Bridging the "Know-Do" Gaps in Five Non-Communicable Diseases Using a Common Framework Driven by Implementation Science.

According to the United Nations High-Level Meeting 2018, five non-communicable diseases (NCDs) including cardiovascular diseases, chronic respiratory diseases, diabetes mellitus, cancer, and mental health conditions accounted for two-thirds of global deaths. These five NCDs share five common risk factors including tobacco use, unhealthy diets, physical inactivity, alcohol use, and air pollution. Low- and middle-income countries (LMICs) face larger burden of NCDs than high-income countries (HICs), due to differences in ecological, technological, socioeconomic and health system development. Based on high-level evidence albeit mainly from HICs, the burden caused by NCDs can be reduced by affordable medicines and best practices. However, "know-do" gaps, ie, gaps between what we know in science and what we do in practice, has limited the impact of these strategies, especially in LMICs. Implementation science advocates the use of robust methodologies to evaluate sustainable solutions in health, education and social care aimed at informing practice and policies. In this article, physician researchers with expertise in NCDs reviewed the common challenges shared by these five NCDs with different clinical courses. They explained the principles of implementation science and advocated the use of an evidence-based framework to implement solutions focusing on early detection, prevention and empowerment, supplemented by best practices in HICs and LMICs. These successful stories can be used to motivate policymakers, payors, providers, patients and public to co-design frameworks and implement context-relevant, multi-component, evidence-based practices. In pursuit of this goal, we propose partnership, leadership, and access to continuing care as the three pillars in developing roadmaps for addressing the multiple needs during the journey of a person with or at risk of these five NCDs. By transforming the ecosystem, raising awareness and aligning context-relevant practices and policies with ongoing evaluation, it is possible to make healthcare accessible, affordable and sustainable to reduce the burden of these five NCDs.

A Methodology for Mapping the Patient Journey for Noncommunicable Diseases in Low- and Middle-Income Countries.

Noncommunicable diseases (NCDs) are responsible for 71% of all worldwide mortality each year, and have an exceptionally large impact in low- and middle-income countries (LMICs). However, there is often a lack of local data from these countries to inform practice and policy improvements. Generating locally contextualized evidence base for NCDs that can help identify gaps, aid decision-making and improve patient care in LMICs needs an innovative approach. The approach used in Mapping the Patient Journey Towards Actionable Beyond the Pill Solutions (MAPS) is designed to quantitatively map different stages of the patient journey in four critical NCDs, ie, hypertension, dyslipidemia, depression, and pain (chronic and neuropathic) across selected LMICs in Africa, the Middle East, South East Asia, and Latin America. The key touchpoints along the patient journey include awareness, screening, diagnosis, treatment, adherence, and control or remission. MAPS employs an evidence mapping methodology that follows a three-step semi-systematic review: 1) systematic peer-reviewed database search; 2) unstructured searches of local or real-world data; and 3) expert opinion. Evidence generation and visualization is based on locally validated and deduplicated data published over the last 10 years. This approach will be the first to provide quantitative mapping of the different stages of the patient journey for selected NCDs in LMICs. By focusing on local, patient-centric data, the goal of the MAPS initiative is to address and prioritize local research and knowledge gaps, then contribute to evidence-based, high-quality, and affordable advances in the management of NCDs in LMICs. This will ultimately improve patient outcomes and contribute towards the achievement of global NCD targets.

Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates.

Background: Programs to screen for Familial hypercholesterolemia (FH) are conducted worldwide. In Western societies, these programs have been shown to be cost-effective with hit/detection rates of 1 in 217-250. Thus far, there is no published data on genetic FH in the Gulf region. Using United Arab Emirates as a proxy for the Gulf region, we assessed the prevalence of genetically confirmed FH in the Emirati population sample. Materials and Methods: We recruited 229 patients with LDL-C >95th percentile and employed a customized next generation sequencing pipeline to screen canonical FH genes (LDLR, APOB, PCSK9, LDLRAP1). Results: Participants were characterized by mean total cholesterol and low-density lipoprotein cholesterol (LDL-c) of 6.3 ± 1.1 and 4.7 ± 1.1 mmol/L respectively. Ninety-six percent of the participants were using lipid-lowering medication with mean corrected LDL-c values of 10.0 ± 3.0 mmol/L 15 out of 229 participants were found to suffer from genetically confirmed FH. Carriers of causal genetic variants for FH had higher on-treatment LDL-c compared to those without causal variants (5.7 ± 1.5 vs 4.7 ± 1.0; p = 3.7E-04). The groups did not differ regarding high-density lipoprotein cholesterol, triglycerides, body mass index, blood pressure, glucose, and glycated haemoglobin. Conclusion: This study reveals a low 7% prevalence of genetic FH in Emiratis with marked hypercholesterolemia as determined by correcting LDL-c for the use of lipid-lowering treatment. The portfolio of mutations identified is, to a large extent, unique and includes gene duplications. Our findings warrant further studies into origins of hypercholesterolemia in these patients. This is further supported by the fact that these patients are also characterized by high prevalence of type 2 diabetes (42% in the current study cohort) which already puts them at an increased risk of atherosclerotic cardiovascular disease. These results may also be useful in public health initiatives for FH cascade screening programs in the UAE and maybe the Gulf region.

Statins and autoimmunity: State-of-the-art.

HMG-CoA reductase inhibitors, or statins, are potent plasma LDL-cholesterol (LDL-c) lowering agents. Since the introduction of the first statin, lovastatin, in 1987, accumulating evidence showed that non-cholesterol lowering effects play an important role in their efficacy to reduce atherosclerotic cardiovascular disease (ASCVD). Thus, these non-LDL-c lowering properties could benefit patients with immune-mediated diseases. Statins and their associated immune-modulating roles have recently received much attention. Different statins have been administered in various experimental and clinical studies focused on autoimmunity. The results indicate that statins can modulate immune responses through mevalonate pathway-dependent and -independent mechanisms. The anti-inflammatory and immune-modulating effects include cell adhesion, migration of antigen presenting cells, and differentiation, as well as activation, of T-cells. In various autoimmune diseases (e.g. rheumatoid arthritis, lupus, and multiple sclerosis), promising results have been obtained to date.

Augmenting Flexnerism Via Twitterism: Need for Integrating Social Media Application in Blueprinting Pedagogical Strategies for Undergraduate Medical Education.

BACKGROUND: Flexnerism, or "competency-based medical education," advocates that formal analytic reasoning, the kind of rational thinking fundamental to the basic sciences, especially the natural sciences, should be the foundation of physicians' intellectual training. The complexity of 21st century health care requires rethinking of current (medical) educational paradigms. In this "Millennial Era," promulgation of the tenets of Flexnerism in undergraduate medical education requires a design and blueprint of innovative pedagogical strategies, as the targeted learners are millennials (designated as generation-Y medical students). OBJECTIVE: The aim of this proof-of-concept study was to identify the specific social media app platforms that are selectively preferred by generation-Y medical students in undergraduate medical education. In addition, we aimed to explore if these preferred social media apps can be used to design an effective pedagogical strategy in order to disseminate course learning objectives in the preclinical phase of a spiral curriculum. METHODS: A cross-sectional survey was conducted by distributing a 17-item questionnaire among the first- and second-year medical students in the preclinical phase at the Mohammed Bin Rashid University of Medicine and Health Science. RESULTS: The study identified YouTube and WhatsApp as the social media app platforms preferred by generation-Y medical students in undergraduate medical education. This study also identified the differences between female and male generation-Y medical students in terms of the use of social media apps in medical education, which we believe will assist instructors in designing pedagogical strategies to integrate social media apps. In addition, we determined the perceptions of generation-Y medical students on the implementation of social media apps in medical education. The pedagogical strategy designed using social media apps and implemented in the Biochemistry course was well accepted by generation-Y medical students and can be translated to any course in the preclinical phase of the medical curriculum. Moreover, the identified limitations of this study provide an understanding of the gaps in research in the integration of social media apps in a medical curriculum catering to generation-Y medical students. CONCLUSIONS: 21st century medical education requires effective use of social media app platforms to augment competency-based medical education: Augmentation of Flexnerism in the current scenario is possible only by the adaptation of Twitterism.

A novel 6D-approach to radically transform undergraduate medical education: preliminary reflections from MBRU.

BACKGROUND: Designers of undergraduate medical education (UME) need to address the exponentially expanding volume and variability of scientific knowledge, where by didactic teaching techniques need to be augmented by innovative student-centric pedagogical strategies and implementation of milieus, where information, communication and technology-enabled tools are seamlessly integrated, and lifelong information gathering, assimilation, integration and implementation is the ultimate goal. In UME, the basic sciences provide a solid scaffold allowing students to develop their personal critical decisional framework as well as define the understanding of normal human physiology, pivotal for the identification, categorization and management of pathophysiology. However, most medical schools confine themselves to "stagnant curricula", with the implementation of traditional "teacher centered" pedagogical techniques in the dissemination of the courses pertaining to basic sciences in UME. METHOD: To tackle the above paucity, we present a novel "6D-Approach" for the dissemination of concepts in basic sciences through mentored journal-clubs. The approach is informed by a teaching principle derived from Constructivism. The technique in which the 6D-approach can be implemented in UME, is shown using an example from a first-year course of Molecular Biology and Principles of Genetics at our medical school. A reflection on the impact of 6D-Approach for students as well as instructors is also presented. RESULT: The 6D-approach was positively received by the students and the formal feedback for the course: Molecular Biology and Principles of Genetics, where the approach was repeatedly employed, indicated that students expressed satisfaction with the teaching strategies employed in the course, with ~ 89% of the students in the cohort strongly agreeing with the highest grading score "extremely satisfied". Further, the approach through the use of mentored journal clubs encourages retention of knowledge, critical thinking, metacognition, collaboration and leadership skills in addition to self-evaluation and peer feedback. CONCLUSION: Hence, through the 6D-Approach, our attempt is to initiate, advance and facilitate critical thinking, problem-solving and self-learning in UME, demonstrated by graduating accomplished, competent and safe medical practitioners.

Blending Gagne's Instructional Model with Peyton's Approach to Design an Introductory Bioinformatics Lesson Plan for Medical Students: Proof-of-Concept Study.

BACKGROUND: With the rapid integration of genetics into medicine, it has become evident that practicing physicians as well as medical students and clinical researchers need to be updated on the fundamentals of bioinformatics. To achieve this, the following gaps need to be addressed: a lack of defined learning objectives for "Bioinformatics for Medical Practitioner" courses, an absence of a structured lesson plan to disseminate the learning objectives, and no defined step-by-step strategy to teach the essentials of bioinformatics in the medical curriculum. OBJECTIVE: The objective of this study was to address these gaps to design a streamlined pedagogical strategy for teaching basics of bioinformatics in the undergraduate medical curriculum. METHODS: The established instructional design strategies employed in medical education-Gagne's 9 events of instruction-were followed with further contributions from Peyton's four-step approach to design a structured lesson plan in bioinformatics. RESULTS: First, we defined the specifics of bioinformatics that a medical student or health care professional should be introduced to use this knowledge in a clinical context. Second, we designed a structured lesson plan using a blended approach from both Gagne's and Peyton's instructional models. Lastly, we delineated a step-by-step strategy employing free Web-based bioinformatics module, combining it with a clinical scenario of familial hypercholesterolemia to disseminate the defined specifics of bioinformatics. Implementation of Schon's reflective practice model indicated that the activity was stimulating for the students with favorable outcomes regarding their basic training in bioinformatics. CONCLUSIONS: To the best of our knowledge, the present lesson plan is the first that outlines an effective dissemination strategy for integrating introductory bioinformatics into a medical curriculum. Further, the lesson plan blueprint can be used to develop similar skills in workshops, continuing professional development, or continuing medical education events to introduce bioinformatics to practicing physicians.

Nonadherence to statins: individualized intervention strategies outside the pill box.

Poor adherence to statin therapy is linked to significantly increased risk of cardiovascular events and death. Unfortunately, adherence to statins is far from optimal. This is an alarming concern for patients prescribed potentially life-saving cholesterol-lowering medication, especially for those at high risk of cardiovascular events. Research on statin adherence has only recently garnered broader attention; hence, major reasons unique to adherence to statin therapy need to be identified as well as suggestions for countermeasures. An integrated approach to minimizing barriers and enhancing facilitation at the levels of the patient, provider, and health system can help address adherence issues. Health care professionals including physicians, pharmacists, and nurses have an obligation to improve patient adherence, as routine care. In order to achieve sustained results, a multifaceted approach is indispensable.

Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women.

BACKGROUND: Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in cardiovascular trials and research. This study aims at a better understanding of lifestyle and genetic factors that affect LDL-C in young women. METHODS: We randomly selected for every year of age 8 women with LDL-C ≤1st percentile (≤50 mg/dL) and 8 women with LDL-C ≥99th percentile (≥186 mg/dL) from 28 000 female participants aged between 25 to 40 years of a population-based cohort study. The resulting groups include 119 and 121 women, respectively, of an average 33 years of age. A gene-sequencing panel was used to assess established monogenic and polygenic origins of these phenotypes. Information on lifestyle was extracted from questionnaires. A healthy lifestyle score was allocated based on a recently developed algorithm. RESULTS: Of the women with LDL-C ≤1st percentile, 19 (15.7%) carried mutations that are causing monogenic hypocholesterolemia and 60 (49.6%) were genetically predisposed to low LDL-C on the basis of an extremely low weighted genetic risk score. In comparison with control groups, a healthier lifestyle was not associated with low LDL-C in women without genetic predispositions. Among women with LDL-C ≥99th percentile, 20 women (16.8%) carried mutations that cause familial hypercholesterolemia, whereas 25 (21%) were predisposed to high LDL-C on the basis of a high-weighted genetic risk score. The women in whom no genetic origin for hypercholesterolemia could be identified were found to exhibit a significantly unfavorable lifestyle in comparison with controls. CONCLUSIONS: This study highlights the need for early assessment of the cardiovascular risk profile in apparently healthy young women to identify those with LDL-C ≥99th percentile for their age: first, because, in this study, 17% of the cases were molecularly diagnosed with familial hypercholesterolemia, which needs further attention; second, because our data indicate that an unfavorable lifestyle is significantly associated with severe hypercholesterolemia in genetically unaffected women, which may also need further attention.

Rationale and design of MultiSELECt: A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by lipoprotein apheresis on Cardiovascular outcomes.

BACKGROUND: Dyslipidemia is a well-known risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). While low density lipoprotein cholesterol (LDL-C) is well-established and taken into consideration for risk management and therapy, lipoprotein(a) is another established CVD risk factor frequently not undergoing screening due to a lack of medical treatment options. For patients suffering from CVD due to massive elevation of Lp(a) in presence of normal LDL-C levels, lipoprotein apheresis is the only available treatment option. While this constellation is an accepted indication for lipoprotein apheresis (LA) in Germany, prospective studies including a control group are still lacking. OBJECTIVE: Primary objective of this trial is to evaluate the clinical benefit of lipoprotein apheresis on myocardial infarction, PCI, CABG and death from cardiovascular disease in subjects with elevated Lp(a). This study evaluates the clinical benefit of weekly LA in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee (treatment group). Comparator will be well-matched subjects under maximum tolerated lipid lowering therapy without access to LA treatment (control group). METHODS: MultiSELECt, is a prospective, multicenter, multinational, two-arm matched-pair cohort study designed to directly compare subjects with significantly elevated Lp(a) approved for LA subsequently undergoing weekly apheresis treatment versus a continuation of maximal medical therapy. The follow-up period will be 2 years after the baseline visit and until at least 60 events of the primary end-point occurred in the control group. A central trial expert committee will review all subjects with respect to their potential indication for LA according to established German guidelines in a blinded fashion. All control subjects will be contacted monthly via telephone visits to compensate for the more frequent visits during apheresis. Approximately 150 matched pairs will be necessary to detect an event reduction of at least 10% in subjects under LA treatment. CONCLUSION: The MultiSELECt trial provides the unique opportunity to demonstrate the efficiency of LA on CVD in patients with elevated Lp(a) under strongly controlled conditions.

Lipid and lipoprotein reference values from 133,450 Dutch Lifelines participants: Age- and gender-specific baseline lipid values and percentiles.

BACKGROUND: Lipids and lipoproteins are recognized as the most important modifiable risk factors for cardiovascular disease. Although reference values for the major lipoproteins, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides, have been collected in numerous studies and cohorts, complete contemporary percentile-based reference values are underreported. OBJECTIVE: We set out to provide such reference lipid data using a large contemporary population-based cohort study. STUDY DESIGN AND SETTING: Lifelines is a cross-sectional population-based Dutch cohort study. We analyzed 133,540 adult fasting participants without cardiovascular disease and without lipid-lowering drug use. Lipid levels were directly measured and selected percentiles of all lipid parameters were calculated. Friedewald LDL-C estimation was calculated as well. RESULTS: From 20 till 49 years of age, men were found to exhibit a steep 64% increase of LDL-C (median +54 mg/dL), while triglyceride levels increased almost two-fold. In women, LDL-C levels did not change from 18 till 35 years, followed by a steep 42% increase till 59 years (median +42 mg/dL). In contrast to men, triglycerides were stable in ageing women. Overall, Friedewald LDL-C levels are lower compared with the direct measurement, especially with increasing triglyceride levels. CONCLUSIONS: This observational study highlights striking gender- and age-related differences in plasma lipid profiles. The given reference ranges of plasma lipids can assist in early identification of individuals with hypocholesterolemia and hypercholesterolemia, especially familial hypercholesterolemia. These reference ranges are available for physicians and patients at www.my-cholesterol.care/.

International Developments in the Care of Familial Hypercholesterolemia: Where Now and Where to Next?

Several international guidelines and consensus statements have recently been published on the care of familial hypercholesterolemia (FH)(1-3)). They agree on approaches to case detection and cascade testing, protocols in children, lifestyle and drug treatment strategies, and indications for lipoprotein apheresis. However, most countries in the world still do not have integrated, systematic FH screening programs to adequately detect and treat cases in the community. This study provides a comprehensive overview of recent and future international initiatives for closing the gaps in the care of FH.

Expanding the Evidence Base: Comparing Randomized Controlled Trials and Observational Studies of Statins.

It is widely accepted that randomized controlled trials (RCTs) are the gold standard for demonstrating the efficacy of a given therapy (results under ideal conditions). Observational studies, on the other hand, can complement this by demonstrating effectiveness (results under real-world conditions). To examine the role that observational studies can play in complementing data from RCTs, we reviewed published studies for statins, a class of drugs that have been widely used to reduce the risk of cardiovascular (CV) events by lowering low-density lipoprotein cholesterol levels. RCTs have consistently demonstrated the benefits of statin treatment in terms of CV risk reduction and have demonstrated that more intensive statin therapy has incremental benefits over less intensive treatment. Observational studies of statin use in 'real-world' populations have served to augment the evidence base generated from statin RCTs in preselected populations of patients who are often at high CV risk and have led to similar safety and efficacy findings. They have also raised questions about factors affecting medication adherence, under-treatment, switching between statins, and failure to reach low-density lipoprotein cholesterol target levels, questions for which the answers could lead to improved patient care.

Clinical review: impact of statin substitution policies on patient outcomes.

BACKGROUND: The increasing awareness of cost issues in health care has led to the increasing use of policy-driven substitution of branded for generic medications, particularly relative to statin treatment for cardiovascular diseases. While there are potential short-term health care savings, the consequences for primary care are under-researched. Our objective was to review data on intensive statin therapy and generic substitution in patients at high cardiovascular risk. RESULTS: Current treatment guidelines for the prevention of cardiovascular disease are consistent in their recommendations regarding statin therapy and treatment targets. Clinical trials demonstrate that to reduce cardiovascular events, a statin is more effective than placebo, intensive statin therapy is more effective than moderate statin therapy in patients with established coronary disease, and in patients receiving intensive statin therapy the lowest risk is associated with the lowest low-density lipoprotein levels. However, in clinical practice, patients at high cardiovascular risk are prone to be undertreated. Observational studies suggest that mandatory statin substitution may increase the gap between achieved and recommended therapeutic targets. CONCLUSIONS: Substitution of generic statins may be cost-saving, particularly at the primary prevention level. However, statin substitution policies have not been adequately studied on a population level. Data raise concern that mandated statin substitution may lead to unfavourable treatment choices at the level of the individual high-risk patient.

Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.

OBJECTIVE: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. DESIGN: Cohort study with a mean follow-up of 8.5 years. SETTING: 27 outpatient lipid clinics. SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. RESULTS: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). CONCLUSION: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population.

Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.

BACKGROUND: The plasma total and low-density lipoprotein-cholesterol (LDL-C) levels that are used as diagnostic criteria for familial hypercholesterolaemia (FH) probands in the general population are too stringent for use in relatives, given the higher prior probability of a first-degree relative being FH (50% vs. 1/500). Our objective was therefore to develop more appropriate LDL-C cutoffs to identify "affected" first-degree relatives found by cascade testing, to test their accuracy and utility in case identification, and to compare them with the published "Make early diagnosis to prevent disease" (MEDPED) cutoffs from the US. METHODS: Using a large, anonymised sample of genetically tested first-degree relatives of Netherlands FH probands (mutation carriers/non-carriers, n=825/2,469), age- and gender-specific LDL-C diagnostic cutoffs for first-degree relatives were constructed. These were used to test similar data from Denmark (n=160/161) and Norway (n=374/742). RESULTS: Gender-specific LDL-C diagnostic cutoffs were established for six different age groups, which achieved an overall accuracy (measured as Youden's index) of 0.53 in the Netherlands data, and performed significantly better amongst younger (<25 years) compared to older first-degree relatives (0.68 vs. 0.42 Youden's index, p<0.001). Compared with the Netherlands data, age- and gender-adjusted mean LDL-C levels were significantly higher (approximately 0.5 mmol/L) in the Denmark and Norway subjects for both mutation carriers and non-carriers. After adjusting for this difference, the LDL-C cut-offs showed a similar accuracy in identifying mutation carriers from Denmark (81%, range 78%-86%) and Norway (84%, range 82%-86%). Although the MEDPED cutoffs performed significantly worse than these for the Netherlands data (p<0.001), they performed equally well in overall accuracy for the Norwegian and Danish data, although the LDL-C cutoffs had a significantly higher sensitivity but lower specificity for all three countries. CONCLUSIONS: The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.

Familial hypercholesterolemia: current treatment and advances in management.

Heterozygous familial hypercholesterolemia is associated with elevated levels of LDL-cholesterol and the development of premature cardiovascular disease. The condition is considerably under-diagnosed and under-treated. Statins are the first choice treatment for all patients with heterozygous familial hypercholesterolemia. For those patients who do not reach their treatment target or who are unable to use adequate statin dose, several alternative treatment modalities can be used, either as add-on therapy or as monotherapy. In this review the various treatment options are discussed.