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Aims Numerous clinical trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors exert a favorable effect on the indices of renal function (albuminuria, glomerular filtration rate decline over time) and the incidence of hard renal endpoints such as renal death or time to initiation of renal replacement therapy. Materials and methods In this review, we describe in detail the evidence regarding the nephroprotective mechanisms of SGLT2 inhibitors and describe the risk factors that may predispose to the development of acute kidney injury in patients receiving these drugs. Results Although the impact of these drugs on renal hemodynamics seems to represent the most important renoprotective mechanism of action, many other effects of these compounds, including beneficial effects on metabolism and blood pressure, have been proposed to contribute to the observed clinical benefit. Conclusions SGLT2 inhibitors clearly act beneficially in terms of kidney function with many proposed mechanisms.

The understanding that statins reduce but not eliminate the cardiovascular risk associated with disturbed lipid metabolism and the existence of forms of dyslipidemia that are unresponsive or only partially responsive to statins have led to the development of many novel lipid-lowering drugs. Accumulating evidence suggests that the interplay between carbohydrate and lipid metabolism is bidirectional. Thus, any intervention that affects lipid metabolism has the potential to influence the homeostasis of glucose. In this review we summarize the available data on the effects of the evolving lipid-lowering drugs on carbohydrate metabolism.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are associated with a decrease in blood pressure (BP) levels. BP reduction was confirmed using 24-h ambulatory blood pressure monitoring in the EM...

Summary Background: Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). Objective: To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. Methods: We previously randomised patients with low-density lipoprotein cholesterol (LDL-C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. Results: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment.

Type 2 diabetes mellitus (T2DM) is a serious health problem of epidemic proportions, which is associated with high cardiovascular morbidity and mortality. Thus, preventing or at least delaying the onset of T2DM is imperative. Subjects with impaired glucose homeostasis (pre-diabetes) are very prone to develop overt T2DM. Treatment of accompanying cardiovascular risk factors, such as hypertension and dyslipidemia, in these patients is frequently complex as it can further impair the distorted glucose homeostasis. This review discusses the pathophysiology of lipid disorders and hypertension in pre-diabetes along with the effects of lipid modifying and antihypertensive therapy in glucose/insulin homeostasis. A critical overview and suggestions of different treatment options for pre-diabetic patients with dyslipidemia and/or hypertension are also presented.

Summary Background/Aims: The consumption of soft drinks has increased considerably during the last decades. Among them, the cola-based preparations are possibly the refreshments with the largest sales worldwide. In addition to the possible detrimental effects of moderate, chronic cola consumption, it has been proposed that the consumption of large amounts of cola-based soft drinks may result in severe hypokalaemia. Methods: In this review, we discuss the clinical significance of these disturbances and summarise the pathophysiological mechanism that may underlie the development of this rare, but potentially severe, side effect. Results/Conclusion: Several lines of evidence suggest that the chronic consumption of large amounts of cola soft drinks may adversely affect potassium homeostasis and result in potentially severe conditions such as hypokalaemic myopathy.

To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile, including lipoprotein(a) levels, and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia (serum total and low-density lipoprotein cholesterol levels240 and 160 mg/dl, respectively, and serum triglyceride level200 mg/dl).This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period.Atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase.Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.

Patients with rheumatoid arthritis (RA) have increased cardiovascular risk. The aim of the present study was the assessment of low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass distribution in patients with early RA (ERA, n = 30) compared with age- and sex-matched healthy subjects (n = 30), as well the effect of treatment for 12 months with the disease-modifying anti-rheumatic drugs (DMARDs) methotrexate and prednisone in this distribution.LDL and HDL subclass distribution was determined using a polyacrylamide gel-tube electrophoresis method.ERA patients exhibited increased levels of inflammatory markers and high disease activity score. ERA patients had higher serum levels of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG) whereas their serum HDL cholesterol (HDL-C) levels were significantly lower compared with controls. ERA patients exhibited significantly higher plasma levels of small dense LDL-C (sdLDL-C), leading to a significantly decreased mean LDL diameter. ERA patients had significantly decreased small HDL particles (HDL-3) concentration whereas serum levels of large HDL particles (HDL-2) did not differ compared with controls. Treatment with DMARDs resulted in a significant decrease in inflammatory markers and disease activity, along with a significant increase in HDL-C serum levels. The concentration of sdLDL-C did not change significantly during treatment. We observed a significant increase in the levels of large HDL-2 whereas the concentration of small HDL-3 did not significantly change.Patients with ERA have increased sdLDL-C levels and decreased HDL-C levels because of decreased concentration of the small HDL-3 subclass. The administration of DMARDs induced a significant increase in HDL-C levels, which was attributed to the increase in large HDL-2 serum concentration.

Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS).To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS.We previously randomised patients with low-density lipoprotein cholesterol (LDL-C)160 and TG200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis.The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL-C levels (by 7.7%, p0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω.All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.

Background and aims Visfatin is associated with atherosclerosis-related diseases. We assessed in non-diabetic individuals the association of plasma visfatin levels with cardiovascular disease (CVD) risk and the atherosclerosis-related metabolic variables. Methods and results When study population ( n = 179, age 49 ± 11 years) was divided according to visfatin tertiles, the 10-year CVD Framingham risk scores were significantly increased in the top visfatin tertile. We observed a positive association between visfatin tertiles with waist circumference and blood pressure, as well as with total cholesterol and triglyceride levels, but not with apolipoprotein C-III, fibrinogen or pre-beta1 high density lipoprotein (HDL). The percentage of large HDL subclasses was significantly lower and the percentage of small HDL subclasses over the HDL-C concentration was significantly higher in the top visfatin tertile compared with the other tertiles. The atherogenic small dense low density lipoprotein subclasses (sdLDL-C) were significantly increased in the top visfatin tertile compared with the lower tertiles. High sensitivity C-reactive protein (hsCRP) concentration was significantly increased in the top visfatin tertile compared with the lower tertiles. Although age and sex distribution did not differ between visfatin tertiles, the simultaneous adjustment for these parameters attenuated the significance of the differences observed in sdLDL-C and hsCRP levels. Similarly, after adjustment for hsCRP or waist circumference, only triglycerides and blood pressure levels, as well as the distribution of HDL subclasses, remained significantly different between visfatin tertiles. Conclusions Our results support a role for visfatin in the detection of subjects with many metabolic abnormalities, which result in increased CVD risk.

Fenofibrate represents the most commonly used fibric acid derivative. The drug exerts its metabolic effects by modulating the expression of several genes involved in lipoprotein metabolism. In addition, numerous studies suggest that fenofibrate may also affect the progression of the atherosclerotic process by several lipid-independent mechanisms. This review considers the clinical pharmacology of fenofibrate and the current evidence on the pleiotropic effects of this fibric acid derivative. Curr Pharm Des

Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A2 (HDL-LpPLA2) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P

Atherosclerosis

Atherosclerosis

Introduction: Recently published data indicate that the effect of ezetimibe on lipoprotein subfraction distribution in patients receiving statin therapy may differ substantially from that observed in patients treated with ezetimibe monotherapy. The aim of our study was to directly compare the effects of ezetimibe added to established atorvastatin treatment on lipoprotein subfractions with those obtained by ezetimibe monotherapy. Material and methods: Forty dyslipidaemic patients who failed to reach their assigned LDL-C target while on atorvastatin therapy (20 mg/day) for at least 6 months were included in the study. Ezetimibe (10 mg/day) was added to atorvastatin in all patients. The concentrations of the individual lipoprotein subfractions were determined using the Lipoprint method at baseline (prior to the addition of ezetimibe) as well as after 16 weeks of combination treatment. The changes in lipoprotein subfraction concentrations were compared with those observed in 40 age- and sex-matched statin-naive patients receiving ezetimibe monotherapy for 16 weeks. Results: Ezetimibe administration reduced VLDL concentrations either when used as monotherapy or when added to established atorvastatin treatment. However, in contrast to ezetimibe monotherapy, which reduced the concentrations of all LDL subfractions, the addition of ezetimibe in patients receiving atorvastatin decreased LDL cholesterol values exclusively by reducing the concentrations of large, buoyant LDL subfractions. In addition, while ezetimibe monotherapy reduced mainly the concentrations of small, dense LDL subspecies, the addition of ezetimibe in patients receiving atorvastatin equally reduced the concentration of all HDL particles. Conclusions: The effect of ezetimibe on lipoprotein subfractions is significantly affected by previous atorvastatin treatment.

Astract. Apolipoprotein (apo) E gene polymorphism and its effect on serum lipid parameters were examined in a Greek population originating from northwestern Greece (n = 555). The allele frequencies were e2: 6.3%, e3: 80.7%, and e4: 13.0%. The e4 allele frequency was higher in our population than was previously reported in individuals from other parts of Greece. ApoE polymorphism was associated with significant differences in serum lipid, and lipoprotein levels. Particularly, individuals with the e2 allele had higher serum triglyceride and apoE levels and lower levels of total cholesterol, low-density lipoprotein cholesterol, and apoB, compared to those with the alleles e3 and e4. However, the impact of the e4 allele on lipid parameters seen in other populations was not observed in our population. Furthermore, the combination of apoE polymorphism and serum apoE concentration explained a larger percentage of serum lipid variability than the polymorphism alone. In conclusion, the results of our study suggest that ethnic differences, as well as alterations of serum apoE levels, significantly modify the relationship between apoE gene polymorphism and serum lipid variability. (received 1 March 2004; accepted 1 May 2004)

Atherosclerosis

Atherosclerosis