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REFLECTIONS
Dyslipidaemia
Dyslipidaemia Global Newsletter #10 2025

Established therapies primarily target cholesterol synthesis and molecules, including muvalaplin, reduce Lp(a) by 50%–86%,
uptake to reduce LDL-C. Statins inhibit HMG-CoAR, lowering and represent a novel, non-injectable therapeutic option. Dyslipidaemia
cholesterol production and upregulating LDL receptors in the Cholesteryl ester transfer protein (CETP) inhibitors, such as
liver. Bempedoic acid inhibits ACLY upstream of HMG-CoAR, obicetrapib, lowered LDL-C by 50% and reduced apoB, non-
offering an alternative for statin-intolerant patients and reducing HDL-C, and Lp(a) levels, providing an additional option for
LDL-C by 20%–30%. Ezetimibe blocks NPC1L1, reducing mitigating residual risk.
intestinal cholesterol absorption, and provides added therapeutic
benefit when used in combination with statins, reinforcing its The field of LLT is rapidly expanding beyond LDL receptor-
role in supporting the achievement of high-risk prevention. dependent therapy. Combining high-intensity statins with LLTs
For individuals with HoFH, lomitapide inhibits microsomal that enhance hepatic LDL receptor activity like ezetimibe,
triglyceride transfer protein (MTP), lowering LDL-C by 40%– bempedoic acid, and PCSK9 inhibitors yields additive LDL-C
50%, independent of LDL receptor function. reductions. CETP inhibitors may further enhance LDL receptor
function, even in heterozygous familial hypercholesterolaemia
PCSK9 inhibitors represent both established and emerging (HeFH). However, patients with HoFH require LDL receptor-
therapies. Monoclonal antibodies, such as evolocumab and independent strategies. Novel agents targeting lipoprotein
alirocumab, reduce LDL-C by up to 50%–60% on top of the synthesis or secretion could address this gap, though long-term
maximum tolerated dose of statins and ezetimibe and have hepatic effects need clarification. The authors also emphasise
demonstrated significant reductions in MACEs in phase 3 the importance of targeting TRLs and Lp(a), and note that
trials. Small interfering (si)RNA therapies, such as inclisiran, drugs like glucagon-like peptide-1 (GLP1) receptor agonists,
typically reduce LDL-C by 50% with twice-yearly dosing dual GLP1/glucose-dependent insulinotropic polypeptide
and are approved for LDL-C reduction along with primary (GIP) agonists, and metabolic agents such as resmetirom and
prevention of hypercholesterolaemia. Novel approaches, pegozafermin may improve lipid profiles through mechanisms
including oral small molecules and clustered regularly beyond LDL-C lowering. Overall, they advocate for a broader,
interspaced short palindromic repeats (CRISPR) base-editing precision-based approach that addresses multiple lipoprotein
therapies (VERVE-101 and VERVE-102), are in development pathways to optimise CV risk reduction.
to achieve durable LDL-C lowering through permanent
modulation of hepatic PCSK9 expression.

Emerging therapies also target residual risk associated with
TRLs and Lp(a). ANGPTL3 inhibition, using monoclonal
antibodies like evinacumab, approved for LDL-C lowering in
HoFH, has demonstrated TG reduction of ~30%–80%. ApoC3
inhibition through antisense oligonucleotides [ASOs], such as
olezarsen, which reduces TGs by ~20%–45%, or siRNAs, such
as plozasiran, which reduces TGs by ~50%–60%, enhances
clearance of TRLs and provides cardioprotection in severe
hypertriglyceridaemia (sHTG) and FCS. Fibroblast growth CLICK HERE
factor 21 (FGF21) analogues, such as pegozafermin, which WATCH DR. CHRISTIE BALLANTYNE
provides a TG reduction of ~35%–65%, regulates lipid and DISCUSS THE LATEST
glucose metabolism and is in development for sHTG. BREAKTHROUGHS IN LIPID
MANAGEMENT.
Lp(a) is a potent, genetically determined CV risk factor. Gene-
silencing strategies targeting apo(a) messenger (m)RNA,
such as ASOs (pelacarsen) and siRNAs (olpasiran, zerlasiran, CLICK HERE
lepodisiran), can reduce Lp(a) by 66%–92% in phase 2 and FOR THE LINK TO FULL ARTICLE
3 trials, with clinical outcome trials still ongoing. Oral small

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