Differential impact of severe familial hypercholesterolemia on regional skeletal muscle and organ blood flows during exercise: Effects of PDE5 inhibition.

OBJECTIVE: Swine with familial hypercholesterolemia (FH) exhibit attenuated exercise-induced systemic vasodilation that is restored by phosphodiesterase 5 (PDE5) inhibition. Whether the impacts of FH and PDE5 inhibition to impair and restore exercise-induced vasodilation, respectively, results from tissue-specific or generalized effects remains unclear. Thus, we hypothesized that FH induces generalized impairment of skeletal muscle vasodilation that would be alleviated by PDE5 inhibition. METHODS: Systemic vascular responses to exercise were assessed in chronically instrumented normal and FH swine before and after PDE5 inhibition with EMD360527. Skeletal muscle and organ blood flows and conductances were determined via the microsphere technique. RESULTS: As previously reported, vs normal swine, FH swine have pronounced elevation of total cholesterol and impaired exercise-induced vasodilation that is restored by PDE5 inhibition. Blood flows to several, not all, skeletal muscle vascular beds were severely impaired by FH associated with reduced blood flow to many visceral organs. PDE5 inhibition differentially impacted skeletal muscle and organ blood flows in normal and FH swine. CONCLUSIONS: These data indicate that FH induces regional, not generalized, vasomotor dysfunction and that FH and normal swine exhibit unique tissue blood flow responses to PDE5 inhibition thereby adding to accumulating evidence of vascular bed-specific dysfunction in co-morbid conditions.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy: Payer Approvals and Rejections, and Patient Characteristics for Successful Prescribing.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are a novel class of medications for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional lipid lowering beyond dietary measures and statin use. Because of the drugs' high cost, rates of prescription approval by payers may be low. We aimed to identify payer approval and rejection rates for PCSK9i prescriptions and the potential factors influencing these rates. METHODS: This is a retrospective, descriptive cohort study using nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set includes >220 million patients from all 50 states and all payer types with 5140 distinct health plans. PCSK9i prescriptions were submitted for 51 466 patients in the pharmacy data set. The main outcome was approval or rejection of PCSK9i prescription claims. Factors associated with approval and rejection of these medications in the United States were assessed. RESULTS: Among patients who were prescribed a PCSK9i, 47.0% were approved for coverage by the payer. Variables that were associated with PCSK9i approval included age >65 years (P<0.01), history of atherosclerotic cardiovascular disease (P<0.01), prescription by a cardiologist or nonprimary care provider (P<0.01), statin intolerance (P=0.03), longer statin duration (P=0.01), and noncommercial payers (P<0.01). Higher low-density lipoprotein cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates (24.4%) and Medicare had the highest (60.9%). CONCLUSIONS: Rates of approval for PCSK9i therapy are low, even for patients who appear to meet labeled indications. Although a combination of clinical characteristics increases the likelihood of approval, payer type is the most significant factor.

Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia.

BACKGROUND AND AIM: Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a key role in atherosclerosis development. It is considered a marker of increased risk of cardiovascular disease (CVD) and plaque vulnerability. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol and a higher prevalence of early CVD. Our aim was to evaluate the differences in Lp-PLA2 activity in a population of hypercholesterolemic patients with and without definite FH. METHODS AND RESULTS: Hypercholesterolemic patients were consecutively recruited. Definite FH was defined according to Dutch Lipid Clinic Network criteria ≥8. All patients underwent routine clinical examination and biological assessments and Lp-PLA2 activity was measured in blood samples. Among 469 patients, 118 had a definite diagnosis of FH. Lp-PLA2 activity was significantly higher in definite FH patients compared to non-definite FH patients (206.5 ± 54.5 vs. 180.8 ± 48.4 nmol/min/mL, p < 0.0001). Lp-PLA2 positively correlated with total cholesterol, LDL-C and apolipoprotein B and negatively with HDL-C and apolipoprotein A-1. In multivariate analysis, definite FH diagnosis, LDL-C, HDL-C and statin treatment remained correlates of Lp-PLA2 independently of systolic blood pressure. CONCLUSIONS: Lp-PLA2 activity was higher in definite FH than in non-definite FH patients independently of LDL-C levels and statin treatment. These results highlight the particular phenotype of FH subjects among hypercholesterolemic patients. As increased Lp-PLA2 activity suggests, FH patients exhibit higher arterial inflammation that may contribute to their high cardiovascular risk. Our results reinforce the potential beneficial role of statins pleiotropic effects and the need for proper identification and treatment of FH patients.

Changes in lipoprotein lipase and endothelial lipase mass in familial hypercholesterolemia during three-drug lipid-lowering combination therapy.

BACKGROUND: This study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs. METHODS: The pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years). The patients were randomly divided into two groups based on the timing when ezetimibe was added. RESULTS: Plasma LPL mass concentration was significantly reduced by rosuvastatin at 20 mg/day (median = 87.4 [IQR: 71.4-124.7] to 67.5 [IQR: 62.1-114.3] ng/ml, P < 0.05). In contrast, ezetimibe at 10 mg/day as well as colestimide at 3.62 g/day did not alter its level substantially (median = 67.5 [IQR: 62.1-114.3] to 70.2 [IQR: 58.3-106.2], and to 74.9 [IQR: 55.6-101.3] ng/ml, respectively) in the group starting with rosuvastatin followed by the addition of ezetimibe and colestimide. On the other hand, the magnitude in LPL mass reduction was lower in the group starting with ezetimibe at 10 mg/day before reaching the maximum dose of 20 mg/day of rosuvastatin. Plasma EL mass concentration was significantly increased by rosuvastatin at 20 mg/day (median = 278.8 [IQR: 186.7-288.7] to 297.0 [IQR: 266.2-300.2] ng/ml, P < 0.05), whereas other drugs did not significantly alter its level. CONCLUSION: The effects on changes of LPL and EL mass differed depending on the lipid-lowering therapy, which may impact the prevention of atherosclerosis differently.

The promise of proprotein convertase subtilisin/kexin 9 inhibitors for the treatment of familial hypercholesterolemia.

Familial hypercholesterolemia comprises a constellation of genetic disorders resulting in very high cholesterol levels since childhood. If untreated, it is associated with accelerated atherosclerosis and premature cardiovascular disease. It has been shown that if aggressive cholesterol lowering is achieved in familial hypercholesterolemia, the incidence of cardiovascular disease can be lowered. However, currently approved pharmacological therapies are not able to lower cholesterol to optimal levels in a large number of these patients. Proprotein convertase subtilisin/kexin 9 inhibitors are a new class of cholesterol-lowering medications that can significantly reduce cholesterol levels in these patients especially those with at least some functioning low-density lipoprotein receptors. In this article, we will briefly review familial hypercholesterolemia and the role of proprotein convertase subtilisin/kexin 9 inhibitors in this condition.

Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis.

RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77 ± 4%). Concomitantly, PCSK9 levels fell by 52 ± 5%, strongly correlating with the LDL drop (P=0.0322; r(2)=0.26), but not with decreases in triglyceride (49 ± 13%) or high-density lipoprotein levels (18 ± 2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81 ± 11% of LDL-bound PCSK9 and 48 ± 14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.

Proprotein convertase subtilisin/kexin type 9 (PCSK9): lessons learned from patients with hypercholesterolemia.

BACKGROUND: Identification of the proprotein convertase subtilisin/kexin type 9 (PCSK9) as the third gene causing familial hypercholesterolemia (FH) and understanding its complex biology has led to the discovery of a novel class of therapeutic agents. CONTENT: PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum and enters the secretory pathway. The PCSK9 gene is under the regulatory control of sterol receptor binding proteins 1 and 2. Statins increase PCSK9 and this may modulate the response to this class of medications. In plasma, PCSK9 binds to the epidermal growth factor-like domain of the LDL receptor (LDL-R) on the cell and, once incorporated in the late endosomal pathway, directs the LDL-R toward lysosomal degradation rather than recycling to the plasma membrane. Thus, gain-of-function PCSK9 mutations lead to an FH phenotype, whereas loss-of-function mutations are associated with increased LDL-R-mediated endocytosis of LDL particles and lower LDL cholesterol in plasma. Inhibition of PCSK9 is thus an attractive therapeutic target. Presently, this is achieved by using monoclonal antibodies for allosteric inhibition of the PCSK9-LDL-R interaction. Phase 2 and 3 clinical trials in patients with moderate and severe hypercholesterolemia (including FH) show that this approach is safe and highly efficacious to lower LDL-C and lipoprotein(a). SUMMARY: PCSK9 has other biological roles observed in vitro and in animal studies, including viral entry into the cell, insulin resistance, and hepatic tissue repair. Given the potential number of humans exposed to this novel class of medications, careful evaluation of clinical trial results is warranted.

Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL. METHODS: LDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats. RESULTS: Compared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation. CONCLUSIONS: LDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS.

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control.

OBJECTIVE: To produce transgenic mice expressing the D374Y variant of the human proprotein convertase subtilisin/kexin type 9 (PCSK9) gene at physiological levels to investigate the mechanisms causing hypercholesterolemia and accelerated atherosclerosis. METHODS AND RESULTS: A bacterial artificial chromosome containing PCSK9 and its flanking regions was modified to introduce the D374Y mutation and a C-terminal myc(2) tag. Transgenic mice that expressed 1 copy of the mutant or wild-type (WT) PCSK9 bacterial artificial chromosome were produced. Human PCSK9 mRNA was expressed at levels comparable to endogenous pcsk9 and with the same tissue specificity. The expression of D374Y or WT human PCSK9 increased the serum cholesterol level and reduced hepatic low-density lipoprotein receptor protein levels in the transgenic mice compared with bacterial artificial chromosome-negative controls; however, the effects were more marked in D374Y mice. The effect of a high-cholesterol diet on increasing serum cholesterol level was greater in D374Y mice, and atherosclerotic plaques after 15 weeks were more extensive in mice expressing D374Y than in WT PCSK9. D374Y mice secreted more triglyceride-rich lipoproteins into the circulation than WT mice. CONCLUSIONS: The expression of human D374Y PCSK9 at physiological levels produced a phenotype that closely matched that found in heterozygous D374Y patients and suggested that reduced low-density lipoprotein receptor activity is not the sole cause of their hypercholesterolemia.

Homozygous familial hypercholesterolemia in a young woman with dual gene mutations of low-density lipoprotein receptor and proprotein convertase subtilisin/kexin type 9.

A 28-year-old woman with a rare combination of homozygous LDLR and heterozygous PCSK9 mutations had a phenotype consistent with homozygous familial hypercholesterolemia. She reported a clinical history of coronary and extracoronary atherosclerosis treated with 3 coronary stenting procedures, one coronary bypass, and aortic and mitral valve replacements. Because the patient refused lipoprotein apheresis, lipid-lowering therapy with statins, ezetimibe, and evolocumab was started. The desired low-density lipoprotein cholesterol target was not achieved. Dose-escalated lomitapide therapy (up to 30 mg/d) was added, enabling achievement of low-density lipoprotein cholesterol levels of 45 mg/dL during 24 months' follow-up. During this period, no cardiovascular events or clinical evidence of side effects occurred. In this case, lomitapide has been used in combination with maximum-tolerated statin therapy to successfully treat a patient with a rare combination of mutations in both LDLR and PCSK9 genes.

Inclisiran, the billion-dollar drug, to lower LDL cholesterol - is it worth it?

INTRODUCTION: If statins are unsuccessful at achieving the LDL cholesterol level goal in subjects with hypercholesterolemia, non-statin therapy should be added to reduce cardiovascular morbidity and mortality. The first inhibitors of proprotein convertase substilisin-kexin type 9 (PCSK9) were human monoclonal antibodies and these reduced LDL cholesterol and cardiovascular events. Inclisiran is a small interfering RNA molecule (siRNAs) directed against PCSK9. AREAS COVERED: This key paper evaluation focuses on Phase 3 trials that assess inclisiran in the treatment of hypercholesterolemia and heterozygous familial hypercholesterolemia. EXPERT OPINION: To date, the findings with inclisiran have been very promising as it causes large decreases in LDL cholesterol with few adverse effects. However, there are some limitations to its widespread use. Firstly, cardiovascular outcomes trials have not been completed, so we do not know how inclisiran compares to the PCSK9 monoclonal antibodies, which, seem to me, to only have a modest effect on cardiovascular outcomes. Secondly, a major problem with the PCSK9 monoclonal antibodies is that they are expensive, and their use is often discontinued or not pursued, which can leave the subjects intended for treatment at high cardiovascular risk. At present, it is not clear whether similar problems around cost will apply to inclisiran.

Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels.

PCSK9 is a natural inhibitor of the LDL receptor. Gain-of-function mutations may cause the familial hypercholesterolemia phenotype, whereas loss-of-function variants associate with reduced LDL-C levels and lower coronary risk. Statins up-regulate PCSK9 in hepatocytes. We developed an assay to measure total PCSK9 in human plasma and evaluated the effect of statins and ezetimibe on PCSK9 in vivo and in vitro. In 254 normal subjects, the mean plasma PCSK9 was 89 +/- 32 ng/ml. PCSK9 levels correlated with plasma cholesterol, LDL-C, triglycerides, fasting glucose, age and body mass index. Sequencing PCSK9 from subjects at the extremes of plasma distribution revealed new variants. In 200 hypercholesterolemic patients, circulating PCSK9 was higher than in controls, increased with increasing statin dose, and further increased when ezetimibe was added. However, ezetimibe treatment of HepG2 (hepatocytes) and Caco-2 (enterocytes) cells caused a slight increase in PCSK9 and NPC1L1 mRNA, but no significant rise in PCSK9 protein secretion, suggesting that these transformed cells are not ideal model cell lines.

Case reports of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition nonresponse.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a novel class of monoclonal antibodies, reduces low-density lipoprotein cholesterol levels and improves cardiovascular outcomes. Given the short time frame, these agents have been available for use; reports of nonresponse to the PCSK9 inhibitor therapy are scarce in literature. We describe 2 cases with substantially lesser than expected low-density lipoprotein cholesterol lowering on PCSK9 therapy. Nonresponse to PCSK9 inhibition was attributed to autosomal recessive hypercholesterolemia (secondary to low-density lipoprotein receptor adaptor protein 1 mutation) and plasmapheresis after PCSK9 inhibitor drug injections. Additional PCSK9 inhibitor nonresponders are likely to emerge as the use of these agents increases overtime.

PCSK9 inhibitors in clinical practice: Delivering on the promise?

BACKGROUND AND AIMS: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. METHODS: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. RESULTS: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. CONCLUSIONS: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials.

Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors.

PURPOSE: To describe patient characteristics and treatment patterns among early initiators of proprotein convertase subtilisin/kexin type nine inhibitors (PCSK9is) who initiated treatment within the first 6 months of market availability. PATIENTS AND METHODS: This retrospective cohort study used IQVIA's longitudinal open-source point-of-sale pharmacy claims database (LRx) and PharMetrics Plus (P+) health plan claims database to identify patients initiating a PCSK9i between January 1, 2016 and June 30, 2016. The index date was defined as the date of the first PCSK9i prescription (index claim) during the enrollment window; patients were followed for ≥6 months postindex. Patient characteristics including use of baseline lipid-lowering therapy (LLT) and measures such as persistence and adherence to PCSK9i therapy were evaluated with respect to health plan type (commercial vs Medicare). RESULTS: Overall, patients initiating PCSK9i (n=13,151) had a mean age of 66 years, and 51% were male. Approximately 67.4% of patients used some form of LLT (statin and/or ezetimibe) in the 24 months prior to initiating PCSK9i therapy. The proportion of patients covered by a commercial health plan (51.2%) was similar to that covered by Medicare (48.8%). Persistence on PCSK9i was marginally longer for patients with commercial insurance than Medicare (mean days on therapy 202.2 vs 198.5). Overall, 42.6% of patients discontinued their PCSK9i during the 180 days of follow-up. CONCLUSION: This study demonstrates that a large proportion of patients discontinue PCSK9i therapy at 30 and 90 days, which are the time frames for which many health plans require recertification to continue access to PCSK9i. Future studies looking at treatment patterns among patients who initiate PCSK9i therapy after the first 180 days once health plan formularies and utilization management criteria were finalized are needed to understand more comprehensively real-world PCSK9i usage patterns.

Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies.

BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Decreased enzyme catalytic efficiency in familial hypercholesterolemia.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) controls the rate of cholesterol biosynthesis and is itself modulated through feedback suppression by internalized low density lipoprotein (LDL) cholesterol. We measured HMG CoA reductase protein concentration and microsomal enzyme activity in freshly isolated mononuclear leukocytes from normal individuals and patients with heterozygous or homozygous familial hypercholesterolemia (FH). Reductase protein concentration was similar in normal and heterozygous subjects, but was over twofold elevated in patients with homozygous FH. Reductase protein concentration was inversely related to LDL receptor status. Total activity and catalytic efficiency of reductase, however, were decreased in heterozygous and homozygous FH patients. The decrease in catalytic efficiency was not due to enzyme phosphorylation or thiol-disulfide formation. Reduction of plasma cholesterol concentration over 2 h by plasmapheresis increased reductase activity, the degree of which was directly proportional to the LDL-receptor status of the subjects. Decreased HMG CoA reductase activity and catalytic efficiency in mononuclear leukocytes and perhaps other cells in FH may represent a fundamental abnormality in the regulation of this enzyme independent of that induced by the LDL-receptor defect and may provide new insight into the control of cholesterol metabolism in FH.