Atherogenic dyslipidemia and risk of silent coronary artery disease in asymptomatic patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: To investigate whether atherogenic dyslipidemia, a dyslipidemic profile combining elevated triglycerides and low high-density lipoprotein (HDL) cholesterol, is predictive of risk of silent myocardial ischemia (SMI) or angiographic coronary artery disease (CAD) in asymptomatic patients with type 2 diabetes. METHODS: Cohort study in 1080 asymptomatic patients with type 2 diabetes with a normal resting electrocardiogram, at least one additional cardiovascular risk factor and low density lipoprotein (LDL) cholesterol <3.35 mmol/L. Patients initially underwent screening for SMI by stress myocardial scintigraphy. Patients with SMI underwent coronary angiography. RESULTS: Overall, 60 (5.5 %) patients had atherogenic dyslipidemia (triglycerides ≥2.26 mmol/L and HDL cholesterol ≤0.88 mmol/L). In multivariate analyses taking into account the parameters associated in univariate analyses with SMI and then CAD, atherogenic dyslipidemia was associated with SMI (odds ratio 1.8[1.0-3.3]), as were male gender (OR 2.1[1.5-2.9]), BMI (OR 0.97[0.94-0.997]), retinopathy (OR 1.4[1.1-1.9]), peripheral occlusive arterial disease (POAD: OR 2.5[1.6-3.8]) and mean blood pressure (OR 1.01[1.00-1.03]); atherogenic dyslipidemia was associated with CAD (OR 4.0[1.7-9.2]), as were male gender (OR 3.0[1.6-5.6]), BMI (OR 0.94[0.90-0.995]), retinopathy (OR 1.7[1.0-2.9], POAD (OR 4.0[2.1-7.4]) and mean blood pressure (OR 1.03[1.01-1.05]). In the subgroup of 584 patients with LDL cholesterol <2.6 mmol/L, atherogenic dyslipidemia was also associated with CAD (OR 3.6[1.5-9.0]). CONCLUSIONS: Atherogenic dyslipidemia was associated with an increased risk of SMI and silent CAD in patients with type 2 diabetes and LDL cholesterol levels <3.35 mmol/L. Specific management of atherogenic dyslipidemia might help reducing the high residual burden of cardiovascular disease.

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

Cardiovascular risk prediction is improved by adding asymptomatic coronary status to routine risk assessment in type 2 diabetic patients.

OBJECTIVE: To evaluate if silent myocardial ischemia (SMI) and silent coronary artery disease (CAD) provide significant additional value to routine cardiovascular risk assessment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We followed up to a first cardiovascular event 688 subjects (322 men, aged 59 ± 8 years) out of 731 consecutive asymptomatic type 2 diabetic patients with ≥1 additional risk factor who had been prospectively screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent CAD by coronary angiography. RESULTS: SMI was found in 207 (30.1%) patients and CAD in 76 of those with SMI. Of the patients, 98 had a first cardiovascular event during a 5.4 ± 3.5 (range: 0.1-19.2) year follow-up period. Cox regression analysis considering parameters predicting events but not SMI and CAD ("routine assessment") showed in univariate analyses that macroproteinuria (hazard ratio [HR] 3.33 [95% CI 1.74-6.35]; P < 0.001), current multifactorial care (0.27 [0.15-0.47]; P < 0.001), and peripheral/carotid occlusive arterial disease (PCOAD; 4.33 [2.15-8.71]; P < 0.001) independently predicted cardiovascular events. When added into the model, SMI (HR 1.76 [1.00-3.12]; P = 0.05) and CAD (2.28 [1.24-4.57]; P < 0.01) were also independently associated with events. SMI added to the prediction of an event in the following 5 years above and beyond routine assessment risk prediction (c statistic with or without SMI 0.788 [0.720-0.855] and 0.705 [0.616-0.794], respectively). CONCLUSIONS: Although screening for SMI and silent CAD should not be systematic, these complications are predictive of cardiovascular events in type 2 diabetic patients in addition to routine risk predictors, especially represented by PCOAD, macroproteinuria, and nonintensive management.

DHA supplementation for late onset Stargardt disease: NAT-3 study.

BACKGROUND: We analyzed the effects of a docosahexaenoic acid (DHA) supplementation in patients affected with late onset Stargardt disease (STGD). METHODS: DHA (840 mg/day) was given to 20 STGD patients for six months. A complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and multifocal electroretinogram (mfERG), was performed at inclusion day 0 (D0) and at month 6 (M6). RESULTS: Overall, no statistical differences have been observed at M6 vs D0 as regards BCVA and mfERG (P > 0.05). Mild Improvement of BCVA and improvement of mfERG was noted in seven/40 eyes of four/20 patients. In the first patient, the peak of the a wave increased from 66 nV/deg(2) to 75.4 nV/deg(2) in the right eye (RE) and 24.5 nV/deg(2) to 49.1 nV/deg(2) in the left eye (LE). The peak of the b wave improved from 122 nV/deg(2) to 157 nV/deg(2) in the RE, and 102 nV/deg(2) to 149 nV/deg(2) in the LE. In the second patient peaks of the a and b waves respectively increased from 11.8 nV/deg(2) to 72.1 nV/deg(2) and 53 nV/deg(2) to 185 nV/deg(2) in the RE. In the third patient the peak of the a wave increased from 37 nV/deg(2) to 43 nV/deg(2) in the RE, and from 31 nV/deg(2) to 45 nV/deg(2) in the LE; the peak of the b wave improved from 70 nV/deg(2) to 89 nV/deg(2) in the RE, and from 101 nV/deg(2) to 108 nV/deg(2) in the LE. In the fourth patient, the peak of the a wave increased from 39 nV/deg(2) to 42 nV/deg(2) in the RE, and from 40 nV/deg(2) to 43 nV/deg(2) in the LE; the peak of the b wave improved from 86 nV/deg(2) to 94 nV/deg(2) in the RE, and from 87 nV/deg(2) to 107 nV/deg(2) in the LE. CONCLUSION: DHA seems to influence some functional parameters in patients affected with STGD. However, no short-term benefit should be expected from DHA supplementation.

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.

Efficacy and tolerability profile of nebivolol vs atenolol in mild-to-moderate essential hypertension: results of a double-blind randomized multicentre trial.

The objective of this 12-week double-blind randomized multicentre study was to compare the efficacy and tolerability of nebivolol, a recently developed beta-blocking agent with vasodilating properties, to the classical beta-blocker atenolol. After a placebo run-in phase, 205 mild-to-moderate middle-age essential hypertensives were randomized to either nebivolol 5 mg daily (n = 105) or atenolol 100 mg daily (n = 100) over a period of 12 weeks. The primary endpoint of the study was the change in sitting systolic and diastolic blood pressure (SBP and DBP respectively) from baseline to week 12 of treatment. The two drugs induced similar significant antihypertensive effects, the SBP and DBP reduction amounting to -18.2 +/-14.0 and -14.6 +/-7.9 mmHg (mean +/- SD) for atenolol and -19.1 +/-12.9 and -14.8 +/- 7.1 for nebivolol (p < 0.01 for all). This was the case also for standing blood pressure. Sitting and standing heart rate values were significantly reduced by both drugs, the bradicardic response induced by nebivolol treatment being significantly less than atenolol. Distribution of responders and non- responders was similar for nebivolol and atenolol, while the former drug showed a better tolerability profile and a lower incidence of side-effects. These data provide evidence, that, for the same antihypertensive effects, nebivolol shows a better tolerability profile than atenolol and a lower incidence of adverse effects.