Prevalence and distributions of severely elevated low-density lipoprotein cholesterol (LDL-c) according to age, gender and clinic location among patients in the Malaysian primary care

BackgroundAdults with severely elevated low-density lipoprotein cholesterol (LDL-c) may have familial hypercholesterolaemia (FH) and are at high risk of atherosclerotic cardiovascular disease (ASCVD). The prevalence of elevated LDL-c in primary care clinics in Malaysia is not known. Therefore, this study aimed to determine the prevalence and distributions of severely elevated LDL-c among adult patients attending public primary care clinics in Malaysia.MethodsA cross-sectional study was conducted at 11 public primary care clinics in the central states of Malaysia, among adults ≥18 years old with LDL-c recorded in the electronic medical record. Sociodemographic and LDL-c data from 2018 to 2020 were extracted. Severely elevated LDL-c was defined as ≥4 mmol/L, which were further classified into: 4.0–4.9, 5.0–5.9, 6.0–6.9 and ≥ 7 mmol/L.ResultsOut of 139,702 patients, 44,374 (31.8 %) had severely elevated LDL-c of ≥4 mmol/L of which the majority were females (56.7 %). The mean (±SD) age of patients with severely elevated LDL-c was younger at 56.3 (±13.2) years compared to those with LDL-c of <4.0 mmol/L at 59.3 (±14.5) years. In terms of LDL-c levels, 30,751 (69.3 %), 10,412 (23.5 %), 2,499 (5.6 %) and 712 (1.6 %) were in the 4.0–4.9, 5.0–5.9, 6.0–6.9 and ≥ 7 mmol/L categories, respectively.ConclusionThe prevalence of severely elevated LDL-c of ≥4.0 mmol/L among adult patients in public primary care clinics was high. These patients need to be further investigated for secondary and inherited causes such as FH. Therapeutic lifestyle modification and pharmacological management are pivotal to prevent ASCVD in these patients

Case Series of Genetically Confirmed Index Cases of Familial Hypercholesterolemia in Primary Care

BACKGROUND: In Malaysia, the prevalence of genetically confirmed heterozygous familial hypercholesterolemia (FH) was reported as 1 in 427. Despite this, FH remains largely underdiagnosed and undertreated in primary care.CASE REPORT: In this case series, we report 3 FH cases detected in primary care due to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein-B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. The mutations in case 1 (frameshift c.660del pathogenic variant in LDLR gene) and case 2 (missense c.10579C>T pathogenic variant in APOB gene) were confirmed as pathogenic, while the mutation in case 3 (missense c.277C>T mutation in PCSK9 gene) may have been benign. In case 1, the patient had the highest LDL-c level, 8.6 mmol/L, and prominent tendon xanthomas. In case 2, the patient had an LDL-c level of 5.7 mmol/L and premature corneal arcus. In case 3, the patient had an LDL-c level of 5.4 mmol/L but had neither of the classical physical findings. Genetic counseling and diagnosis were delivered by primary care physicians. These index cases were initially managed in primary care with statins and therapeutic lifestyle modifications. They were referred to the lipid specialists for up-titration of lipid lowering medications. First-degree relatives were identified and referred for cascade testing.CONCLUSIONS: This case series highlights different phenotypical expressions in patients with 3 different FH genetic mutations. Primary care physicians should play a pivotal role in the detection of FH index cases, genetic testing, management, and cascade screening of family members, in partnership with lipid specialists

Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study

Background:Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool.Objective:This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting.Methods:This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the “think-aloud” methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool.Results:The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023.Conclusions:This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients’ perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease.International Registered Report Identifier (IRRID):DERR1-10.2196/4791