Management of familial hypercholesterolaemia in Hong Kong

Risk of premature ASCVD in FH patients
FH is a common hereditary disorder of lipid metabolism characterized by high circulating levels of LDL-C caused by defects in genes related to LDL clearance. [J Endocr Soc 2021;doi:10.1210/jendso/bvaa122] Loss-of-function mutations in the LDL receptor or apolipoprotein B genes or gain-of-function mutations in the PCSK9 gene result in marked elevation of plasma LDL-C levels from birth. Estimated prevalence of heterozygous FH (HeFH) in Hong Kong is 1/300. [J Atheroscler Thromb 2021;28:417-434] On the other hand, homozygous FH (HoFH) is considerably rarer, with an estimated prevalence of 1/300,000 based on a Dutch population sample. [Eur Heart J 2015;36:560-565]

“Chronic exposure to high levels of circulating LDL-C since a young age leads to premature development of ASCVD,” said Lui. “Compared with patients with non-FH, FH mutation carriers have higher cumulative exposureto LDL-C and as a result have a much higher risk of coronary artery disease [CAD].”

A gene sequencing study involving >26,000 participants with and without CAD found a 22-fold greater risk of CAD in FH mutation carriers with LDL-C level ≥190 mg/dL (≥4.9 mmol/L) vs control participants with no FH mutations whose LDL-C level was <130 mg/dL (<3.4 mmol/L) (odds ratio [OR], 22.3; 95 percent confidence interval [CI], 10.7–53.2). In contrast, participants with LDL-C level ≥190 mg/dL (≥4.9 mmol/L) and no FH mutations had a 6-fold higher risk of CAD vs controls (OR, 6.0; 95 percent CI, 5.2–6.9). [J Am Coll Cardiol 2016;67:2578-2589]

Treatment strategy
“Since the prognosis of FH largely depends on LDL-C levels, the treatment strategy is aimed at reducing LDL-C levels,” explained Lui. “Effective control of LDL-C significantly reduces CV morbidity and mortality in FH, and treatment should start as early as possible.” [J Endocr Soc 2021;doi:10.1210/jendso/bvaa122]

Physicians in Hong Kong commonly use the 2019 guidelines by the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) for FH management, which set an LDL-C target of <1.8 mmol/L along with ≥50 percent reduction from baseline for FH patients without other major risk factors. FH patients with ASCVD or another major risk factor (eg, diabetes, hypertension, obesity) should aim for LDL-C <1.4 mmol/L in addition to ≥50 percent reduction from baseline. [Eur Heart J 2020;41:111-188]

Statin monotherapy may not be sufficient
“Available therapeutic options are similar for familial and other types of hypercholesterolaemia. The challenge is attaining the lower LDL-C target set for FH, which some patients cannot achieve with statin therapy alone and thus require additional agents,” said Lui.

Statins, along with dietary and lifestyle modifications and smoking cessation, significantly improve prognosis and are the cornerstone of FH management. [J Endocr Soc 2021;doi:10.1210/jendso/bvaa122] A long-term cohort study in >2,000 FH patients without coronary heart disease (CHD) at baseline showed that statin-treated patients had an overall 76 percent lower risk of CHD onset vs untreated patients (hazard ratio, 0.24; 95 percent CI, 0.18–0.30). [BMJ 2008;337:a2423]

Statins have also demonstrated efficacy in HoFH. A large cohort study of HoFH patients showed that lipid-lowering therapy (predominantly statins) reduced total mortality and major CV events (66 percent and 51 percent reduction, respectively, vs no treatment), even though the mean reduction in LDL-C level was only 26.4 percent in these patients (n=149). [Circulation 2011;124:2202-2207]

The extent of LDL-C reduction with statins may be lower for FH patients vs patients with other types of hypercholesterolaemia. In a study of nearly 400 Chinese patients with different types of hypercholesterolaemia treated with rosuvastatin 10 mg daily, the 166 patients with FH had a 2.6 percent smaller reduction in LDL-C levels vs patients without FH (p<0.05). [Pharmacogenet Genomics 2010;20:634-637] “There is interindividual variability in terms of response to statins,” remarked Lui.

In Hong Kong, all adult FH patients are offered statin therapy. When the LDL-C goal is not achieved despite high-intensity statin therapy, add-on ezetimibe is recommended as the second-line therapy and can further reduce LDL-C levels by 24 percent when used in combination with a statin. [J Endocr Soc 2021;doi:10.1210/jendso/bvaa122]

“In Hong Kong, some patients with HoFH or severe HeFH not controlled by pharmacotherapy receive plasmapheresis, which is carried out in a day-centre setting once every few weeks, depending on LDL-C control and patient preference,” added Lui.

Role of evolocumab
“For patients who fail to achieve their target LDL-C level with maximally tolerated statin and ezetimibe, we add a PCSK9 inhibitor to further reduce LDL-C level,” said Lui.

Evolocumab is a PCSK9 inhibitor with proven long-term efficacy and safety in HoFH and HeFH patients.

TESLA Part B was a double-blind phase III trial of evolocumab (n=33) vs placebo (n=16) in patients with HoFH on stable lipid-lowering therapy. Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL-C at 12 weeks by 30.9 percent (95 percent CI, -43.9 to -18.0; p<0.0001). Treatment-emergent adverse events (TEAEs) occurred in 36 percent vs 63 percent of patients in the evolocumab vs placebo group. [Lancet 2015;385:341-350]

In the double-blind phase III RUTHERFORD-2 trial, HeFH patients on stable lipid-lowering therapy were randomized to receive evolocumab 140 mg Q2W (n=111), evolocumab 420 mg Q4W (n=110), placebo Q2W (n=55), or placebo Q4W (n=55). Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL-C from baseline at week 12 (140 mg: 59.2 percent reduction; 95 percent CI, 53.4–65.1; 420 mg: 61.3 percent reduction; 95 percent CI, 53.6–69.0; both p<0.0001) and at the mean of week 10 and week 12 (140 mg: 60.2 percent reduction; 95 percent CI, 54.5–65.8; 420 mg: 65.6 percent reduction; 95 percent CI, 59.8–71.3; both p<0.0001). Evolocumab was well tolerated, with rates of AEs similar to placebo. The most common AEs occurring more frequently in evolocumab-treated vs placebo-treated patients were nasopharyngitis (9 percent vs 5 percent) and muscle-related AEs (5 percent vs 1 percent). [Lancet 2015;385:331-340]

Long-term data
“Evolocumab’s long-term ability to sustain LDL-C lowering among FH patients was confirmed by the TAUSSIG trial, where patients received evolocumab for a median of 4.1 years,” said Lui. [J Am Coll Cardiol 2020;75:565-574]

TAUSSIG was an open-label, single-arm study, where 300 patients with HoFH or severe HeFH ≥12 years of age who were on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg Q2W if they were receiving lipoprotein apheresis. After 12 weeks, evolocumab could be uptitrated to 420 mg Q2W in patients not on apheresis.

Mean change in LDL-C from baseline to week 12 was -21.2 percent and -54.9 percent in patients with HoFH and HeFH, respectively, with LDL-C persistently reduced through week 216. Of 48 patients with HoFH whose evolocumab dose was uptitrated, mean change in LDL-C improved from -19.6 percent at week 12 to -29.7 percent after 12 weeks of evolocumab 420 mg Q2W. The adjudicated CV event rate was 2.7 percent per year, which was markedly lower than expected by TAUSSIG investigators, given the high risk of these patients and the event rates observed in other studies. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. (Figure)

A total of 3.7 percent of patients discontinued evolocumab because of TEAEs. Injection-site reactions were mostly minor and did not lead to evolocumab discontinuation. “This is consistent with our clinical experience,” noted Lui. “Evolocumab comes in a prefilled autoinjector with a fine and concealed needle, which most patients are comfortable using.”

No clinically significant changes were reported in fasting blood glucose and HbA_1c. No neutralizing antievolocumab antibodies were detected throughout the study period. Safety results were similar overall for the adolescent group.

There was no notable difference in the safety profile of evolocumab in TAUSSIG compared with previous studies. The most common TEAEs reported in TAUSSIG were nasopharyngitis (17.7 percent), influenza (12.7 percent), upper respiratory tract infection (11.7 percent), headache (11.3 percent), myalgia (10.0 percent), and diarrhoea (10.0 percent).

Final thoughts
“As physicians, we need to raise awareness, both among our colleagues across various specialties and among patients, that LDL-C level is not just a number– it is a very reliable indicator of CV risk. We should educate patients on the importance of treatment and help them achieve their guideline-recommended risk-dependent LDL-C level goals by escalating therapy in a timely manner, from intensifying their statin therapy all the way to adding a PCSK9 inhibitor, if necessary,” advised Lui.