Alterations of paraoxonase and platelet-activating factor acetylhydrolase activities in patients on peritoneal dialysis.

OBJECTIVE: The more atherogenic lipid profile seen in peritoneal dialysis (PD) patients cannot fully explain the increased incidence of atherosclerosis in this population. Oxidative modification of low-density lipoproteins (LDL) is considered to play a central role in the atherogenic process, whereas high-density lipoprotein (HDL) protects LDL from oxidation. On the other hand, it has been suggested that the LDL and HDL of PD patients are more resistant to oxidation than those of control subjects, while PD-HDL equally protects LDL from oxidation compared to control-HDL. Two HDL-associated enzymes have been shown to protect both LDL and HDL from oxidation: paraoxonase (PON1) and HDL-associated platelet-activating factor acetylhydrolase (HDL-PAF-AH). Furthermore, low PON1 activity and high total plasma PAF-AH concentration, which represents mainly the LDL-associated enzyme, have been shown to be independent risk factors for coronary artery events in the general population. However, there are limited data regarding possible alterations of these enzymes in PD patients. The aim of our study was to examine the possible alterations of PON1 and PAF-AH activities in patients undergoing PD. DESIGN: A cross-sectional study. SETTING: A university medical center. PARTICIPANTS: 56 PD patients of Caucasian origin and 86 matched controls were studied. MEASUREMENTS: In all subjects, serum PON1 activity toward paraoxon (paraoxonase) and phenylacetate (arylesterase), as well as total serum and HDL-PAF-AH activities were measured; PON1 genetic polymorphisms known to influence PON1 activity (Q192R and M55L) were determined. RESULTS: The PD patients exhibited significantly increased serum PON1 (paraoxonase) and PON1 (arylesterase) activities compared to controls, regardless of the PON1 polymorphisms or the levels of HDL cholesterol. Additionally, PD patients had significantly elevated activities of total serum PAF-AH and HDL-PAF-AH, independently of the levels of LDL or HDL cholesterol. The ratio of HDL-PAF-AH/ total PAF-AH, which has recently been suggested to be a potential marker of atherogenicity, was decreased in these patients compared to controls. Moreover, no difference in the prevalence of PON1 polymorphisms between PD patients and controls was found. CONCLUSION: The elevated activities of PON1 and HDL-PAF-AH could explain the increased resistance of PD-HDL to oxidation; the higher activity of total PAF-AH and the decreased HDL-PAF-AH/ total PAF-AH ratio could contribute to the increased incidence of atherosclerosis in these patients.     

Statins and their increased risk of inducing diabetes

Introduction: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses.

Areas covered: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic β cells together with increased insulin resistance of various tissues.

Expert opinion: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution.     

SGLT2 inhibitors: are they safe?

Sodium–glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.     

Effectiveness and metabolic effects of perindopril and diuretics combination in primary hypertension

The effectiveness as well as the metabolic effects of the combination of diuretics [hydrochlorothiazide (HCT) vs indapamide (IND)] and perindopril (P) in 14 patients (7 male, 7 female) aged 37-62 years with mild idiopathic hypertension were studied. Following a 4-week wash-out period and a 4-week period of monotherapy with P (4 mg/daily), IND (2.5 mg/daily) or HCT (25 mg/daily) was added for 4 weeks. Selection of the diuretic agent was random. Following a 4-week wash-out period from the diuretic, in which only P was given, the alternative diuretic was administered for another period of 4 weeks. P decreased blood pressure levels significantly. However, the drug was more efficacious in patients with higher plasma renin activity (PRA). Combination treatment induced an additional decrease in the blood pressure levels, mainly in patients with lower PRA. The combination of P + HCT was more effective than the combination P + IND. The addition of either HCT or IND evoked a small but statistically significant increase in serum glucose levels while fasting as well as during the 75 g oral glucose challenge. However, insulin levels did not change significantly during the study. Small but not statistically significant changes in serum electrolytes and lipid parameters were observed during the various phases of the study, while a statistically significant increase in the serum uric acid was noticed when the combination P + HCT was given. We conclude: (1) P in small doses is an effective and safe antihypertensive agent, (2) PRA has a predictive value in determining the effectiveness of P treatment, (3) the combination of P with small doses of HCT or IND is more efficacious than P alone, (4) the combination treatment has adverse effects in the carbohydrate tolerance, while there are not significant changes in serum electrolyte and lipid parameters.     

Increased platelet reactivity to the aggregatory effect of platelet activating factor, in vitro, in patients with heterozygous familial hypercholesterolaemia

Patients with familial hypercholesterolaemia (FH) present with high plasma total- and low density lipoprotein (LDL)-cholesterol levels and develop premature and often severe atherosclerosis. Elevations of total- and LDL cholesterol levels are not only related to an increased risk of atherosclerosis, but may also exert prothrombotic effects via platelet activation leading to acute coronary events. In the present work, the platelet response to the aggregatory effect of platelet-activating factor (PAF) in relation to the plasma PAF-acetylhydrolase (PAF-AH) activity and to their lipidemic profile was studied in 20 heterozygous FH patients. The PAF EC(50) aggregation values in the patient group were significantly decreased ( P < 0.03) compared with the control group (19.5 5.2 nM and 30.4 7.2 nM, respectively). Moreover, the maximal percentage of aggregation to 100 nM PAF was significantly increased in the patient group compared with controls (26.5 8.2% vs 15.2 3.1%, respectively, P < 0.03). Both platelet aggregation parameters were correlated to the plasma total- and LDL-cholesterol levels, as well as to the apolipoprotein B (apo B) levels. The maximal percentage of aggregation to 10 microM ADP was also significantly increased in the patient group compared with controls (51.5 10.3% vs 32.4 9.0%, respectively, P < 0.02) but was not correlated to any plasma lipid parameter. The total plasma PAF-AH activity in the heterozygous FH patients was significantly higher compared with controls (109.8 15.9 nmol/ml per min vs 68.4 18.0 nmol/ml per min, respectively, P < 0.0001), whereas the HDL-associated PAF-AH activity did not differ significantly between the two groups. Our results suggest that the increased aggregatory response of platelets to PAF despite the significantly higher plasma PAF-AH activity, could be an important factor contributing to the higher atherogenicity and incidence of acute coronary events observed in patients with heterozygous FH.     

The effect of moxonidine on plasma lipid profile and on LDL subclass distribution

Moxonidine is a new antihypertensive agent whose mechanism of action appears to involve specific stimulation of imidazoline receptors resulting in an inhibition of the activity of the central and peripheral sympathetic nervous system. The drug seems to behave neutrally with respect to plasma lipid parameters. However, there are no data on the effects of moxonidine on the low-density lipoprotein (LDL) subclass pattern or on the LDL oxidation susceptibility, both of which are known to play a prominent role in the pathogenesis of atherosclerosis. Thus, we undertook the present study to examine the influence of moxonidine on the LDL subspecies profile and their susceptibility to copper-induced oxidative modification in 20 hypertensive patients (11 men, 9 women) aged 38-61 years. Moxonidine administered at a dose of 0.4 mg daily for 8 weeks produced a significant decrease in both systolic and diastolic blood pressure (from 147 +/- 10 to 131 +/- 11 mm Hg, P < 0.001, and from 98 +/- 4.5 to 86 +/- 5 mm Hg, P < 0.001, respectively). No significant change in plasma lipid profile was observed after moxonidine administration. Additionally, no change in the susceptibility of LDL subclasses to copper-induced oxidative modification was noticed. Finally, drug therapy was not followed by any change in either LDL phenotype or in mass and composition of the three LDL subfractions. We conclude, that unlike other antihypertensive drugs, such as beta-blockers which may predispose to expression of a relatively atherogenic lipoprotein subclass pattern, moxonidine does not affect either plasma lipid parameters or lipoprotein composition.     

Multiple metabolic abnormalities in a patient with essential thrombocytosis

A patient with extreme essential thrombocytosis who exhibited an array of real or spurious metabolic abnormalities is described. Careful venipuncture and prompt measurement avoided unnecessary further laboratory investigation and potentially dangerous overtreatment.