In an interesting debate session at the European Atherosclerosis Society (EAS) 2022, Michal Vrablík, Czech Republic, and Ulrich Laufs, Germany, argued whether oral lipid-lowering therapies such as statins and ezetimibe are sufficient for cardiovascular disease (CVD) prevention or whether we need the support of injectables, i.e, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for low-density lipoprotein cholesterol (LDL-C) attainment goal. The session was chaired by Carl E. Orringer, the United States, and Kausik K. Ray, United Kingdom.

Michal Vrablík, Czech Republic

Speaking in favor of currently available oral lipid-lowering therapies, Dr Vrablík states that we still have powerful weapons in our hands that don't need to be injected. The LDL-C attainment goal has become more stringent over the years. We started at <3 mmol/L in 1988 and now we are at <1.4 mmol/L in 2019. If we look at the 2019 European Society of Cardiology (ESC)/EAS guidelines treatment algorithm for pharmacological LDL-C lowering, injectables are right at the bottom. This is because we have very good options to suppress LDL-C, particularly high-intensity statins combined with ezetimibe. This combination on average is able to suppress LDL-C by two-thirds, which is sufficient to bring the majority of the high-risk patients closer to their LDL-C attainment goal.

The DA VINCI study is the first analysis that looked at goal attainment after the 2019 guidelines were published. Although the study showed that the LDL-C attainment remained dismal, much of that could be attributed to the underutilization of the high-intensity statin plus ezetimibe combination. In the DA VINCI cohort, 44% of the participants were using moderate-intensity statins as monotherapy, 38% were using high-intensity statins as monotherapy, and only 9% were using a combination of high-intensity statins and ezetimibe. What's surprising is that this is the situation after 5 years of the IMPROVE-IT trial and when ezetimibe has become generic in several countries. Dr Vrablík states: "We don't need to wait [for injectables] and we should stick to what is traditionally available and what is widely available."

Dr Vrablík agrees that while nonadherence to statins remains a problem in the real-world setting, patients cannot be completely blamed for nonadherence. We need clever strategies to convince patients to adhere to treatments. Using fixed-dose combinations of antihypertensives and lipid-lowering therapies could be a good strategy to improve patient adherence. At the end of his talk, Dr Vrablík also emphasizes the need for clinicians to overcome therapeutic inertia and actively practice treatment intensification.

Ulrich Laufs, Germany

Speaking against the motion that oral lipid-lowering therapies are sufficient, Dr Laufs says that we definitely need injectables for patients with insufficient LDL-C lowering primarily because of high LDL-C levels and medication intolerance. A meta-analysis found that overall 9.1% of patients had statin intolerance, which still represents a large population of statin users. Registry data from Germany show that two-thirds of PCSK9 inhibitor prescriptions are due to statin-associated muscle symptoms.

There are strong efficacy data for the two PCSK9 inhibitors showing a 50%-60% additional reduction in LDL-C on top of other treatments. Furthermore, the LDL-C lowering with PCSK9 inhibitors remains consistent over a long time.

The PCSK9 inhibitor studies have shown that in contrast to other cardiovascular risk factors, such as blood pressure or glucose, there is no lower limit of the association between achieved LDL-C and relative risk reduction of CVD, which means the lower the better. The safety of these drugs has been well established in hundreds of thousands of patients treated in randomized controlled studies. Additionally, the OSLER-1 study showed no evidence of the development of anti-drug antibodies over 5 years.

Evidence from the ORION-11 study shows that the new PCSK9 small interfering RNA agent inclisiran could result in a 40%-50% reduction in LDL-C with only twice-yearly dosing and had an excellent safety profile.

Dr Laufs goes on to say that we also need injectables for selected patients, such as those with familial chylomicronemia syndrome and familial hypercholesterolemia, who have limited oral options.

EAS 2022 — Do we really need injectable lipid-lowering therapies for CVD prevention?

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