Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia.

BACKGROUND AND AIMS: Cardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins. METHODS AND RESULTS: Among primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included. LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects. CONCLUSION: According to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.

Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes.

BACKGROUND: LADA is probably the most prevalent form of autoimmune diabetes. Nevertheless, there are few data about cardiovascular disease in this group of patients. The aim of this study was to investigate the frequency of carotid atherosclerotic plaques in patients with LADA as compared with patients with classic type 1 diabetes and type 2 diabetes. METHODS: Patients with LADA were matched for age and gender in different proportions to patients with type 2 diabetes, and classic type 1 diabetes. None of the patients had clinical cardiovascular disease. All subjects underwent B-mode carotid ultrasound to detect atheroma plaques. Demographics were obtained from all subjects. RESULTS: We included 71 patients with LADA, 191 patients with type 2 diabetes and 116 patients with type 1 diabetes. Carotid atherosclerosis was more frequent in patients with LADA compared with type 2 diabetes (73.2% vs. 56.9%, P = 0.0018) and classic type 1 diabetes (57.1%, P = 0.026); these changes occurred despite healthier macrovascular risk profiles in the former. Age (P < 0.001), smoking (P = 0.003) and hypertension (P = 0.019) were independently associated with carotid atherosclerosis. Multiple plaques were also more frequent in patients with LADA as compared with classic type 1 diabetes and type 2 diabetes (45.1% and 33.6% vs. 27.2%, respectively, P = 0.022). The frequency of carotid plaques increased with increasing diabetes duration in LADA patients compared with type 2 diabetes (85.7% vs. 58.8%, inverse OR 5.72 [1.5-21.8]; P = 0.009). CONCLUSIONS: LADA patients do not present with less carotid atherosclerosis than patients with type 1 and type 2 diabetes. Their macrovascular risk occurs despite a healthier macrovascular risk profile than those patients with type 2 diabetes.

Cataract Surgery in Elderly Subjects with Heterozygous Familial Hypercholesterolemia in Prolonged Treatment with Statins.

BACKGROUND: Cataracts are the main cause of blindness and represent one fifth of visual problems worldwide. It is still unknown whether prolonged statin treatment favors the development of cataracts. We aimed to ascertain the prevalence of cataract surgery in elderly subjects with genetically diagnosed heterozygous familial hypercholesterolemia (HeFH) receiving statin treatment for ≥5 years, and compare this with controls. METHODS: This is an observational, multicenter, case-control study from five lipid clinics in Spain. We collected data with the following inclusion criteria: age ≥65 years, LDL cholesterol levels ≥220 mg/dL without lipid-lowering drugs, a pathogenic mutation in a candidate gene for HeFH (LDLR, APOB, or PCSK9) and statin treatment for ≥5 years. Controls were selected from relatives of HeFH patients without hypercholesterolemia. Linear and logistic regressions based on generalized linear models and generalized estimating equations (GEE) were used. Cataract surgery was used as a proxy for cataract development. RESULTS: We analyzed 205 subjects, 112 HeFH, and 93 controls, with a mean age of 71.8 (6.5) and 70.0 (7.3) years, respectively. HeFH subjects presented no difference in clinical characteristics, including smoking, hypertension, and type 2 diabetes mellitus, compared with controls. The mean duration of lipid-lowering treatment in HeFH was 22.5 (8.7) years. Cataract surgery prevalence was not significantly different between cases and controls. The presence of cataracts was associated neither with LDLc nor with the length of the statin therapy. CONCLUSION: In the present study, HeFH was not a risk factor for cataract surgery and prolonged statin treatment did not favor it either. These findings suggest that statin treatment is not related with cataracts.

Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy.

Hypercholesterolemia and statins are risk factors for aortic stenosis (AS) and vascular calcification, respectively. Whether heterozygous subjects with familial hypercholesterolemia (HeFH) treated with statins are at risk of AS is unknown. We study the prevalence of AS, aortic valve calcification (AoVC), and aortic sclerosis (ASc) in elderly subjects with HeFH in a prolonged statin treatment. Case-control study, cases were adults ≥65 years of age with a genetic diagnosis of HeFH, LDLc >220 mg/dl, and statin treatment ≥5 years. Controls were relatives of HeFH patients, with LDLc <190 mg/dl. Participants underwent a cardiac ultrasound for aortic valve analysis. We studied 205 subjects, 112 HeFH and 93 controls, with mean age 71.8(6.5) years and 70.0(7.3) years, respectively. HeHF, with respect to controls, presented greater gradients of aortic transvalvular pressure, 7.4(7.3) mmHg versus 5.0(2.8) mmHg, and maximum aortic velocity, 1.7(0.7) m/s versus 1.5(0.4) m/s, and lower aortic valve opening area, 2.0(0.7) cm2 versus 2.4(0.6) cm2 (all p < 0.05). AoVC and ASc were also more prevalent in HeFH (p < 0.05 between groups). Moderate/severe AS prevalence was higher among HeFH: 7.1% versus 1.1% (age- and sex-adjusted odds ratio (OR) 8.33, p = 0.03). Independent risk factors for aortic valve disease in HeFH were age and LDLc before treatment. The number of years under statin treatment was not associated with any aortic valve measurement. Subjects ≥65 years with HeFH in prolonged statin treatment show more aortic valvular disease and higher frequency of AS than controls. Life-long elevated LDLc exposure, rather than time of exposure to statins, explains this higher risk.

Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians.

OBJECTIVE: In severely obese individuals and patients with diabetes, accumulation and activation of macrophages in adipose tissue has been implicated in the development of obesity-associated complications, including insulin resistance. We sought to determine whether in a healthy population, adiposity, sex, age, or insulin action is associated with adipose tissue macrophage content (ATMc) and/or markers of macrophage activation. RESEARCH DESIGN AND METHODS: Subcutaneous ATMc from young adult Pima Indians with a wide range of adiposity (13-46% body fat, by whole-body dual-energy X-ray absorptiometry) and insulin action (glucose disposal rate 1.6-9 mg/kg estimated metabolic body size/min, by glucose clamp) were measured. We also measured expression in adipose tissue of factors implicated in macrophage recruitment and activation to determine any association with ATMc and insulin action. RESULTS: ATMc, as assessed by immunohistochemistry (Mphi) and by macrophage-specific gene expression (CD68, CD11b, and CSF1R), were correlated with percent body fat, age, and female sex. Gene expression of CD68, CD11b, and CSF1R but not Mphi was correlated negatively with glucose disposal rate but not after adjustment for percent body fat, age, and sex. However, adipose tissue expression of plasminogen activator inhibitor type-1 (PAI-1) and CD11 antigen-like family member C (CD11c), markers produced by macrophages, were negatively correlated with adjusted glucose disposal rate (r = -0.28, P = 0.05 and r = -0.31, P = 0.03). CONCLUSIONS: ATMc is correlated with age and adiposity but not with insulin action independent of adiposity in healthy human subjects. However, PAI-1 and CD11c expression are independent predictors of insulin action, indicating a possible role for adipose tissue macrophage activation.