Rosa Bonet

Low-density lipoprotein size and lipoprotein-associated phospholipase A2 in HIV-infected patients switching to abacavir or tenofovir

BACKGROUND The aim of this study was to assess changes in the size and cholesterol content of low-density lipoproteins (LDL) and changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC). METHODS This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48. RESULTS A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDL-PLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm. CONCLUSIONS A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients.

Effect of improving glycemic control on low-density lipoprotein particle size in type 2 diabetes

The current study sought to assess the effect of improving glycemic control in type 2 diabetes on the components of diabetic dyslipidemia, especially low-density lipoprotein (LDL) size. A total of 33 type 2 diabetic patients (48.5% women, age 59.6 +/- 11.1 years, body mass index [BMI] 28.9 +/- 4.9, diabetes duration 6 [0 to 40] years, 40.7% on insulin) were seen at the hospital because of poor glycemic control (hemoglobin A(1c) [HbA(1c)] 10.33% +/- 1.89%). Triglyceride, LDL-cholesterol (LDLc, Friedewald/ ultracentrifugation), high-density lipoprotein HDL-cholesterol (HDLc, direct method), apolipoproteins AI (apoAI) and B (apoB) (immunoturbidimetry), and LDL size (gradient gel electrophoresis) were measured at baseline and after improvement in glycemic control (decrease >/= 1 percentage point in HbA(1c) and final HbA(1c) </= 8%). Improvement in glycemic control (HbA(1c) 7.01% +/- 0.63%, P <.0005 v baseline) after a follow-up of 3.5 (range, 1 to 13) months resulted in a significant reduction in LDLc (3.34 +/- 1.02 v 3.62 +/- 1.15 mmol/L, P <.05) and apoB (1.07 +/- 0.25 v 1.17 +/- 0.29 g/L, P <.01) and an increase in HDLc (1.21 +/- 0.32 v 1.13 +/- 0.34 mmol/L, P <.05) and apoAI (1.36 +/- 0.24 v 1.27 +/- 0.24 mmol/L, P < 0.01) in the whole group, and an increase in LDL particle size (25.61 +/- 0.53 v 25.10 +/- 0.31 nm, P <.005) in the 14 patients showing LDL phenotype B at baseline. No significant changes were seen in body weight or BMI. We conclude that improvement of glycemic control in type 2 diabetes improves most of the components of diabetic dyslipidemia, including a shift towards larger LDL particles in subjects with phenotype B.

The effect of VLDL particles on the accuracy of a direct LDL-cholesterol method in type 2 diabetic patients.

OBJECTIVE To assess the accuracy of the direct method LDL-c Plus, in type 2 diabetic patients.LDL-c Plus was measured in 64 consecutive samples of type 2 diabetic patients and compared with betaquantification (BQ), Friedewalds and an alternative formula. METHODS LDL-c Plus was also measured in the VLDL (d<1.006 Kg/L) fraction of these samples and in total serum and the VLDL fraction of a phenotype III patient, before and after diluting it with saline or VLDL from normolipidemic subjects. RESULTS LDL-c Plus showed a significant, constant bias (-8.5 +/- 5.6%) against BQ which correlated with VLDL-cholesterol/total triglyceride ratio (r = 0.760, p < 0.0005); bias decreased to zero when the ratio increased. In the VLDL fraction of the diabetic patients and the phenotype III patient LDL-c Plus measured 20.7 +/- 11.6% and 56.2% of the cholesterol, respectively. Dilution with saline did not alter the latter percentage, whereas dilution with normolipidemic VLDL reduced it showing that LDL-c Plus recognized cholesterol-enriched particles in the d<1.006 Kg/L. Friedewalds formula also showed a significant, constant bias (-3.1 +/- 6.4%) against BQ, whereas the alternative formula did not (0.5 +/- 6.1%). Both calculations classified patients better than LDL-c Plus did at NCEP cut-off points. CONCLUSIONS In type 2 diabetic patients, LDL-c Plus underestimates LDL-c but measures cholesterol associated to IDL particles in the d<1.006 Kg/L fraction. Although LDLc-Plus might be a better cardiovascular risk estimator when well standardized, at the moment, it does not seem to be superior to calculations.

Lack of Change of Lipoprotein(a) Levels by the Optimization of Glycemic Control With Insulin Therapy in NIDDM Patients

OBJECTIVE To evaluate the effect of glycemic control improvement with insulin therapy on lipoprotein(a) [Lp(a)] levels in patients with NIDDM. RESEARCH DESIGN AND METHODS We performed a longitudinal study in a tertiary referral center to compare lipid and Lp(a) levels before and after 3 months of insulin therapy in 60 poorly controlled NIDDM patients (32 men, 28 women). Patients previously treated with oral hypoglycemic agents (n = 50) received one to two insulin doses, and those previously treated with insulin (n = 10) received multiple insulin doses. Lp(a) levels were measured by the Terumo method. Differences between the two periods were assessed by the paired t test and Wilcoxons test. RESULTS After 3 months of insulin therapy, HbA1c decreased from 9.6 ± 1.9 to 6.0 ± 1.4% (P < 0.0005) in all patients and from 9.1 ± 2.1 to 6.1 ± 2.9% (P < 0.05) in patients under multiple insulin doses, being ≤ 6.0% in 59% of patients. Total triglyceride and VLDL cholesterol levels decreased (P < 0.01) and HDL cholesterol increased significantly (P < 0.0005). However, no changes in Lp(a) levels were observed in all patients (25.3 ± 25.0 vs 25.7 ± 27.2% mg/dl) and in patients with baseline Lp(a) levels above (63.5 ± 15.5 vs. 65.1 ± 23.1 mg/dl) or below 30 mg/dl (11.5 ± 7.5 vs. 11.5 ± 7.3 mg/dl). In addition, patients reaching HbA1c levels ≤ 6.0% or > 6.0% presented similar Lp(a) levels (26.0 ± 29.1 vs 25.3 ± 25.0 mg/dl). Moreover, no correlations were observed between changes in Lp(a) levels and in the glycemic control parameters. CONCLUSIONS This study shows that the improvement of glycemic control by insulin therapy does not influence plasma Lp(a) levels, measured by the Terumo method, in NIDDM patients, independently of baseline values and the degree of glycemic control reached.

Plasma lipoprotein(a) levels are not influenced by glycemic control in type 1 diabetes.

OBJECTIVE To determine the influence of glycemic control improvement with intensive therapy on lipoprotein(a) [Lp(a)] concentrations in type 1 diabetic patients. RESEARCH DESIGN AND METHODS A total of 105 poorly controlled type 1 diabetic patients (60 men, 45 women) without diabetic complications participated in a longitudinal study performed in a tertiary referral center, to compare lipid, lipoprotein, and Lp(a) levels before and after 3 months of intensive therapy with multiple insulin doses. Lp(a) levels were measured by the Terumo method. Differences between the two periods were assessed by the paired t test and Wilcoxons test. RESULTS After 3 months of intensive therapy, all patients exhibited improved glycemic control. HbA1c decreased from 8.9 ± 2.4 to 6.5 ± 1.6% (P < 0.0001), being ≤6% in 47% of patients. However, although a more favorable lipoprotein profile was obtained, no changes in Lp(a) concentrations were observed in the whole group of patients (16.7 ± 17.3 vs. 17.2 ± 17.7 mg/dl) or in patients with baseline Lp(a) levels above 30 mg/dl (47.1 ± 14.8 vs. 47.4 ± 18.9 mg/dl) or below 30 mg/dl (9.6 ± 7.3 vs. 10.2 ± 6.7 mg/dl). In addition, patients reaching HbA1c ≤6 or >6% presented similar Lp(a) levels (19.7 ± 18.0 vs. 15.0 ± 17.4 mg/dl), and changes in Lp(a) did not correlate with those observed in HbA1c. CONCLUSIONS These data demonstrate that the improvement of glycemic control does not influence plasma Lp(a) concentrations in type 1 diabetic patients independently of baseline Lp(a) levels and the degree of glycemic control.

Postprandial lipidemia is normal in non-obese type 2 diabetic patients with relatively preserved insulin secretion.

To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with diet only, 12 non-obese patients (8 males, hemoglobin A(1c) [HbA(1c)] 6.80 +/- 0.67%) and 14 controls of similar age, body mass index (BMI), and fasting triglyceride (Tg) were given a test meal (58 g fat, 100,000 IU vitamin A). Fasting low-density lipoprotein (LDL) cholesterol (LDLc), high-density lipoprotein (HDL) cholesterol (HDLc), free fatty acids, and apolipoprotein B (apoB), and fasting and postprandial Tg, retinylpalmitate (RP), LDL size, glucose, and insulin were measured. The homeostasis assessment model (HOMA) index and lipoprotein (Lpl) and hepatic (HL) lipase activities were estimated. Patients showed lower fasting HDLc (1.12 +/- 0.26 v 1.40 +/- 0.28 mmol/L, P =.02) and a trend towards smaller LDL particles, which was significant 4 hours postprandially (25.86 +/- 0.40 v 26.16 +/- 0.30 nm, P =.04). The area under the curve of Tg (AUC-Tg) and RP, and Lpl were similar, but HL was higher in patients (156.63 +/- 23.89 v 118 +/- 43.27 U/L, P =.011). HL correlated inversely with LDL size and directly with the HOMA index. In conclusion, normotriglyceridemic type 2 diabetic patients with insulin resistance but relatively preserved insulin secretion show low fasting HDLc and increased HL, but normal postprandial lipidemia.

Molecular diagnosis of lecithin: cholesterol acyltransferase deficiency in a presymptomatic proband.

Abstract We report the molecular diagnosis of a lecithin : cholesterol acyltransferase deficiency in a 12-year old proband with a high-density lipoprotein deficiency. The increased percentage of free cholesterol in plasma and high-density lipoprotein indicated an inherited lecithin : cholesterol acyltransferase deficiency as the underlying cause. This diagnosis was confirmed by a low plasma lecithin : cholesterol acyltransferase activity and a combination of genetic analyses which demonstrated compound heterozygosity for two mutations in the lecithin : cholesterol acyltransferase gene of the proband. One was a previously unreported 2 bp deletion leading to a stop signal in codon 77 and the other a point mutation causing Arg 135 → Gln transition. To our knowledge, this is the first diagnosis of lecithin : cholesterol acyltransferase deficiency in a pre-symptomatic patient. Whether the proband will develop signs of complete lecithin : cholesterol acyltransferase deficiency or the milder form (Fish Eye Disease) is uncertain, although the former possibility is more likely. The risk of premature atherosclerosis conferred by lecithin : cholesterol acyltransferase deficiency is not well established. The proband will need to be carefully monitored in the future.