Germany
Germany (Deutschland)
PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function (GCKD)
There's very little that needs to be said about the Germans. Winners of four (4) FIFA World Cup trophies (second only to Brazil), Germany is considered the most successful team in FIFA World Cup play: having played in eight (8) championship matches.
Their chances at this year's FIFA Tournament are as good as their chances in the NephroWorldCup by addressing the (relatively) new kid on the block of cardiovascular disease: PCSK9 (Figure 1). Proprotein convertase subtilisin/kexin type 9 (yeah....just stick with the acronym) impairs the uptake of LDL by hepatocytes: resulting in atherosclerotic plaque formation. Numerous studies are underway to assess the effectiveness of PCSK9 inhibitors (inclisiran; evolocumab) in plaque development and cardiovascular outcomes, especially since the current data suggests a once or twice yearly administration of the inhibitor can control plaque formation (Figure 2).
Carousel 1: Subgroup analysis of the FOURIER trial | Presented at the 2018 American Society of Nephrology annual meeting | Courtesy of Drs. David Charytan and Brendon Neuen.
Figure 1: PCSK9 | Presented at the 2022 European Renal Association meeting | Courtesy of Dr. Rafael Valdez
The German team expands on the PCSK9 story by taking it into the world of kidney disease. Are PCSK9 levels elevated in CKD? And do these elevations have a correlation with cardiovascular disease in these patients? We know from previous subgroup studies (e.g., the FOURIER trial) that PCSK9 inhibitors (evolocumab) can reduce LDL levels and Kaplan-Meier events in patients with mild CKD (Carousel 1).
Unfortunately, trials like FOURIER offer a glimpse into the PCSK9 story in patients with CKD. Most available evidence today studying the connection between PCSK9 levels and CKD progression or cardiovascular mortality is equivocal (Carousel 2). Hence the need to start back at zero with an analysis of this German Chronic Kidney Disease (GCKD) prospective cohort study.
In this study, researchers analyzed the PCSK9 levels of 5138 patients with CKD (eGFR 30-60 mL/min/1.73s square meter or eGFR > 60 mL/min/1.73 square meter and UACR > 300 mg/g). They correlated those PCSK9 levels with the incidence of major adverse cardiovascular events (three-point or four-point MACE). Three-point MACE comprised of:
death from cardiovascular cause (MI, CAD, sudden death, ischemic stroke)
acute non-fatal MI (STEMI or NSTEMI)
non-fatal stroke.
Four-point MACE comprised of the three-point MACE plus
fatal peripheral ischemia, amputation due to PVD, and surgical revascularization due to PVD.
After a 6.5 year median follow-up period, levels of PCSK9 did not form a linear relationship with the onset of three- or four-point MACE (Carousel 3).
Carousel 3: Primary outcomes: three- and four-point MACE by PCSK9 level
Model 1: adjusted for age, se, eGFR, UACR
Model 1b: adjusted for Model 1 components + statin treatment
Model 2: adjusted for Model 1b components + HDL, Lp(a), hs-CRP, diabetes, HTN, 🚬, baseline cardiovascular disease
Model 3: adjusted for Model 2 components + LDL
PCSK9 levels were then grouped into one of four quartiles. With increasingly higher quartile levels the incidence of both cardiovascular outcomes increased (baseline: quartile 1) (Carousel 4). This finding was specific for those CKD patients with a prevalent history of cardiovascular disease; CKD patients who did not have prevalent cardiovascular disease did not have a higher incidence of three- or four-point MACE with increasing PCSK9 quartiles.
Carousel 4: Primary outcomes: three- and four-point MACE by PCSK9 quartile
Where does the German team take us on the PCSK9 journey? Like much of the evidence currently available, this study does not clarify the connection between PCSK9 and cardiovascular events in patients with CKD. Add to this mystery the persistently unclear link between LDL cholesterol and the development of CKD/ESRD, and we need to turn our attention to new mechanisms and biomarkers that may explain a connection. PCSK9 appears to be a novel pathway in non-CKD patients. The German squad makes a strong attempt to show such a connection in CKD patients but misses the mark.
Targeting PCSK9 levels in the CKD population remains an area of untapped research potential and should open the door for novel therapies in the armamentarium of nephrologists, cardiologists and general practitioners.