Historical treatments

Fibrates have been used for decades to reduce the risk of acute pancreatitis in severe hypertriglyceridaemia. Their use in the prevention of CV risk remains controversial. In the large FIELD trial in individuals with type 2 diabetes, fenofibrate failed to reduce the primary outcome of coronary events compared with placebo [37, 38]. In the ACCORD CVOT, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, non-fatal MI or non-fatal stroke compared with placebo in participants with type 2 diabetes [39]. Prespecified subgroup analyses suggested a possible benefit for men and for participants with both hypertriglyceridemia ≥2.30 mmol/l and low HDL-C ≤0.88 mmol/l at baseline. In the recent PROMINENT CVOT including individuals with type 2 diabetes with mild-to-moderate hypertriglyceridemia, low levels of HDL-C and well-controlled levels of LDL-C, pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, did not reduce the risk of CV events. At 4 months, pemafibrate resulted in mean favourable changes in TG (−26.2%) and HDL-C (+5.1%) levels, a neutral change in non-HDL-C levels (−0.2%) and unfavourable changes in LDL-C (+12.3%) and apoB (+4.8%) levels compared with placebo [40]. A meta-analysis of 18 prospective RCTs assessing the effects of fibrates on CV outcomes compared with placebo showed that fibrate therapy produced a significant 10% RR reduction in major cardiovascular events and a 13% RR reduction in coronary events, but had no benefit on stroke, all-cause mortality, cardiovascular mortality, sudden death or non-vascular mortality. There was no difference in the results for coronary events between those with diabetes and those without diabetes [41]. Another meta-analysis of five RCTs of fibrate (ACCORD, FIELD, BIP, HHS and VA-HIT) showed that fibrate treatment produced a significant 35% RR reduction in coronary heart disease in the subgroup of participants with atherogenic dyslipidaemia (high TG levels and low HDL-C levels), which is common in diabetes [42]. These data have led to divergent guidelines. In ADA standards of care in diabetes, statin plus fibrate combination therapy is generally not recommended [43], whereas in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines fenofibrate or bezafibrate may be considered in combination with statins for primary prevention or in high-risk individuals at LDL-C target levels with TG levels >2.3 mmol/l [44]. We consider that fenofibrate may be considered in combination with statins in high- or very-high-risk individuals at LDL-C target levels with TG levels >2.3 mmol/l and HDL-C levels <1 mmol/l in men or <1.3 mmol/l in women.

Considering the apparent contrasting effects of fibrates, new-generation therapies are needed to improve the lipid abnormalities seen in atherogenic dyslipidaemia.

Newly approved treatments Omega-3 fatty acids

Omega-3 fatty acids can be used at pharmacological doses (2–4 g/day) to lower TG levels. A meta-analysis of RCTs including 77,917 people treated with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) at doses between 226 and 1800 mg/day showed a neutral effect on mortality and CV events, including in the subgroup with diabetes [45]. Two more RCTs have confirmed the inability of omega-3 supplementation (1 g/day and 4 g/day of EPA and DHA, respectively) to reduce CV events in participants with diabetes without evidence of CV disease [46] and in statin-treated participants at high CV risk (70% of people with diabetes) [47]. However, the REDUCE-IT study, which included 8179 secondary prevention participants or participants with diabetes at high CV risk who had been receiving statins and had TG levels between 1.5 and 5.6 mmol/l and LDL-C levels between 1 and 2.6 mmol/l, showed that high-dose treatment with 4 g/day of icosapent ethyl (IPE) was associated with significant reductions of 25% in the primary endpoint (CV death, non-fatal MI, non-fatal stroke, coronary revascularisation or unstable angina), 20% in CV mortality and 28% in fatal and non-fatal fatal stroke and a non-significant reduction of 13% in total mortality [48]. Median changes between the last visit and baseline in the IPE group were −14.1% for TG, −3% for HDL-C, −8.6% for non-HDL-C, −7.4% for LDL-C and −6.7% for apoB (Table 1). However, lowering of TGs is unlikely to be the full explanation for the CV benefit of IPE, as benefits were similar irrespective of the degree of TG lowering in those receiving IPE. The median follow-up in this study was 4.9 years.

Currently, IPE 2×2 g/day is recommended in high-risk (or above) individuals with TG levels between 1.5 and 5.6 mmol/l (135 and 499 mg/dl) despite statin treatment, to reduce CV risk [42, 43].

Therapy targeting apoC-III

ApoC-III is currently recognised as a key regulator of TRL metabolism and mediates its effects through both lipoprotein lipase (LPL)-dependent and LPL-independent mechanisms (Fig. 1). The plasma apoC-III concentration is strongly positively correlated with the plasma TG concentration and is increased in insulin-resistant states. Importantly, hyperglycaemia in individuals with type 1 or type 2 diabetes is associated with increased apoC-III levels [49]. Elevated apoC-III has been postulated to contribute to atherogenic dyslipidaemia through the impairment of TRL and HDL metabolism [50, 51]. Volanesorsen, an antisense oligonucleotide targeting hepatic apoC-III, was first studied in the APPROACH and COMPASS Phase III trials in individuals with familial chylomicronaemia syndrome (FCS) [52] and in individuals with multifactorial chylomicronaemia syndrome (MCS), including 40% of participants with diabetes [53]. In the latter study, volanesorsen reduced mean TG levels by 71.2% and mean non-HDL-C levels by 27.3% and increased mean HDL-C levels by 61.2% and mean LDL-C levels by 95.5% from baseline to 3 months, with no change in apoB levels (Table 1). In the BROADEN Phase II/III trial, which included individuals with familial partial lipodystrophy and concomitant hypertriglyceridaemia and diabetes, volanesorsen reduced mean TG levels by 88% from baseline to 3 months and the hepatic fat fraction by 52% from baseline to 12 months, with no change in HbA1c [54]. The main side effects of volanesorsen were injection site reactions and thrombocytopenia.

In summary, volanesorsen is very effective at reducing TG levels and should be very helpful in reducing the risk of acute pancreatitis; however, because of its side effects, particularly thrombocytopenia, volanesorsen has not been approved by the FDA and further CVOTs are needed.

Therapy targeting angiopoietin-like 3

Angiopoietin-like 3 (ANGPTL3), a protein that is exclusively synthesised in the liver, may increase VLDL secretion and inhibits the activity of two extracellular lipases: LPL, leading to a decrease in TRL catabolism, and endothelial lipase, leading to decreased LDL hepatic uptake and the abrogation of HDL phospholipid catabolism, raising HDL-C levels [50] (Fig. 1). In 2021, the first-in-class human anti-ANGPTL3 monoclonal antibody, evinacumab, was approved by the EMA and FDA for use in homozygous familial hypercholesterolaemia. Recently, because of the high efficacy of evinacumab to decrease TG levels, several studies have been carried out in individuals with hypertriglyceridaemia. Two Phase II studies in participants with TG >1.7 mmol/l but ≤5.1 mmol/l and LDL-C ≥2.6 mmol/l (but without diabetes) were randomised to s.c. or i.v. evinacumab at different doses compared with placebo. The maximal difference between evinacumab and placebo was −88% for TG, −28% for HDL-C, −35% for non-HDL-C and −25% for LDL-C (Table 1). Evinacumab was well tolerated with no serious adverse events [55].

In summary, evinacumab is very effective at reducing TG levels in people with MCS and should be very helpful at reducing the risk of acute pancreatitis and reducing LDL-C levels. It is well tolerated but further CVOTs are needed.

Potential future therapies Therapy targeting apoC-III

Because of the main side effects of volanesorsen (injection site reactions and thrombocytopenia), olezarsen, an N-acetyl-galactosamine (GalNac)-conjugated antisense oligonucleotide that binds more specifically to apoC-III in the liver, was designed. Olezarsen has enhanced safety and tolerability compared with volanesorsen as it is used at a lower dose and injection volume with less frequent dosing. A randomised, double-blind, placebo-controlled, dose-ranging study of olezarsen was conducted in 114 individuals at high risk for or with established CV disease (67.5% with type 2 diabetes) and with fasting serum TG levels of 2.26–5.65 mmol/l [56]. Treatment with olezarsen resulted in mean per cent TG reductions from baseline of 23–60%. HDL-C increased significantly (from 12% to 42%) in each olezarsen dose group (10 or 50 mg every 4 weeks, 15 mg every 2 weeks or 10 mg every week), non-HDL-C decreased significantly (from 15% to 24%) and apoB decreased significantly (from 10% to 16%) but not in all olezarsen groups, and LDL-C increased significantly (23%) in only one olezarsen group. Regarding side effects, there were no platelet count, liver or renal function changes in any of the olezarsen groups and the most common adverse event was mild erythema at the injection site. Several Phase III studies of olezarsen are in progress in FCS (NCT04568434) MCS (NCT05079919 and NCT05552326) and individuals with hypertriglyceridaemia and at high risk for or with established CV disease (NCT05610280). In the context of the dual effect of olezarsen—improvement in some lipid levels (reduction in TG and non-HDL-C and increase in HDL-C) but deterioration in others (increase in LDL-C and no significant change in apoB for all treated groups)—CVOTs will be very important to assess the effect of the drug on ASCVD risk. Indeed, whereas, in general, LDL-C, non-HDL-C and apoB are very highly correlated and provide very similar information about ASCVD risk, under certain circumstances, including in people with diabetes, LDL-C measurement is less reliable. In this case, apoB, which provides an accurate estimate of the total concentration of atherogenic particles, can be the preferred measurement to further refine the estimate of ASCVD risk that is modifiable by lipid-lowering therapy [43].

Moreover, injection of the hepatocyte-targeted GalNac-conjugated siRNA ARO-APOC3 is currently under development in Phase III studies (NCT04998201, NCT04720534 and NCT05089084). A monoclonal antibody approach to lowering of apoC-III has also been described [57].

Therapy targeting ANGPTL3

The development programme for vupanorsen, a (GalNac)-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits ANGPTL3 protein synthesis, was discontinued in 2022. Indeed, the magnitude of decreases in TG and non-HDL-C levels observed in the TRANSLATE-TIMI 70 study (Phase IIb) did not support continuation of the clinical development programme for CV risk or severe hypertriglyceridaemia. Vupanorsen was also associated with dose-dependent increases in liver fat, and higher doses were associated with elevations in the liver enzymes alanine aminotransferase and aspartate aminotransferase [58].

The effects of a single or repeat s.c. doses of the (GalNac)-conjugated siRNA ARO-ANG3, which degrades ANGPTL3 mRNA in healthy volunteers and in individuals with hepatic steatosis, were recently described. In the cohort of participants with hepatic steatosis, which is common in type 2 diabetes, repeat dosing of 200 mg resulted in mean reductions in TG (−42%), non-HDL-C (−37%), LDL-C (−36%), apoB (−20%) and HDL-C (−57%) levels at day 113 compared with baseline. The treatment was well tolerated [59]. More work is needed to confirm these results.

Fibroblast growth factor 21 agonists

Fibroblast growth factor 21 (FGF21) is an endogenous stress hormone, a member of the FGF family, and is primarily produced by the liver. It binds to and activates FGF receptors and regulates lipid and glucose metabolism and energy expenditure. Several FGF21 analogues are in development. Most of the Phase I and II trials have been dedicated to type 2 diabetes or included a large proportion of participants with type 2 diabetes. The results of these studies vary according to drug, dose and duration of treatment. However, generally, reductions of up to 69% in TG, 30% in LDL-C, 34% in non-HDL-C and 25% in apoB and an increase of up to 61% in HDL-C are observed [60, 61]. In the study of non-alcohol-related steatohepatitis (NASH) [60], the liver fat fraction was reduced after treatment with the FGF21 analogue. Glucose control was not systematically improved, but longer studies are needed. The different drugs are well tolerated and the most common adverse events are related to gastrointestinal disturbances. Phase III studies are ongoing with pegozafermin (NCT05852431) and efruxifermin (NCT06161571).

Therapy targeting cholesteryl ester transfer protein

Cholesteryl ester transfer protein (CETP) inhibitors lead to the greatest elevations in HDL-C levels (Fig. 1), but the results of clinical trials have been disappointing [62]. A recent randomised Phase II trial in dyslipidaemic participants using a new CETP inhibitor (obicetrapib) in combination with background high-intensity statin treatment found that, after 8 weeks, there was a significant decrease in median TG (−11% only with obicetrapib 5 mg), non-HDL-C (by up to −44%), LDL-C (by up to −51%) and apoB (by up to −30%) levels and an increase in median HDL-C levels (by up to 165%) [63]. Two meta-analyses found a significant reduction in the risk of new-onset diabetes of 12% [64] and 16% [65] in the CETP inhibitors group compared with the placebo group; glycaemic measures were also significantly improved in those with and without diabetes across most trials [65]. The results of the CVOT PREVAIL (NCT05202509) are eagerly awaited.