R3i Editorial

Triglyceride-rich lipoproteins have attracted much attention as a likely therapeutic target to reduce residual cardiovascular risk, supported by evidence from extensive epidemiologic, genetic, and mechanistic studies ¹. There are also insights from the fibrate trials suggesting clinical benefit in patients with type 2 diabetes and atherogenic dyslipidemia, i.e., the combination of mild-to-moderate hypertriglyceridemia, and low plasma concentration of high-density lipoprotein cholesterol (HDL-C) ². Despite this, randomized controlled studies have so far failed to demonstrate conclusively that lowering triglycerides (TG), a surrogate for triglyceride-rich lipoproteins, reduces residual cardiovascular risk (3-5). Additionally, the observed relative risk reductions in cardiovascular events in REDUCE-IT did not relate to the extent of TG lowering with icosapent ethyl ⁶.

This background provided impetus for the development of the selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) pemafibrate, aiming to address issues with current fibrates (PPARα agonists) by improving potency, selectivity and tolerability ⁷. In clinical trials, pemafibrate showed robust lowering of TG, remnant cholesterol and apolipoprotein (apo)CIII, and a favourable safety profile (8-11). The next logical step was to investigate whether lowering TG with pemafibrate would reduce cardiovascular events in high-risk patients, specifically those with type 2 diabetes and atherogenic dyslipidemia on intense statin therapy.

PROMINENT (Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with diabetes) was designed to answer this question ¹². Disappointingly, however, the results from the trial were neutral. Despite lowering TG, very low-density lipoprotein cholesterol, remnant cholesterol, and apoCIII by 20 to 30%, pemafibrate did not impact cardiovascular event rates in patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, low HDL-C, and well-controlled low-density lipoprotein cholesterol (LDL-C) levels ¹³. These results were similar across the various subgroups, including those with and without cardiovascular disease, or with TG above or below the population median ¹³.

What are the messages that we can take from PROMINENT? The lack of significant effect with pemafibrate in high-risk patients with low LDL-C levels (median LDL-C at baseline 78 mg/dL or 2.0 mmol/L), reinforces LDL-C as the prime driver of lipid-related residual risk. In support, two major prospective studies with PCSK9 monoclonal antibody therapy (FOURIER and ODYSSEY OUTCOMES) showed that in patients with controlled LDL-C levels on intense statin therapy (~90 mg/dL or 2.3 mmol/L), further lowering LDL-C by 50-60% significantly reduced major adverse cardiovascular events by 15% over the relatively short duration of the trials (<3 years) ^14,15. Another interpretation, however, is that the mode of action of TG lowering is relevant. Indeed, this is a valid consideration given the complexity of pathways involved in the regulation of TG levels and the metabolic processing of TRL and their remnants. It may be necessary to target both remnant formation and clearance pathways to deliver clinically meaningful cardiovascular benefit ¹⁶. Other novel TG-lowering therapeutics in development may provide answers to this question.

Insights from the PROMINENT safety data also merit discussion. Compared with placebo, the pemafibrate group showed increases in venous thromboembolism events and renal adverse events. These findings are perhaps not unexpected given similar prior observations with fenofibrate ¹⁷. A novel finding, however, was reduction in hepatic adverse events (219 versus 265, hazard ratio 0.83, 95% CI 0.69–0.99) and investigator-reported non-alcoholic fatty liver (155 versus 200, hazard ratio 0.78, 95% CI 0.63–0.96) ¹³. Although requiring validation, these results suggest that pemafibrate may have therapeutic potential in the setting of non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction) associated fatty liver disease (MAFLD), in accordance with changed nomenclature ¹⁸. In support, mechanistic studies showed that pemafibrate improved non-alcoholic steatohepatitis (NASH) and prevented disease progression in rodent NASH models (19,20), and a phase 2 trial showed that treatment with pemafibrate for up to 72 weeks improved magnetic resonance elastography -based liver stiffness ²¹. Given the scale of the MAFLD pandemic, already affecting up to 30% of the worldwide population ²², further study is clearly merited. An ongoing trial is investigating the potential of pemafibrate in patients with NASH with liver fibrosis ²³.

In conclusion, although PROMINENT was a neutral trial, exploratory data have opened the door to the possibility of alternative indications for pemafibrate. Given that management of MAFLD represents a major unmet clinic need, an ongoing trial with pemafibrate in this setting offers new opportunities. The SPPARMα story in cardiometabolic risk continues.

References

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