PCSK9i lowers lipids and lipoproteins in familial dysbetalipoproteinemia

Introduction and methods

Background

Familial dysbetalipoproteinemia (FD), also known as “remnant removal disease”, is the second most common monogenic lipid disorder (prevalence 1 in 850–3500), after heterozygous familial hypercholesterolemia [1]. FD is characterized by accumulation of cholesterol-enriched remnants of triglyceride-rich lipoproteins, particularly during the postprandial phase, and is therefore associated with a very high risk of premature CVD [2-4].

As LDL and LDL-c levels are generally low or absent in patients with FD [5,6], treatment goals for this patient population are based on non–HDL-c levels. However, even with optimal therapy, 60% of FD patients do not achieve these goals [2]. Interestingly, in patients with T2DM, PCSK9i treatment resulted in a reduction of postprandial triglyceride-rich lipoproteins by 30%-40% [7-10].

Aim of the study

The study aim was to evaluate the effect of evolocumab added to standard lipid-lowering therapy on levels of fasting and post–fat load lipids and lipoproteins in FD patients.

Methods

The EVOLVE-FD (Effects of EVOLocumab VErsus placebo added to standard lipid-lowering therapy on fasting and post fat load lipids in patients with familial dysbetalipoproteinemia) trial was a randomized, investigator-initiated, placebo-controlled, double-blind, cross-over study conducted at 4 Dutch university medical centers. In this RCT, 28 patients with an FD genotype (confirmed by genotyping or isoelectric focusing) received evolocumab 140 mg subcutaneously every 2 weeks or placebo for 12 weeks. After an 8-week washout period, they were crossed over to the other treatment (evolocumab or placebo) for another 12 weeks.

At the start and end of each treatment period, patients received an oral fat load (unsweetened fresh cream) after a ≥12 hour overnight fast. Before and at several time points after consumption of the fat load, venous blood samples were collected.

Outcomes

The primary endpoint was the 8-hour post–fat load area under the curve (AUC) in non–HDL-c level (the AUC reflects the total exposure of atherogenic lipoproteins in FD after the oral fat load). Secondary endpoints included fasting and post–fat load levels of lipids and lipoproteins.

In addition, the proportion of patients who achieved their non–HDL-c treatment goals (defined as <131 mg/dL [<3.4 mmol/L] for FD patients without CVD and <100 mg/dL [<2.6 mmol/L] for FD patients with established CVD or T2DM) was calculated. The safety of evolocumab was assessed by monitoring adverse events.

Main results

Fasting lipids and lipoproteins

• The mean (± SD) absolute reduction in fasting non–HDL-c levels after 12 weeks of treatment with evolocumab versus placebo was 75 ± 44 mg/dL (1.9 ± 1.1 mmol/L), corresponding to a relative reduction of 51% (95%CI: 43–57; P<0.001).
• The mean relative reduction at 12 weeks for evolocumab versus placebo in fasting levels was for triglycerides 27% (95%CI: 17–36; P<0.001), for total cholesterol 39% (95%CI: 32–45; P<0.001), for apoB 48% (95%CI: 42–53; P<0.001), for VLDL-c 42% (95%CI: 29–53; P<0.001), and for remnant-cholesterol 44% (95%CI: 30–55; P<0.001); the median relative reduction in fasting Lp(a) levels was 35% (95%CI: 16–42; P<0.001).
• The mean fasting HDL-c level after 12 weeks did not differ between the evolocumab and placebo groups (relative difference: –4.3; 95%CI: –10 to –3; P=0.20).
• Similar results were seen when baseline levels were taken into account.

Post–fat load lipids and lipoproteins

• The mean (± SD) absolute reduction in non–HDL-c exposure 8 hours after an oral fat load for evolocumab versus placebo was 590 ± 352 mg/dL.8h (15.3 ± 9.1 mmol/L.8h), corresponding to a relative reduction of 49% (95%CI: 42–55; P<0.001).
• The mean relative reduction at 12 weeks for evolocumab versus placebo in 8-hour post–fat load levels for triglycerides was 20% (95%CI: 10–29; P<0.001), for total cholesterol 38% (95%CI: 31–43; P<0.001), for apoB 47% (95%CI: 41–53; P<0.001), for VLDL-c 45% (95%CI: 32–55; P<0.001), and for remnant-cholesterol 49% (95%CI: 38–59; P<0.001).
• The 8-hour post–fat load HDL-c level after 12 weeks did not differ between the evolocumab and placebo groups (relative difference: –3.4%; 95%CI: –8.5 to –2.1; P=0.21).
• Compared with placebo, evolocumab had no significant effect on the postprandial response (incremental AUC; iAUC) during the 8 hours after consumption of the fat load for any of the lipids and lipoproteins. In fact, for all atherogenic lipoproteins, the reduction in AUC was primarily based on a reduction in fasting concentrations, rather than a change in iAUC.
• Again, the results were similar when baseline levels were taken into account.

Non–HDL-c treatment goals

• After 12 weeks of evolocumab treatment, 89% of the patients achieved their non–HDL-c treatment goal compared with 36% of the placebo-treated patients.
• In addition, 54% of the patients achieved a non–HDL-c reduction >50% in the evolocumab group compared with none in the placebo group.

Adverse events

• In the evolocumab group, 30 adverse events occurred in 13 patients in total, whereas 45 adverse events were reported in a total of 17 patients in the placebo group.
• Most adverse events were mild and temporary, such as nausea, myalgia, and diarrhea.

Conclusion

References

Find this article online at J Clin Lipidol.