Methods: Adult patients with definite IE according to the Modified Duke criteria presenting betwe... more Methods: Adult patients with definite IE according to the Modified Duke criteria presenting between 1998 and 2010 were included. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. Results: 148 patients with IE were followed up for a mean of 3.8 ± 3 years. The mean age was 57 ± 17 years and 66% were male. The all-cause mortality was 47%, with inhospital mortality of 24%. Comorbid conditions included: diabetes mellitus (21%); ischaemic heart disease (16%); heart failure (14%); renal failure (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59%. Cardiac surgery was performed in 45% of patients. On Cox regression, ACCI > 3 (HR = 3.
Introduction: Recent large cardiovascular event outcome trials with ezetimibe and a proprotein co... more Introduction: Recent large cardiovascular event outcome trials with ezetimibe and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to statins demonstrated benefit from additional LDL-C reduction. Despite availability of approved injectable PCSK9 inhibitors, there still remains a need for novel, efficacious, safe, well-tolerated, and cost-effective oral LDL-C lowering therapies. Gemcabene (GEM) has been shown to significantly lower LDL-C, non-HDL-C, ApoB, and hsCRP further in hypercholesterolemic subjects when added to background statin therapy. GEM neither interacts pharmacokinetically nor has shown increased adverse effects with statins. Hypothesis: GEM added to high- or moderate-intensity statin +/-ezetimibe therapy will provide additional LDL-C reduction for subjects not at goal. Methods: High-risk subjects including those with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease on appropriate diet and stable statin therapy for at least 12 weeks and LDL-C ≥ 100 mg/dL (2.59 mmol/L) and triglycerides < 500 mg/dL (5.65 mmol/L) were randomized into a 12-week, placebo-controlled, parallel-group, double-blind study to assess the efficacy of GEM 600 mg QD on LDL-C and other lipoproteins and hsCRP. Safety and tolerability were evaluated. The subjects were stratified by high- or moderate-intensity statin therapy, with or without ezetimibe, with a target of 52 subjects (26 GEM; 26 placebo) in each stratum. The study (NCT02634151) enrolled 105 subjects (53% women, 77% Caucasian, mean age 61 years). Mean baseline LDL-C for all subjects was approximately 134 mg/dL (3.48 mmol/L) with most subjects in the high-intensity statin stratum on atorvastatin and most subjects in the moderate-intensity stratum on either simvastatin or atorvastatin. Results: Data for the full cohort was previously reported. Data by statin-intensity stratum (high and moderate) including LDL-C, non-HDL-C, ApoB, Lp(a) and hsCRP as well as safety and tolerability will now be reported. Conclusion: The trial and data analysis by statin-intensity stratification, including efficacy and safety, will be completed in October 2017 in time for presentation at the American Heart Association Scientific Sessions.
In South Africa there exists a large difference in the incidence of coronary artery disease (CAD)... more In South Africa there exists a large difference in the incidence of coronary artery disease (CAD) between the younger members, age 25–44, of the various ethnic groups. The most striking difference occurs between the Caucasian group, which has the highest incidence in the world, and the Negroes, in whom the disease is rare. Furthermore, within the Caucasian group the Jewish and Afrikaans sectors experience a higher incidence of CAD than the other Caucasian groups (Schrire, 1971). In the present study an attempt was made to assess the contribution of genetically determined lipoprotein abnormalities towards CAD in South Africa by cord blood analysis.
Total and high-density lipoprotein (HDL) cholesterol levels of 2,387 adults were screened at a wo... more Total and high-density lipoprotein (HDL) cholesterol levels of 2,387 adults were screened at a worksite and a bloodbank. Hypothetical referral decisions were made according to three sets of guidelines: the 1984 National Institutes of Health Consensus Conference guidelines (NIHCC), a single referral cutpoint of 5.2 millimoles per liter (mmol per L), and the current National Cholesterol Education Program (NCEP) guidelines for screening in physicians' office. Under the NIHCC guidelines, 31 percent of the participants would have been referred to their physicians, 32 percent under the NCEP guidelines, and 56 percent would have been referred had the 5.2 mmol per L cutpoint been used. Twenty-four percent of the participants would have been referred under both the NIHCC and NCEP guidelines; 7 percent would have been referred under the NIHCC guidelines, but not the NCEP's. Eight percent would have been referred under the NCEP guidelines, but not the NIHCC's. Those who would have been referred were older, and more likely to be male and to have low levels of HDL cholesterol than the 7 percent who would have been referred under NIHCC guidelines only. All of the 8 percent had coronary heart disease, or two or more other coronary risk factors, whereas none of the 7 percent did. If low HDL had been used as a risk factor under NCEP guidelines, the number of persons referred would have increased slightly (to 34 percent) and low HDL levels would have become one of the most prevalent risk factors. The researchers concluded that public cholesterol screening programs should use the NCEP guidelines (with or without HDL), rather than the NIHCC guidelines, or a single 5.2 mmol per L cutpoint.
Advances in Experimental Medicine and Biology, 1975
Despite the fact that the homozygous form of familial hyperbetalipoproteinemia (HβLP) is exceedin... more Despite the fact that the homozygous form of familial hyperbetalipoproteinemia (HβLP) is exceedingly rare, 17 such patients (from fourteen families) have been seen at a treatment centre for lipid disorders in Johannesburg during the past three years.
European journal of cardiovascular prevention & rehabilitation, Apr 1, 2000
Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonst... more Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. To describe the baseline characteristics of the study's cohort. This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65-6.83 mmol/l (180-264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20-40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 +/- 0.54 mmol/l (221 +/- 21 mg/dl), low-density lipoprotein cholesterol level 3.88 +/- 0.44 mmol/l (150 +/- 17 mg/dl), high-density lipoprotein cholesterol 0.96 +/- 0.15 mmol/l (37 +/- 6 mg/dl), and median triglyceride level 1.78 +/- 0.86 mmol/l (158 +/- 76 mg/dl). The mean age is 58 years (ranges 45-73 years for men and 55- 73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.
Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswi... more Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswithserioushealthconsequences,affecting approximately 1 in BOO persons in the United states. Persons with hFH generally manifest elevatlons of low density lipoprotein (IDL) cholesterol throughout their lives and have a markedly increased risk of death from coronary artery disease. The hyperchulesterolemia of hFH is responsive to medication and diet, and, if detected early, aggredve LDL cholesterol control may prevent or substantially delay cardiovascular diiease. However, evidence suggests that many persons with hFH are undetected and inadequately treated. On July 20-25 1992, the National Heart, Lung, and Blood Instttute sponsored awwkshopto assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for kientificatiin and management that are known to be effective, and to identify opportunities and needs for intewention and research.
Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for famil... more Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype. Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was nonsignificant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
Methods: Analysis was based on 22,063 participants from the REGARDS study who were free of CHD, o... more Methods: Analysis was based on 22,063 participants from the REGARDS study who were free of CHD, other cardiovascular disease (CVD) and cancer at baseline and were categorized by baseline HDL-C into <30, 30-<40 and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. Results: After adjustment for age, race and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.49 (95% confidence interval [CI]: 1.28, 1.73) for all-cause mortality; 1.37 (95%Cl: 1.03, 1.81) for cancerspecific mortality and 1.38 (95%Cl: 0.98, 1.94) for incident CHD. These associations became non-significant in models adjusting for demographics, CV risk factors, and treatment for dyslipidaemia. We found evidence for an "HDL Paradox" whereby low HDL (30-<40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully-adjusted complete-case model (HR 0.61; 95% CI: 0.44, 0.85) and after multiple imputation analyses (HR 0.75; 95% CI 0.59, 0.96) (Table 1). HDL-C (<30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.15; 95%Cl: 1.13, 4.09) in a fully adjusted compete case model, but the finding was not replicated using multiple imputation (HR 1.62; 95% CI 0.88, 2.97). Conclusions: Low HDL was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted model.
The Journal of Clinical Endocrinology & Metabolism, 1992
Male pseudohermaphrodites with 5 alpha-reductase deficiency have ambiguous genitalia and nonpalpa... more Male pseudohermaphrodites with 5 alpha-reductase deficiency have ambiguous genitalia and nonpalpable prostates on rectal examination, suggesting the dihydrotestosterone dependency of these structures. To clearly delineate the status of the prostate, male pseudohermaphrodites with 5 alpha-reductase deficiency had transrectal sonography of the prostate performed, and the results were compared to that of age-matched male controls. In six male pseudohermaphrodites, magnetic resonance imaging studies of the prostate were also performed. Heterozygote fathers also had transrectal sonography of the prostate performed and the results compared to age-matched controls. The prostates of the male pseudohermaphrodites appeared as platelike soft tissue structures posterior to the urethra on both prostatic ultrasound and magnetic resonance imaging. Prostatic volume, as determined on prostatic ultrasound by two different methods, was significantly smaller (approximately one-tenth) than the volume of age-matched controls. Transurethral ultrasound guided biopsy of the prostate in two affected subjects revealed stromal tissue. These results correlate with undetectable prostate-specific antigen in affected subjects, suggesting atrophic epithelium or lack of epithelial differentiation. This study demonstrates the dihydrotestosterone dependence of the prostate for normal differentiation and growth. The presence of some prostatic tissue in the male pseudohermaphrodites may be due to the fact that there is a decrease and not an absence of 5 alpha-reductase activity, and/or that the increased level of testosterone in subjects with this condition partially compensates for the decreased level of dihydrotestosterone. There was no difference, however, in prostate size between heterozygous fathers and age-matched control males. The heterozygote fathers had dihydrotestosterone production sufficient for normal prostate growth and development.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-... more Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.
Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a les... more Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). Basic investigation and genetic studies, however, suggest that the atherogenic particle subpopulations (LDL & VLDL) are similarly important and that the number of particles is more important than their lipid content. Methods: We performed a prospective cohort analysis in two populations: 1) 389,529 primary prevention patients w/o lipid-lowering therapy from UK Biobank, and 2) 45,708 statin-treated patients w/ established atherosclerosis from the FOURIER and IMPROVE-IT trials. Incident MI was assessed over a median follow up of 11.1 yrs in UKBB and 3.6 yrs in the trials. Adjusted HRs were calculated to determine whether lipid content (non-HDL-C & TG) or particle type (using LDL-C concentration as a surrogate for LDL, and TG concentration as a surrogate for TG-rich lipoproteins) offer predictive value beyond atherogenic particle concentration (apoB). Results...
Purpose Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in stati... more Purpose Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients. Methods Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. Results A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02 mmol/L (192-194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. Conclusion Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.
Methods: Adult patients with definite IE according to the Modified Duke criteria presenting betwe... more Methods: Adult patients with definite IE according to the Modified Duke criteria presenting between 1998 and 2010 were included. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. Results: 148 patients with IE were followed up for a mean of 3.8 ± 3 years. The mean age was 57 ± 17 years and 66% were male. The all-cause mortality was 47%, with inhospital mortality of 24%. Comorbid conditions included: diabetes mellitus (21%); ischaemic heart disease (16%); heart failure (14%); renal failure (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59%. Cardiac surgery was performed in 45% of patients. On Cox regression, ACCI > 3 (HR = 3.
Introduction: Recent large cardiovascular event outcome trials with ezetimibe and a proprotein co... more Introduction: Recent large cardiovascular event outcome trials with ezetimibe and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to statins demonstrated benefit from additional LDL-C reduction. Despite availability of approved injectable PCSK9 inhibitors, there still remains a need for novel, efficacious, safe, well-tolerated, and cost-effective oral LDL-C lowering therapies. Gemcabene (GEM) has been shown to significantly lower LDL-C, non-HDL-C, ApoB, and hsCRP further in hypercholesterolemic subjects when added to background statin therapy. GEM neither interacts pharmacokinetically nor has shown increased adverse effects with statins. Hypothesis: GEM added to high- or moderate-intensity statin +/-ezetimibe therapy will provide additional LDL-C reduction for subjects not at goal. Methods: High-risk subjects including those with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease on appropriate diet and stable statin therapy for at least 12 weeks and LDL-C ≥ 100 mg/dL (2.59 mmol/L) and triglycerides &amp;lt; 500 mg/dL (5.65 mmol/L) were randomized into a 12-week, placebo-controlled, parallel-group, double-blind study to assess the efficacy of GEM 600 mg QD on LDL-C and other lipoproteins and hsCRP. Safety and tolerability were evaluated. The subjects were stratified by high- or moderate-intensity statin therapy, with or without ezetimibe, with a target of 52 subjects (26 GEM; 26 placebo) in each stratum. The study (NCT02634151) enrolled 105 subjects (53% women, 77% Caucasian, mean age 61 years). Mean baseline LDL-C for all subjects was approximately 134 mg/dL (3.48 mmol/L) with most subjects in the high-intensity statin stratum on atorvastatin and most subjects in the moderate-intensity stratum on either simvastatin or atorvastatin. Results: Data for the full cohort was previously reported. Data by statin-intensity stratum (high and moderate) including LDL-C, non-HDL-C, ApoB, Lp(a) and hsCRP as well as safety and tolerability will now be reported. Conclusion: The trial and data analysis by statin-intensity stratification, including efficacy and safety, will be completed in October 2017 in time for presentation at the American Heart Association Scientific Sessions.
In South Africa there exists a large difference in the incidence of coronary artery disease (CAD)... more In South Africa there exists a large difference in the incidence of coronary artery disease (CAD) between the younger members, age 25–44, of the various ethnic groups. The most striking difference occurs between the Caucasian group, which has the highest incidence in the world, and the Negroes, in whom the disease is rare. Furthermore, within the Caucasian group the Jewish and Afrikaans sectors experience a higher incidence of CAD than the other Caucasian groups (Schrire, 1971). In the present study an attempt was made to assess the contribution of genetically determined lipoprotein abnormalities towards CAD in South Africa by cord blood analysis.
Total and high-density lipoprotein (HDL) cholesterol levels of 2,387 adults were screened at a wo... more Total and high-density lipoprotein (HDL) cholesterol levels of 2,387 adults were screened at a worksite and a bloodbank. Hypothetical referral decisions were made according to three sets of guidelines: the 1984 National Institutes of Health Consensus Conference guidelines (NIHCC), a single referral cutpoint of 5.2 millimoles per liter (mmol per L), and the current National Cholesterol Education Program (NCEP) guidelines for screening in physicians' office. Under the NIHCC guidelines, 31 percent of the participants would have been referred to their physicians, 32 percent under the NCEP guidelines, and 56 percent would have been referred had the 5.2 mmol per L cutpoint been used. Twenty-four percent of the participants would have been referred under both the NIHCC and NCEP guidelines; 7 percent would have been referred under the NIHCC guidelines, but not the NCEP's. Eight percent would have been referred under the NCEP guidelines, but not the NIHCC's. Those who would have been referred were older, and more likely to be male and to have low levels of HDL cholesterol than the 7 percent who would have been referred under NIHCC guidelines only. All of the 8 percent had coronary heart disease, or two or more other coronary risk factors, whereas none of the 7 percent did. If low HDL had been used as a risk factor under NCEP guidelines, the number of persons referred would have increased slightly (to 34 percent) and low HDL levels would have become one of the most prevalent risk factors. The researchers concluded that public cholesterol screening programs should use the NCEP guidelines (with or without HDL), rather than the NIHCC guidelines, or a single 5.2 mmol per L cutpoint.
Advances in Experimental Medicine and Biology, 1975
Despite the fact that the homozygous form of familial hyperbetalipoproteinemia (HβLP) is exceedin... more Despite the fact that the homozygous form of familial hyperbetalipoproteinemia (HβLP) is exceedingly rare, 17 such patients (from fourteen families) have been seen at a treatment centre for lipid disorders in Johannesburg during the past three years.
European journal of cardiovascular prevention & rehabilitation, Apr 1, 2000
Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonst... more Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. To describe the baseline characteristics of the study&#39;s cohort. This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65-6.83 mmol/l (180-264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20-40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 +/- 0.54 mmol/l (221 +/- 21 mg/dl), low-density lipoprotein cholesterol level 3.88 +/- 0.44 mmol/l (150 +/- 17 mg/dl), high-density lipoprotein cholesterol 0.96 +/- 0.15 mmol/l (37 +/- 6 mg/dl), and median triglyceride level 1.78 +/- 0.86 mmol/l (158 +/- 76 mg/dl). The mean age is 58 years (ranges 45-73 years for men and 55- 73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.
Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswi... more Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswithserioushealthconsequences,affecting approximately 1 in BOO persons in the United states. Persons with hFH generally manifest elevatlons of low density lipoprotein (IDL) cholesterol throughout their lives and have a markedly increased risk of death from coronary artery disease. The hyperchulesterolemia of hFH is responsive to medication and diet, and, if detected early, aggredve LDL cholesterol control may prevent or substantially delay cardiovascular diiease. However, evidence suggests that many persons with hFH are undetected and inadequately treated. On July 20-25 1992, the National Heart, Lung, and Blood Instttute sponsored awwkshopto assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for kientificatiin and management that are known to be effective, and to identify opportunities and needs for intewention and research.
Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for famil... more Background and aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype. Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was nonsignificant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
Methods: Analysis was based on 22,063 participants from the REGARDS study who were free of CHD, o... more Methods: Analysis was based on 22,063 participants from the REGARDS study who were free of CHD, other cardiovascular disease (CVD) and cancer at baseline and were categorized by baseline HDL-C into <30, 30-<40 and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. Results: After adjustment for age, race and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.49 (95% confidence interval [CI]: 1.28, 1.73) for all-cause mortality; 1.37 (95%Cl: 1.03, 1.81) for cancerspecific mortality and 1.38 (95%Cl: 0.98, 1.94) for incident CHD. These associations became non-significant in models adjusting for demographics, CV risk factors, and treatment for dyslipidaemia. We found evidence for an "HDL Paradox" whereby low HDL (30-<40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully-adjusted complete-case model (HR 0.61; 95% CI: 0.44, 0.85) and after multiple imputation analyses (HR 0.75; 95% CI 0.59, 0.96) (Table 1). HDL-C (<30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.15; 95%Cl: 1.13, 4.09) in a fully adjusted compete case model, but the finding was not replicated using multiple imputation (HR 1.62; 95% CI 0.88, 2.97). Conclusions: Low HDL was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted model.
The Journal of Clinical Endocrinology & Metabolism, 1992
Male pseudohermaphrodites with 5 alpha-reductase deficiency have ambiguous genitalia and nonpalpa... more Male pseudohermaphrodites with 5 alpha-reductase deficiency have ambiguous genitalia and nonpalpable prostates on rectal examination, suggesting the dihydrotestosterone dependency of these structures. To clearly delineate the status of the prostate, male pseudohermaphrodites with 5 alpha-reductase deficiency had transrectal sonography of the prostate performed, and the results were compared to that of age-matched male controls. In six male pseudohermaphrodites, magnetic resonance imaging studies of the prostate were also performed. Heterozygote fathers also had transrectal sonography of the prostate performed and the results compared to age-matched controls. The prostates of the male pseudohermaphrodites appeared as platelike soft tissue structures posterior to the urethra on both prostatic ultrasound and magnetic resonance imaging. Prostatic volume, as determined on prostatic ultrasound by two different methods, was significantly smaller (approximately one-tenth) than the volume of age-matched controls. Transurethral ultrasound guided biopsy of the prostate in two affected subjects revealed stromal tissue. These results correlate with undetectable prostate-specific antigen in affected subjects, suggesting atrophic epithelium or lack of epithelial differentiation. This study demonstrates the dihydrotestosterone dependence of the prostate for normal differentiation and growth. The presence of some prostatic tissue in the male pseudohermaphrodites may be due to the fact that there is a decrease and not an absence of 5 alpha-reductase activity, and/or that the increased level of testosterone in subjects with this condition partially compensates for the decreased level of dihydrotestosterone. There was no difference, however, in prostate size between heterozygous fathers and age-matched control males. The heterozygote fathers had dihydrotestosterone production sufficient for normal prostate growth and development.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-... more Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.
Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a les... more Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). Basic investigation and genetic studies, however, suggest that the atherogenic particle subpopulations (LDL & VLDL) are similarly important and that the number of particles is more important than their lipid content. Methods: We performed a prospective cohort analysis in two populations: 1) 389,529 primary prevention patients w/o lipid-lowering therapy from UK Biobank, and 2) 45,708 statin-treated patients w/ established atherosclerosis from the FOURIER and IMPROVE-IT trials. Incident MI was assessed over a median follow up of 11.1 yrs in UKBB and 3.6 yrs in the trials. Adjusted HRs were calculated to determine whether lipid content (non-HDL-C & TG) or particle type (using LDL-C concentration as a surrogate for LDL, and TG concentration as a surrogate for TG-rich lipoproteins) offer predictive value beyond atherogenic particle concentration (apoB). Results...
Purpose Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in stati... more Purpose Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients. Methods Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. Results A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02 mmol/L (192-194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. Conclusion Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.
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Papers by Evan Stein