Patient characteristics and laboratory parameters at baseline
We identified 237 eligible patients who received Alirocumab or Evolocumab (104 and 133 patients) between January 2016 and September 2019.
The median age of the population was 65.2 years (interquartile range [IQR] 57.8 – 71.5), 47.7% were female. Almost all patients (97.5%; n=231) received PCSK9 inhibitors for secondary prevention.
Medical history included 74.7% (n=177) coronary heart disease, 46.4% (n=110) at least one percutaneous coronary intervention, 16.0% (n=38) coronary artery bypass graft (CABG), 13.5% (n=32) stroke or transient ischemic attack, 30.8% (n=73) carotid artery stenosis, 18.1% (n=43) peripheral artery disease, and 9.7% (n=23) chronic kidney disease. Any type of familial hypercholesterolemia (mostly diagnosed using clinical criteria, no one identified with homozygous FH) was present in 21.5% (n=51) of the patients. The following relevant comorbidities were identified at baseline: arterial hypertension (68.8%; n=163), diabetes mellitus (25.3%; n=60) (10.0% [n=6] type 1, 86.6% [n=52] type 2, and 3.3% [n=2] other forms) and active smoker status (5.9%; n=14).
Out of the 237 included patients, 83.1% (n=197) reported intolerance to at least one statin, 44.7% (n=106) reported side-effects to ezetimibe. 42.6% (n=101) indicated statin and ezetimibe intolerance.
The full characteristics of the patient cohort including the distribution among PCSK9 treatment agent are listed in Table 1.
The majority of patients (n= 231; 97.5%) received PCSK9 inhibitor therapy for secondary prevention. Apart from hypercholesterolemia, more than half of the study population (53.6%) had two or more additional cardiovascular risk factors (arterial hypertension, chronic kidney disease, Age ≥ 65 years, diabetes mellitus, smoking). About one third (31.2%) had clinical manifest vascular disease affecting two or more sites (coronary heart disease, stroke or TIA, peripheral or carotid artery disease). Table 2 indicates further comorbidities present at baseline.
At baseline LDL-C levels were ≥100 mg/dl in 86.9% of the patients, ≥150 mg/dl in 46.4% and ≥200 mg/dl in 18.6% (Figure 1). Two patients were prescribed PCSK9 inhibitor therapy despite LDL-C ≤55 mg/dl because they were at high cardiovascular risk (secondary prevention), but required discontinuation of statin therapy due to side effects.
At the time of the first prescription of a PCSK9 inhibitor 29.5% of the patients were on statin therapy (mostly rosuvastatin or atorvastatin, Table 3), 39.7% on ezetimibe and 2.5% on fibrates. 48.9% did not receive lipid-lowering medication (i.e. no statins, ezetimibe or fibrates) at that time. Statin intolerance was reported in 83.1% of the patients.
Effect on LDL Cholesterol Levels
Due to the retrospective design of this study, we were not able to ascertain laboratory data at predefined time-points from all patients (i.e. every 3 months after therapy initiation) due to loss of follow-up, discontinuation of treatment or infrequent outpatient clinic visits. Ten patients (4.2%) discontinued PCSK9 inhibitor therapy (five after 3 months from baseline, one after 6 months, one after 9 months, three after 12 months) and were not further included in the analysis after discontinuation. 35 patients (14.8%) were lost to follow-up (missing documentation regarding PCSK9 inhibitor therapy ≥1 year).
Time-course changes of LDL-C are shown in Figure 2. During course of treatment, a substantial proportion of patients achieved LDL-C levels ≤70 mg/dl or ≤55 mg/dl. However, in some patients LDL-C remained above 100 mg/dl during the course of treatment (16.5% after 3 to 6 months, in 16.5% after 6 to 9 months, in 13.4% after 9 to 12 months, in 21.3% after 12 to 18 months).
As illustrated in Figure 3 and Supplemental Table 1, a relevant LDL-C reduction from baseline level and a stable median percentage reduction in LDL-C (-58.3% [45.4 – 70.5] after 3 to 6 months; -54.9% [44.4 – 57.3] after 6 to 9 months; -58.1% [47.5 – 68.3] after 9 to 12 months; -53.2% [42.6 – 67.1] after 12 to 18 months was found over time.
As illustrated in Figure 2, a reduction of ≥50% from baseline LDL-C level was achieved in 66.9% of the patients after 3 to 6 months, 61.7% after 6 to 9 months, 70.1% after 9 to 12 months, and 56.2% after 12 to 18 months.
Triglyceride levels slightly decreased compared to median level of 138 (99 – 215) mg/dl at baseline, to 120 (80 – 193) mg/dl after 3 to 6 months; 104 (72 – 171) mg/dl after 6 to 9 months; 115 (89 – 169) mg/dl after 9 to 12 months; 111 (84 – 177) mg/dl after 12 to 18 months. Median percentage changes are shown in Supplemental Table 2.
Considering lipid-lowering medication at baseline (i.e. patients taking neither statins nor ezetimibe at baseline; patients taking statins at baseline; patients taking ezetimibe at baseline; patients taking statins and ezetimibe at baseline), the median level of LDL-C differed significantly between these groups at baseline (p<0.001), after 3 to 6 months from baseline (p = 0.001), after 6 to 9 months from baseline (p=0.018), after 9 to 12 months (p=0.001). No statistical significance (p=0.079) was found after 12 to 18 months (Supplemental Table 3). The median LDL-C levels of the groups are illustrated in Figure 3. After initiation of PSCK9-inhibitor therapy, there was no difference in the percentage reduction of LDL-C between these groups (Supplemental Table 4).
Concurrent lipid-lowering medication was only assessed at baseline; dose adjustments or discontinuations of additional lipid-lowering treatment over time were not considered in the analysis.
In a separate analysis there was no significant difference in LDL reduction when people with diabetes were compared to those without diabetes at baseline (Supplemental Table 5).
Effect on HbA1c Levels
The baseline HbA1c of the overall cohort was 41 mmol/mol (37-49). HbA1c level did not significantly change over time: 1 to 3 months (42 mmol/mol [38-50; p=0.268]), 3 to 6 months (40 mmol/mol [37-52; p=0.666]), 6 to 9 months (43 mmol/mol [37-52; p=0.349]), 9 to 12 months (41 mmol/mol [37-48; p=0.397]), and 12-18 months (40 mmol/mol [37-48; p=0.195]).
The baseline HbA1c level of patients diagnosed with any type of diabetes mellitus was 52 mmol/mol (48-60). Also in these patients no significant changes were observed over time: 1-3 months (51 mmol/mol [45–59; p=0.696]), 3-6 months (54 mmol/mol [45–65; p=0.726]), 6-9 months (53 mmol/mol [47–57; p=0.812]), 9-12 months (52 mmol/mol [46– 56; p=0.812]), and 12-18 months (49 mmol/mol, [44–56; p=0.325]). Detailed data on HbA1c can be found in the Supplementary Appendix (Supplemental Table 6 and Supplemental Table 7).
Therapy Adjustments, Discontinuation, Adverse Effects
In eight patients, adjustments of the PCSK9 inhibitor agent (i.e. change from Alirocumab to Evolocumab and vice versa) occurred. Eight patients discontinued PCSK9 inhibitor treatment due to side-effects (mostly because of joint or muscle pain, skin lesions or pruritus, or gastrointestinal symptoms), one discontinued PCSK9 inhibitor treatment because of insufficient response the therapy and one did not fulfill the criteria for health insurance coverage of PCSK9 inhibitor treatment (ongoing smoking). Adverse effects to PCSK9 inhibitor therapy were documented in 27 patients; all of the reported effects were of mild quality. Side effects associated with the PCSK9 inhibitor therapy are shown in Table 4. The most frequent side effects were joint or muscle pain (ten patients), rhinitis (five patients), flu-like symptoms (five patients), fatigue (four patients), skin lesions or pruritus (four patients). Side effects were reported by the patients, documented in patient letters and were not systematically inquired.