Management of Dyslipidemia With Evolocumab in Kidney Transplant Recipients

Proprotein convertase subtilisin/kexin type 9 inhibitors have been shown to reduce major adverse cardiovascular events in very high cardiovascular risk patients, even with chronic kidney disease.1 However, the experience is very scarce in kidney transplant (KT) recipients.2–4 We performed a prospective cohort study of KT recipients who were started on evolocumab in our hospital (September 15, 2022–May 11, 2023) and were followed for at least 6 mo. The criteria for its prescription were not achieving therapeutic low-density lipoprotein cholesterol (c-LDL) goals despite high-potency statins and ezetimibe treatment or adverse effects of statins (myalgias and hypertransaminasemia). Total cholesterol, c-LDL, triglycerides, estimated glomerular filtration rate (eGFR), and albuminuria were compared at baseline, first, third, and sixth months after starting the treatment. We also collected drug-related adverse effects and immunosuppressive trough levels. In this period, 13 KT recipients were started on evolocumab (Table 1). Previous lipid-lowering treatments were continued. The mean KT vintage was 32.4 mo and 69.2% of recipients had a personal history of ischemic heart disease. The median follow-up was 7 mo. TABLE 1. - Characteristic and laboratory data of patients included in the study Characteristics Values Receptor Male, n (%) 8 (61.5) Age, y, mean (SD) 61.9 (7.1) HBP, n (%) 13 (100) Diabetes, n (%) 6 (46.2) Coronary heart disease, n (%) 9 (69.2) KT vintage, mo, mean (SD) 32.4 (19.7) PRA, medium (IQR) % 0 (35.3) Cold ischemia time, h, mean (SD) 16.5 (6.6) sCr, mg/dL, mean (SD) 1.6 (0.5) eGFR at baseline, mL/min/1.73 m2, mean (SD) 49 (21.3) Albuminuria at baseline, mg/g, medium (IQR) 210.6 (640.4–48.6) Tacrolimus levels at baseline, ng/mL, mean (SD) 6.7 (1.8) Total cholesterol at baseline, mg/dL, mean (SD) 190.8 (44) c-LDL at baseline, mg/dL, mean (SD) 102.9 (39.1) Triglycerides at baseline, mg/dL, mean (SD) 185.1 (95.8) Previous lipid-lowering treatment, n (%) High-potency statins + ezetimibe Ezetimibe 12 (92.3)1 (7.7) Reason to PCSK9i prescription, n (%) Not achieving c-LDL goals despite optimal treatment Statins adverse effects 12 (92.3)1 (7.7) Donor Male, n (%) 10 (76.9) Age, y, mean (SD) 53.4 (14.5) Living donor, n (%) 1 (7.7) Brain-dead donor, n (%) 7 (53.8) Donor after circulatory death, n (%) 5 (38.5) Baseline laboratory variables and after starting the treatment Values P Total cholesterol, mg/dL, mean (SD) Baseline 192.8 (47.7) First month 137.8 (56.6) 0.239 Third month 109.4 (35.4) 0.008 Sixth month 108.2 (23.9) <0.001 c-LDL, mg/dL, mean (SD) Baseline 107.8 (45.5) First month 46.9 (44.5) 0.107 Third month 31.4 (31.7) 0.009 Sixth month 29.8 (22.8) 0.002 Triglycerides, mg/dL, mean (SD) Baseline 205.8 (108.6) First month 160.2 (50.6) 0.706 Third month 144.2 (76.2) 0.133 Sixth month 146.2 (81) 0.252 eGFR, mL/min/1.73 m2, mean (SD) Baseline 53.5 (21.3) First month 53.3 (21.2) 1 Third month 54.1 (20.9) 1 Sixth month 55.5 (12.8) 1 Albuminuria, mg/g, median (IQR) Baseline 210.6 (640.4–48.6) First month 81.6 (453.4–19.9) 0.269 Third month 95.5 (299.2–30.6) Sixth month 128.3 (348.3–22.9) Tacrolimus levels, ng/mL, mean (SD) Baseline 7.1 (2) First month 6.6 (1.6) 1 Third month 6.2 (1.7) 1 Sixth month 6.6 (1.6) 1 Tacrolimus dose, mg/d, mean SD Baseline 4.3 (1.9) First month 4.3 (1.1) 0.188 Third month 3.3 (1.4) Sixth month 3 (2) c-LDL, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; HBP, high blood pressure; IQR, interquartile range; KT, kidney transplant; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; PRA, panel reactive antibody; sCr, serum creatinine. The mean baseline c-LDL was 102.9 mg/dL and eGFR was 49 mL/min/1.73 m2. In the third month after starting the treatment, we observed a reduction in cholesterol and c-LDL (P = 0.008, P = 0.009), which was maintained at 6 mo (P < 0.001, P = 0.002). However, no differences were found in the levels of triglycerides, eGFR, albuminuria, and plasma immunosuppressants (Figure 1). No cases of acute rejection or adverse effects were reported. In 5 patients, anti-HLA antibodies were determined as a part of their routine follow-up 6 mo after the drug prescription and were negative.FIGURE 1.: Baseline laboratory variables and after starting the treatment. Alb, albuminuria; c-LDL, low-density lipoprotein cholesterol; eGFR, estimated glomerular; Tac, tacrolimus; TC, total cholesterol; Tgl, triglyceride.We present the largest cohort of KT recipients treated with evolocumab so far. The evidence with proprotein convertase subtilisin/kexin type 9 inhibitors is mostly based on heart transplant recipients,2 whereas only 2 cases of KT recipients treated with alirocumab have been published.3,4 However, in the general population, evolocumab has been reported to be more effective in reducing cardiovascular events than alirocumab.5 In our experience, we observed good results with evolocumab, because total cholesterol and c-LDL reduced rapidly after starting the treatment. Furthermore, renal function remained stable and no change in proteinuria and no other safety concerns reported. The evolocumab data sheet warns of an increase in upper respiratory tract infections.5 In contrast, one of the cases previously mentioned presented a case of severe pneumonia in a KT recipient treated with everolimus shortly after starting alirocumab, which may raise concerns about potential interactions with immunosuppressants.3 Thus, close monitoring is recommended in these cases. However, its degradation does not involve cytochrome P450-mediated metabolism, so it rarely interacts with most immunosuppressants in KT, thus becoming a safe option.1 In our case, neither tacrolimus nor everolimus trough levels remained unchanged, and no immunological adverse outcomes were notified. This is a small cohort and the follow-up is limited. However, due to the high frequency and severity of cardiovascular disease in KT recipients, our results support the use of evolocumab in very high cardiovascular risk patients who do not achieve an adequate lipid profile with standard lipid-lowering therapy. More studies in this population and with longer follow-ups are needed to assess the benefits of KT recipients and graft survival.