefit of a lipid-modifying therapy added to statin therapy.
FOURIER — Reduction of LDL to a median of 30 mg/dL with the PCSK9 inhibitor evolocumab (Reptha, Amgen) in patients with ASCVD was associated with lowered risk for CV events. In the FOURIER study, most patients were also assigned statin therapy, and some were also assigned ezetimibe. Compared with placebo, evolocumab at 48 weeks was associated with a least-squares mean percentage reduction in LDL of 59% from a median of 92 mg/dL at baseline to a median of 30 mg/dL, and 87% of those in the evolocumab group had LDL reduced to 70 mg/dL, whereas 67% had it reduced to 40 mg/dL and 42% had it reduced to 25 mg/dL (P < .001 vs. placebo for all).
ODYSSEY Outcomes — Reducing LDL to very low levels with the PCSK9 inhibitor alirocumab (Praluent, Sanofi) lowered risk for major adverse CV events and all-cause mortality in patients with acute coronary syndrome on statin therapy. All trial participants were prescribed maximally tolerated dose of atorvastatin or rosuvastatin for 2 to 16 weeks before randomization, had an LDL of at least 70 mg/dL, non-HDL of at least 100 mg/dL and apolipoprotein B of at least 80 mg/dL.
Bempedoic acid can also play a role, particularly for statin-intolerant patients, Michos said. In the CLEAR Harmony study, patients with either ASCVD, heterozygous familial hypercholesterolemia or both who were assigned bempedoic acid with maximally tolerated statin therapy saw significant decreases in LDL levels without a higher incidence of overall adverse events compared with those assigned placebo.
“Because it is a prodrug that is only activated in the liver, it does not have the same muscle effects as statins do, making it useful for statin intolerant patients,” Michos said. “But it has been shown in the CLEAR Harmony trial to have efficacy in combination with a statin, too.”
A fixed-dose combination of bempedoic acid/ezetimibe (Nexlizet, Esperion Therapeutics) may be “better together,” with data showing stronger LDL lowering with the two therapies combined compared with either agent alone, Michos said.
Avoiding clinical inertia
Michos said clinicians should not hesitate to be more aggressive in LDL lowering for very high-risk patients, considering combination therapy if a patient’s LDL level is more than 50% above goal and intensifying treatments “every 6 to 12 weeks” until goal is achieved. Single-pill combination therapy may also help with adherence, she said.
“Start thinking about initial combination therapy earlier,” Michos said. “There is a lot of clinical inertia, where patients are started on a single agent and are supposed to come back to clinic and hopefully get LDL measured, and then therapy intensified after that. That visit may be 3 months, 6 months or 1 year out. We know with these agents what the expected LDL lowering should be. We should know [a patient’s] starting LDL. If you know where you are starting and where you want to go ... and you are more than 50% above your target goal, you more than likely need combination therapy.”
References:
Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410489.
Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
Schwartz GG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801174.
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Michos ED. Novel agents and combination therapy in management of dyslipidemia. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 2-4, 2021; Los Angeles (hybrid meeting).
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