Discussion
obesity, NAFLD, SHTG, FCS, T2DM, TG, TG-rich lipoproteins, chronic liver disease, dyslipidemia
OBESITY, FAMILIAL CHYLOMICRONEMIA SYNDROME, CARDIOVASCULAR MORBIDITY, METABOLIC SYNDROME, INSULIN RESISTANCE, ACUTE PANCREATITIS, HEPATIC STEATOSIS, EVENTS, ATHEROGENIC DYSLIPIDEMIA, CHRONIC LIVER DISEASE, DYSLIPIDEMIA
This placebo-controlled, randomized study demonstrated that treatment with the FGF21 analog pegozafermin resulted in significant reductions in TGs in patients with SHTG. Significant reductions were also observed in atherogenic lipoproteins, including non-HDL-C and ApoB, as well as ApoC3, an important regulator of lipoprotein lipase, suggesting pegozafermin reduces production and improves clearance of TG-rich lipoproteins. Whereas the levels of LDL-C remained relatively stable, there was a numerical increase in HDL-C across all doses, most notably at the 27-mg dose; the 27-mg dose was also the most efficacious for reducing TGs and lipoproteins. Every-other-week dosing had less impact across the various outcome parameters, likely due to the pharmacokinetics of the drug and volatility of TG levels.Eligibility criteria allowed for the enrollment of participants on stabilized regimens of approved lipid-modifying therapies (LMTs), such as statins, prescription fish oil and/or fibrates. Approximately 55% of participants enrolled were on background LMT, with a majority on a statin (45% (25% high-intensity statin)), followed by prescription fish oil (14%) and fibrates (7%). Initially, fibrates had been excluded due to potential crosstalk between FGF21 and peroxisome proliferator-activated receptor alpha (PPARα) pathwaysIn the current study, it should be noted that the effect of pegozafermin remained consistent regardless of the presence or absence of background LMT, suggesting that pegozafermin can substantially improve many important lipid parameters when used as an adjunct to diet and exercise or as add-on therapy in patients who are unable to achieve TG < 500 mg dlWhile the primary target for CV risk reduction remains LDL-C, identifying new therapies that can address residual CV risk after LDL treatment is of significant interest. Most clinical trials using therapies that lower TGs (that is, fibrates, niacin and omega-3 fatty acids, with the exception of icosapent ethyl (IPE)) have not demonstrated an add-on reduction in CV events in patients on statin therapyNewer RNA-based therapies (antisense oligonucleotide (ASO) and RNA interference (RNAi)) also are being developed to substantially lower TG in both familial chylomicronemia syndrome (FCS) and SHTG. Early data suggest that traditional ASO approaches may be associated with safety concerns. For example, while volanesorsen (ASO In the 8-week study reported here, pegozafermin substantially reduced TG, non-HDL-C, ApoB and liver fat; increased HDL-C with minimal change in LDL-C; and improved liver transaminases, all while maintaining a favorable safety and tolerability profile. Taken together, these data suggest that pegozafermin provides an overall metabolic benefit with, as yet, no identified safety signals.While patients with SHTG have an elevated risk for CV events, the primary clinical risk in patients with TG ≥ 500 mg dlValdivielso et al. demonstrated that elevated levels of chylomicrons are necessary to trigger acute pancreatitis in the setting of high serum TGsPegozafermin demonstrated a robust 50% reduction of ApoC3 at the 27-mg dose, suggesting that increased lipoprotein lipase activity may contribute to the observed ApoB48 reduction. Indeed, post hoc analyses assessing the correlation between percent change in TG and ApoC3 in the pooled pegozafermin group at week 8 demonstrated a reasonable correlation between the two (Pearson Current guidelines from the National Cholesterol Education Program Adult Treatment Panel III recommend reducing TGs to <500 mg dlPatients with SHTG often have metabolic comorbidities associated with dyslipidemia and insulin resistance, such as obesity, metabolic syndrome, T2DM and NAFLD, further increasing the risk of cardiovascular morbidity and mortality. Dramatic increases in obesity and T2DM over the past decades have exacerbated the development of NAFLD, making it a rising health concern in the United States and globally. NAFLD is currently the most common form of chronic liver disease in the United States and is often considered the hepatic manifestation of metabolic syndrome, a patient population that frequently suffers from atherogenic dyslipidemia. An important finding of the present study was the prevalence of liver fat in this population with SHTG—100% of patients who underwent MRI-PDFF screening had baseline hepatic steatosis, as defined by >5% liver fat (range 6.2–39.2%). Interestingly, baseline MRI-PDFF values did not correlate with baseline TG values, although every patient tested who had a baseline fasting TG level of >500 mg dlPegozafermin therapy demonstrated significant reductions in fat accumulation in the liver, hitting key reduction targets of ≥30% and ≥50% in 88% and 41% of participants, respectively. These are important thresholds as it has been established in the literature that a ≥30% relative reduction in MRI-PDFF is associated with histologic response (categorized as a responder) and that a ≥50% relative reduction in MRI-PDFF evokes a substantially higher histologic response (defined as a super responder)Pegozafermin treatment was able to normalize liver fat to ≤5% in 24% of participants in just 8 weeks. The data presented here report a significant reduction in quantified liver fat with a treatment targeting TG-rich lipoproteins in SHTG and suggest a potential benefit for lowering the risk of severe acute pancreatitis. The mechanism by which pegozafermin lowers liver fat remains to be fully characterized. Based on preclinical data in hepatocytes, FGF21 is thought to affect hepatic steatosis by modulating AMPK phosphorylation to regulate lipid accumulation, reducing sterol regulatory element-binding transcription factor 1 (SREBF1) to inhibit lipid synthesis, increasing In summary, the FGF21 analog pegozafermin substantially reduced atherogenic lipoproteins, ApoC3 and liver fat in patients with SHTG and has the potential to positively impact other aspects of metabolic dysregulation. Indeed, these ‘metabolic patients’ are likely to benefit the most from a therapy that can function as a metabolic regulator across multiple comorbidities. If these findings are confirmed in an appropriately powered phase 3 trial, pegozafermin may be useful to treat SHTG and simultaneously address several other cardiometabolic risk factors.