https://orcid.org/0000-0001-6441-3339
The top 10 papers in dyslipidaemias: Left hand side shows the lipid/lipopprotein targets and the right hand side shows what are the new developments related to the lipoprotein as discussed in the text.
This year, exciting developments in the lipid field have added novel therapies to our armamentarium of lipid-lowering agents and provided new insight on biomarkers. A recent study in 293 876 UK Biobank adults without cardiovascular disease at baseline evaluated whether measuring LDL-C, non-HDL-C, and triglycerides provide sufficient information for clinical care.1 ApoB was found to be a more accurate marker of cardiovascular risk than LDL-C or non-HDL-C.1 For a given value of apoB, a wide range of values of LDL-C, non-HDL, or triglycerides are possible, with significant residual information contained in apoB in predicting new-onset atherosclerotic cardiovascular disease (ASCVD) events.1 Whether targeting apoB instead of LDL cholesterol will provide better information in intervention trials needs to be seen.
Challenging the current stepwise approach for cholesterol lowering after MI, a recent study of 56 262 patients with myocardial infarction from the SWEDHEART registry showed that patients who achieved an early and sustained non-HDL-C goal (<2.2 mmol/L) had the lowest risk for all outcomes. A secondary analysis showed that patients in the quartile with the greatest reduction in non-HDL-C at 2 months had the lowest rates for all outcomes.2 Among patients who achieved a reduction in non-HDL-C ≥ 46% at 1 year, a higher proportion used a high-intensity statin or the combination of a high-intensity statin with ezetimibe. These findings confirm that the use of combination therapies significantly increases the achievement of lipid goals to reduce cardiovascular risk.
Due to their strong LDL-C-lowering effect, treatment with anti-PCSK9 monoclonal antibodies has become an important therapeutic option. Lerodalcibep is an adnectin with an anti-PCSK9 binding domain that has a high affinity for PCSK9, is administered subcutaneously monthly at a dose of 300 mg, and does not require refrigeration. A phase 3, placebo-controlled randomized clinical trial evaluated lerodalcibep in patients with cardiovascular disease taking maximally tolerated statins plus other oral lipid-lowering medications had an LDL-C ≥ 70 mg/dL (1.8 mmol/L) or ≥100 mg/dL (2.58 mmol/L) if at high CVD risk and triglycerides ≤ 400 mg/dL (4.51 mmol/L).3 Participants (992) received either lerodalcibep 300 mg or placebo monthly for 48 weeks.3 The mean placebo-adjusted reduction in LDL-C and the mean for weeks 50–52 were 56.2% (2.2%) and 62.7%, respectively. A total of 555 of 615 subjects (90%) achieved both an LDL-C reduction of ≥50% and the recommended LDL-C goal of ≤55 mg/dL (1.42 mmol/L) for patients with CVD and ≤70 mg/dL (1.81 mmol/L) for patients at high risk of CVD. Lerodalcibep also significantly reduced non-HDL-C, VLDL-C, apoB, Lp(a), and triglycerides (all P < .001). Mild to moderate injection site reactions (6.9% in patients receiving lerodalcibep vs. 0.3% in those receiving placebo) were seen, and 0.4% of study participants (n = 22) had in vitro neutralizing antibodies.
Despite their triglyceride and triglyceride-rich remnant lipoprotein-lowering effects, fibrates have not been shown to reduce incident cardiovascular events leading to the development of drugs reducing both remnants and apoB concentrations. Angiopoietin-like 3 (ANGPTL3) inhibits the activity of lipoprotein lipase and endothelial lipase, and individuals heterozygous for ANGPTL3 loss-of-function genetic variants have lower circulating levels of most lipoproteins and a lower risk of ASCVD. Evinacumab, a monoclonal antibody targeting ANGPTL3, is approved for the treatment of patients with homozygous familial hypercholesterolaemia (HoFH). A recent long-term safety and efficacy study has shown an LDL-C reduction of ∼44% in a large cohort of HoFH patients (102 adults and 14 adolescents) treated for a median duration of 104 weeks.4 Mean LDL-C reduction was 41.7% in adults and 55.4% in adolescents. Evinacumab also decreased significantly apoB, non-HDL-C, total cholesterol, fasting triglycerides, and Lp(a). Overall, evinacumab was well tolerated, confirming that the efficacy and safety were sustained over the long-term.
Zodasiran is a small interfering RNA that reduces the expression of ANGPTL3. The lipid-lowering efficacy and safety of this drug in adults with mixed hyperlipidaemia were investigated in a multi-centre, double-blind, placebo-controlled trial in subjects with fasting triglycerides of 150–499 mg/dL (1.69–5.63 mmol/L) and either an LDL-cholesterol level of ≥70 mg/dL (1.81 mmol/L) or a non-HDL-cholesterol level of ≥100 mg/dL (2.59 mmol/L).5 Participants (N = 204) were randomized to receive subcutaneous zodasiran 50, 100, or 200 mg or placebo on Day 1 and week 12 and were followed until Week 36. A significant dose-dependent triglyceride reduction of −51, −57, and −63% at the 50, 100, and 200 mg doses, respectively, and a concomitant dose-dependent reduction in ANGPTL3 levels at each dose were reported at 24 weeks. Changes in apolipoprotein B from baseline were −19, −15, and −22% for the three doses. There was a mild increase in glycated haemoglobin, primarily in patients with pre-existing diabetes with no change observed in the homoeostasis model assessment of insulin resistance.
Apolipoprotein C-III by inhibiting lipoprotein lipase reduces lipoprotein lipase-mediated lipolysis, promotes hepatic VLDL secretion, chylomicron formation, and suppresses hepatic clearance of triglyceride-rich lipoproteins. Plozasiran, an N-acetylgalactosamine-conjugated small interfering RNA that reduces hepatic expression of APOC3, was evaluated in a randomized, double-blind, placebo-controlled, phase 2b trial in patients with triglyceride levels of 150–499 mg/dL and either an LDL-C ≥ 70 mg/dL (1.81 mmol/) or a non-HDL-C level ≥ 100 mg/dL (2.59 mmol/L).6 Subjects (N = 353) were randomized to receive subcutaneous plozasiran or placebo. Participants received plozasiran 10, 25, or 50 mg or placebo on Day 1 and at Week 12 (quarterly doses), whereas in the fourth cohort, subjects received plozasiran 50 mg or placebo on Day 1 and at Week 24 (half-yearly dose). Compared to placebo, the least square mean per cent change of triglycerides from baseline was −49.8, −56.0, and −62.4%, and −44.2% for the 10, 25, and 50 mg (quarterly), and the 50 mg (half-yearly) dose, respectively. The least square mean difference in apolipoprotein B change from baseline with plozasiran vs. placebo was −10.3, −13.0, and −19.1% with the 10, 25, and 50 mg quarterly doses, and −6.5% with the 50 mg half-yearly dose. Worsening glycaemic control occurred in 10% of the participants in the placebo group and in 12, 7, and 20%, and 21% in the 10, 25, and 50 mg quarterly, and 50 mg half-yearly groups, respectively, with higher incidence in the highest dose but the homoeostasis model assessment of insulin resistance was unchanged. No changes in mean platelet counts were reported. These two studies suggest that therapies with these agents should be further investigated as therapeutic options with cardiovascular outcome trials.
While therapies that increase HDL-C levels have not been associated with a reduction in ASCVD risk, there is ongoing interest in whether treatments that improve cholesterol efflux capacity may be beneficial. CSL112 is a human apolipoprotein A1 that can be administered intravenously, resulting in a doubling of apolipoprotein A1 levels and a four-fold increase in cholesterol efflux capacity. CSL112 was tested in a randomized, double-blind, placebo-controlled trial to determine the potential clinical benefit after an acute Type 1 myocardial infarction.7 Patients, 88% of whom underwent percutaneous intervention for the index event and were also receiving statin and dual anti-platelet therapy, were randomized to receive either four weekly infusions of CSL112 or matching placebo, with the first infusion administered within 5 days after the acute myocardial infarction. No significant reduction was observed in the risk of composite primary endpoint of myocardial infarction, stroke, or cardiovascular death between patients receiving CSL112 and placebo over 90 days (439 patients in the CSL112 group vs. 472 patients in the placebo group, HR 0.93, 95% CI: 0.81–1.05, P = .24). Thus, CSL112 administered to patients with a recent myocardial infarction continues the string of unsuccessful attempts to reduce ASCVD events with HDL-raising therapeutics.
Lp(a), an important risk factor for ASCVD and aortic valve stenosis, has a high inflammatory activity most likely due to the enrichment in oxidized phospholipids. Earlier studies have suggested that high-sensitivity C-reactive protein (hs-CRP) levels can modify the risk associated with elevated Lp(a). To investigate whether systemic low-grade inflammation may modulate the association between Lp(a) and coronary heart disease (CHD) risk, data from 71 678 individuals from the general population were analysed.8 Among individuals without CHD at baseline, Lp(a) levels were associated with the risk of future CHD independently of hs-CRP levels: the magnitude of the association was similar in individuals with hs-CRP < 2 mg/dL (hazard ratio 1.45, P < .001, highest vs. lowest fifth of Lp(a) distribution) and in individuals with hs-CRP ≥ 2 mg/dL (hazard ratio 1.48, P < .001, highest vs. lowest fifth). In contrast, in participants with established CHD at baseline, elevated Lp(a) levels were associated with future cardiovascular events in those with hs-CRP ≥ 2 mg/dL and only borderline in those with hs-CRP < 2 mg/dL. These observations suggest no interaction between Lp(a) and hs-CRP in primary prevention while in individuals with established CHD, the relationship between Lp(a) and inflammation is rather complex, possibly affecting the effects of upcoming Lp(a)-lowering therapies.
ASCVD outcome trials using therapies to lower circulating levels of lipoprotein(a) [Lp(a)] are ongoing. Zerlasiran is an N-acetylgalactosamine-conjugated siRNA silencing drug with a prolonged duration of action. In a phase 2, double-blind, placebo-controlled trial, 178 patients with stable ASCVD and Lp(a) ≥ 125 nmol/L were randomized into five groups in a 1:1:2:2:2 ratio to receive subcutaneous injections of placebo every 16 weeks for three doses (N = 23), placebo every 24 weeks for two doses (N = 24), zerlasiran 450 mg every 24 weeks for two doses (N = 45), zerlasiran 300 mg every 16 weeks for three doses (N = 42), or zerlasiran 300 mg every 24 weeks for two doses (N = 44).9 The least-squares mean time-averaged per cent change in Lp(a) concentration at Week 36 ranged from −81.3% (95% CI: −87.6% to −76.0%) to −85.6% and the median per cent change in Lp(a) concentration from baseline to Week 36 ranged from −90% (95% CI: −97.3% to −81.3%) to −96.4%. The drug was well tolerated, with mild injection site reactions occurring in 2.3%–7.1% of subjects.
Muvalaplin, a small molecule that prevents the assembly of Lp(a) particles by disrupting the interaction between apolipoprotein(a) and apoB, is the first oral Lp(a)-lowering drug. A phase 2, placebo-controlled, double-blind trial randomized 233 subjects with ASCVD, diabetes mellitus, or familial hypercholesterolaemia and Lp(a) concentration ≥ 175 mmol/L to receive daily oral doses of muvalaplin of 10 (N = 34), 60 (N = 64), and 240 mg (N = 68) or placebo (N = 67) for 12 weeks.10 The primary endpoint was the placebo-adjusted percentage change from baseline in Lp(a) at Week 12. Treatment with muvalaplin was associated with a placebo-adjusted percentage change for the 10, 60 and 240 mg doses of −47.6% (95% CI: 35.1%–57.7%), −81.7% (95% CI: −78.1 to −84.6%), and −85.8% (95% CI: −83.1 to −88.0%) using an intact Lp(a) assay, and of −40.4% (95% CI: −28.3 to −50.5%), −70.0% (95% CI: −65.0 to −74.2%), and −68.9% (95% CI: −63.8 50 −73.3%) using an apolipoprotein(a)-based assay. No significant safety or tolerability issues were observed. Whether any of these drugs will play a role in clinical practice will depend on the results of planned ASCVD outcome studies.
Declarations
Disclosure of Interest
L.T., in the last three years, has received honoraria, lecture fees, or research grants from Abbott, Amgen, Amarin, Bayer, Daiichi Sankyo, Eli Lilly, MSD, Menarini, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, and Ultragenyx. A.L.C., in the last three years, has received honoraria, lecture fees, or research grants from Aegerion, Akcea Therapeutics, Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscape Education, Menarini, Merck, Mylan, Novartis, Novo Nordisk, PeerVoice, Pfizer, Recordati, Regeneron, Sanofi, The Corpus, and Viatris.
