Optimizing LDL-C control with nonstatin oral therapy in high CV risk patients

Inadequate control of cardiovascular (CV) risk factors, particularly hypercholesterolaemia, continues to drive high global mortality rates from CV disease (CVD). At a recent industry-sponsored meeting, Dr Carlos Escobar Cervantes from La Paz University Hospital, Spain, discussed major barriers to achieving optimal LDL-cholesterol (LDL-C) control, while Professor Ioanna Gouni- Berthold from the University of Cologne, Germany, shared insights and real-world evidence on CV risk reduction with bempedoic acid.

Four in five patients not meeting LDL-C targets
Hypercholesterolaemia is the ma­jor cause of atherosclerosis. “This is why it is crucial to reach guideline-recommended cholesterol targets as early as possible,” explained Esco­bar. [Semergen 2020;46:4-15; Eur Heart J 2020;41:111-188; Eur Heart J 2024;45:3912-4018]

Despite proven benefits of lipid man­agement, real-world data reveal that most patients fail to meet LDL-C targets. The SANTORINI study (n=9,044) in 14 Eu­ropean countries found that only 20.1 percent of patients achieved the recom­mended LDL-C targets. Even among those with atherosclerotic CVD (ASC­VD), only 20.7 percent achieved LDL-C goals. (Figure 1) [Lancet Reg Health Eur 2023;29:100624]

Global barriers to achieving optimal LDL-C control
Undertreatment is considered the pri­mary cause of poor LDL-C control. In the SANTORINI study, only 50.2 percent of patients received statin monotherapy, and just 24.0 percent were prescribed com­bination therapy. [Lancet Reg Health Eur 2023;29:100624]

A US study further showed that use of high-intensity statins for second­ary prevention dramatically declined in patients aged >60 years. “Age should not be a reason to underprescribe lipid-lowering therapy, as evidence shows that older patients also benefit from these treatments,” said Escobar. [Circ Cardio­vasc Qual Outcomes 2023;16:533-543; Lancet 2019;393:407-415]

A Spanish study also revealed a dis­connect between physicians’ percep­tions and reality. While physicians per­ceived that 62 percent of their patients attained LDL-C control, the actual con­trol rate was only 31 percent in the over­all patient population (p<0.01), and only 22 percent in patients with high CV risk (p<0.01). In addition, therapy remained unchanged for years in many patients, indicating undertreatment. [Atheroscle­rosis 2023;375:38-44]

Even with combination therapy, some patients still failed to reach LDL-C targets, as highlighted by the DA VINCI study. This underscores the need for newer options (eg, bempedoic acid) to enhance current treatment strategies. [Eur J Prev Cardiol 2021;28:1279-1289]

To overcome these barriers, the latest treatment paradigm has shifted from a stepwise approach to a "fire-to-target" strategy, which individualizes treatment based on patient needs, al­lowing timely initiation of combination therapy to optimize lipid management. [Eur Heart J 2020;41:111-188; Eur Heart J 2023;44:3720-3826]

LDL-reduction with inclisiran
Inclisiran is a small interfering ribo­nucleic acid (siRNA) molecule that is delivered via subcutaneous injection by healthcare professionals as a lipid-lowering treatment. Inclisiran demon­strated consistent LDL-C–lowering effects over time in ORION-8. With a mean cumulative exposure of 3.7 years, the overall study population achieved a mean percentage change in LDL-C of -49.4 percent. In the ASCVD and ASCVD-risk–equivalent populations, the mean percentage change in LDL-C was -51.0 and -42.4 percent, respectively, at the end of the study. [Cardiovasc Res 2024;120:1400-1410]

About two-thirds (66.3 percent) of pa­tients with ASCVD on inclisiran achieved the LDL-C goal of <55 mg/dL (1.4 mmol/L), while 46.6 percent of patients at equivalent ASC­VD risk reached LDL-C levels of <70 mg/dL (1.8 mmol/L).

CV risk reduction with bempedoic acid
Bempedoic acid is an oral, nonstatin, lipid-lowering therapy. The CLEAR Out­comes trial evaluated the effects of bempe­doic acid on major CV events in 13,970 statin-intolerant patients. After 6 months of treatment, bempedoic acid reduced mean LDL-C level by 21.7 percent (vs 0.6 percent with placebo). This effect remained stable over time, with a 26.1 percent reduction in LDL-C level achieved with bempedoic acid vs 10.6 percent with placebo at 60 months. [N Engl J Med 2023;388:1353-1364]

The primary composite endpoint of four-component major adverse CV events (MACE-4; CV death, nonfatal MI, nonfatal stroke, or coronary revascularization) oc­curred in 11.7 vs 13.3 percent of patients in the bempedoic acid vs placebo group (haz­ard ratio [HR], 0.87; 95 percent confidence interval [CI], 0.79–0.96; p=0.004).

Bempedoic acid was generally well tolerated, with slightly higher risks of gout (3.1 vs 2.1 percent) and cholelithiasis (2.2 vs 1.2 percent) vs placebo, as well as small increases in serum creatinine, uric acid, and hepatic enzyme levels.

Effects in subgroups with diabetes or obesity
The trial’s prespecified subgroup analysis showed that patients with dia­betes achieved an absolute reduction of 2.4 percent in MACE-4 with bempedoic acid vs placebo (p=0.0063). In addition, no increased risk of new-onset diabetes was observed with bempedoic acid vs placebo. [Lancet Diabetes Endocrinol 2024;12:19-28]

“Potential increase in risk of diabetes is a concern for long-term statin users. How­ever, this was not shown at all with bempe­doic acid,” highlighted Gouni-Berthold.

Among patients with obesity (BMI ≥30 kg/m²), bempedoic acid significant­ly reduced LDL-C by 22.5 percent and MACE-4 by 23 percent (HR, 0.77; 95 percent CI, 0.67–0.89) vs placebo. (Figure 2) [J Am Heart Assoc 2025;14:e037898].

Real-world evidence of bempedoic acid
The ongoing European study MILOS evaluates the LDL-C–lowering effective­ness and safety of bempedoic acid or be­mpedoic acid/ezetimibe fixed-dose com­bination (FDC) in real-world clinical settings in adults with primary hypercholesterolae­mia or mixed dyslipidaemia. In the German cohort (n=973), 11 percent of patients ex­perienced an adverse drug reaction relat­ed to bempedoic acid or bempedoic acid/ ezetimibe FDC, with myalgia reported in 3.5 percent of patients. Notably, only 0.3 percent of patients had serious adverse drug reactions related to the treatment. [Clin Res Cardiol 2024;113:1514]

Regarding efficacy, the proportion of patients achieving their LDL-C goal im­proved by 30.4 percent in the overall pop­ulation after 2 years of treatment. “Among subgroups, goal attainment increased by 35 percent in the low/moderate CV risk group, 26.9 percent in the high CV risk group, and 31.6 percent in the very high CV risk group,” said Gouni-Berthold. [Clin Res Cardiol 2024;113:1514]

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