Modest Lp(a) lowering with PCSK9 inhibitor not enough to reduce arterial wall inflammation
Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment
Introduction and methods
Lipoprotein(a) [Lp(a)], composed of an apolipoprotein(a) tail covalently bound to an LDL-c core, is a potential, independent and causal risk factor for CVD. The Lp(a)-mediated risk is partly driven by pro-inflammatory oxidized phospholipids (OxPL), which are present on the apo(a) tail [1,2]. In patients with elevated Lp(a) levels, Lp(a)-associated OxPL act as crucial intermediates in arterial wall inflammation [3].
To date, no potent Lp(a)-lowering therapies are available, thus it is recommended to target other modifiable CVD risk factors to lower CVD risk in individuals with high Lp(a)[4]. Monoclonal antibodies directed at PCSK9 not only lower LDL-c levels, but also modestly reduce Lp(a). In patients without elevated Lp(a) levels, the PCSK9 inhibitor evolocumab was shown to lower Lp(a) by about 20-30% [5]. A posthoc analysis of FOURIER data showed that patients with elevated baseline Lp(a) showed greater absolute CVD risk reduction after evolocumab treatment [6], although they had a smaller percent reduction in Lp(a) levels than seen in those with normal Lp(a) levels at baseline [7]. Thus, low Lp(a) levels were not achieved with PCSK9 inhibition.
The multicenter phase 3b, double-blind ANITSCHKOW study evaluated whether potent LDL-c lowering combined with modest Lp(a) lowering with evolocumab attenuates arterial inflammation as a surrogate for CVD risk in patients with elevated Lp(a). Eligible patients had a fasting LDL-C of
≥2.6mmol/L (100mg/dL), an Lp(a) level of ≥125 nmol/L (50mg/dL). Patients also had arterial wall inflammation as assessed by a most diseased segment target-to-background ratio (MDS TBR) of >_1.6 in an index vessel measured with 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT). 129 Patients were randomized to monthly subcutaneous injections of either evolocumab 420 mg or placebo, for 16 weeks. Mean (SD) LDL-c level at baseline was 3.7 (1.0) mmol/L [144.0 (39.7) mg/dL] and median (IQR) Lp(a) level was 200.0 (155.5, 301.5) nmol/L [80.0 (62.5-121.0) mg/dL) in the total study population.
Main results
- Treatment with evolocumab significantly reduced LDL-c at week 16 by 60.7% (95%CI: -65.8 to -55.5, P<0.0001) as compared with placebo. In the evolocumab-treated group, mean LDL-c at week 16 was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL).
- After treatment with evolocumab, a mean percent change in Lp(a) from baseline of -13.9% (95%CI: -19.3 to 08.5%, P<0.0001) was seen, as compared with placebo.
- Median absolute changes in Lp(a) were -28.0 (IQR: -56.5 to 9.0) nmol/L [-11.2 IQR: -22.6 to 3.6) mg/dL] for evolocumab vs. 1.5 (-19.o to 18.0) nmol/L [0.6 (7.6 to 7.2) mg/dL] for placebo. The median Lp(a) level at week 16 in the evolocumab group was 188.0 (IQR: 140.0-268.0) nmol/L [75.2 (IQR: 56.0-107.2) mg/dL].
- Least square (LS) mean percentage change from baseline in MDS TBR of the index vessel was -8.3% (95%CI: -11.6 to -5.0%) in those treated with evolocumab, compared with -5.3% (95%CI: -8.6% to -2.0%) in the placebo group. No significant treatment difference was observed (-3.00, 95%CI: -7.40 to 1.39, P=0.18).
- In evolocumab-treated patients, the effect on MDS TBR of the index vessel did not depend on baseline statin use.
- No significant correlation was found between baseline Lp(a) and baseline MDS TBR (Pearson correlation coefficient R= -0.05, P=0.61), nor between baseline Lp(a) and baseline MDS TBR (R= -0.06, P=0.48).
- Absolute change in LDL-c or Lp(a) were not correlated to change in MDS TBR in patients receiving evolocumab (LDL-c: R=0.01, P=0.95; Lp(a): R=-0.16, P=0.21).
Conclusion
This study demonstrated that 16 weeks of treatment with evolocumab did not significantly alter arterial wall inflammation, as assessed by MDS TBR of the index vessel in patients with elevated Lp(a) levels. This implies that in these patients with persistently elevated Lp(a) levels, 16 weeks of potent LDL-c reduction (mean: ~61%) and modest Lp(a) reduction (mean: ~14%) failed to attenuate the pro-inflammatory state of the arterial wall. These findings support further evaluation of more potent Lp(a) lowering strategies to reduce arterial wall inflammation, and ultimately to improve CV outcomes.
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