V. Tsimihodimos

Comparison of the Efficacy of Atorvastatin and Micronized Fenofibrate in the Treatment of Mixed Hyperlipidemia

Objective 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 levels >240 and 160 mg/dl, respectively, and serum triglyceride level >200 mg/dl). Methods 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. Results 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. Conclusion 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.

Cola‐induced hypokalaemia: pathophysiological mechanisms and clinical implications

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.

Increased plasma visfatin concentration is a marker of an atherogenic metabolic 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.

Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

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).

Effects of 12 months of treatment with disease-modifying anti-rheumatic drugs on low and high density lipoprotein subclass distribution in patients with early rheumatoid arthritis: a pilot study.

Objectives: 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. Method: LDL and HDL subclass distribution was determined using a polyacrylamide gel-tube electrophoresis method. Results: 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. Conclusions: 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.

Dipeptidyl peptidase-4 inhibitors and protection against stroke: A systematic review and meta-analysis.

BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with an increased risk of stroke and an unfavourable outcome following stroke. Apart from pioglitazone, glucose-lowering modalities have not been shown to protect against stroke. Nevertheless, there is evidence from experimental studies of potential neuroprotective effects with dipeptidyl peptidase (DPP)-4 inhibitors, especially if treatment starts before stroke. OBJECTIVE To perform a meta-analysis of available evidence regarding the risk of stroke in individuals taking DPP-4 inhibitors. METHODS All available data from prospective randomized placebo-controlled trials involving DPP-4 inhibitors in T2DM patients published up to December 2015 were considered. The included trials reported data on the incidence of stroke with a recruitment rate of at least 100 diabetes patients and a follow-up of at least 12 weeks. RESULTS A total of 19 small randomized clinical trials (RCTs) evaluating the efficacy and safety of gliptins (n=9278), along with three multicentre prospective double-blind placebo-controlled RCTs assessing cardiovascular outcomes as the primary endpoint and involving 36,395 T2DM patients, were included in the analysis. Pooled analysis of the small RCTs showed a non-significant trend towards benefit with DPP-4 inhibitors against stroke [odds ratio (OR): 0.639, 95% confidence interval (CI): 0.336-1.212; P=0.170]. In contrast, in the analysis of RCTs reporting on cardiovascular safety, there was no difference in the risk of stroke with gliptin treatment compared with a placebo (OR: 0.996, 95% CI: 0.850-1.166; P=0.958). CONCLUSION The promising data from experimental studies regarding cardioprotective gliptin-associated effects against stroke were not supported by available data from trials specifically looking at cardiovascular safety.

Effect of ezetimibe on lipoprotein subfraction concentrations: the role of atorvastatin pretreatment

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.

Therapy with statins is effective in some patients with homozygous familial hypercholesterolemia

Patients with homozygous familial hypercholesterolemia have elevated markedly low-density lipoprotein (LDL) cholesterol levels that are refractory to commonly used doses of hypolipidemic drugs, including statin [1]. We read with great interest the recently published report by Raal et al. who showed that high doses of atorvastatin (80 mg/day) are effective in lowering LDL cholesterol by 28% in patients with homozygous FH through inhibition of VLDL (and possibly LDL) synthesis by the liver cell [2]. High doses of statins (simvaststin 80–160 mg/day or atorvastatin 80 mg/day) have been shown previously to be partially effective in lowering LDL cholesterol levels in these patients [3–5]. Interestingly, statins reduced LDL cholesterol, not only in patients with defective LDL receptors but also in patients with no functioning LDL receptors. However, there are no data concerning the effect of statins in patients with class V mutations of the LDL receptor. In class V mutation, the LDL receptor retains the ability to bind and internalise its ligand but fails to release it in the endosome and thus the receptor does not recycle to the cell surface [6]. It has been pointed out that individuals with such mutations have lower lipid levels and are more responsive to hypolipidemic drug therapy [6]. We have identified recently five patients who are homozygous for the G1775A mutation, which has been previously characterized as a class V mutation. These patients had relatively low serum total and LDL cholesterol levels (422980 and 354975 mg/dl, respectively) and they were treated with relatively high doses of statins (lovastatin 40 mg/day, pravastatin 40 mg/day, simvastatin 40 mg/day or fluvastatin 80 mg/day) before atorvastatin was available in our country. As shown in the Table 1, significant decreases in the LDL cholesterol levels (mean decrease by 23.5%) were achieved, comparable to those which were noticed after atorvastatin administration in previous studies [2,4,5]. When atorvastatin (80 mg/day) was administered in these patients, a more pronounced decrease in LDL cholesterol levels by 35% was observed. It is suggested that therapy with statins and especially with the most potent drugs of this class should be considered in patients with homozygous FH either as an adjuvant to apheresis or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.

Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors

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 EMPA-REG BP (12 week efficacy and safety study of empagliflozin in hypertensive patients with type 2 diabetes mellitus) trial, which showed that empagliflozin administration in both the 10 and 25 mg/d doses resulted in a decrease in 24-h systolic blood pressure (SBP) by 3.44 and 4.16 mmHg, respectively, and a smaller decrease in diastolic blood pressure (DBP) by 1.36 and 1.72 mmHg, respectively [1]. The drug modestly decreased nighttime BP values and seemed to beneficially affect surrogate markers of arterial stiffness in patients with type 2 diabetes mellitus and hypertension [2]. The SGLT2 inhibitor-induced decrease in BP seems to be higher in patients with baseline SBP >140 mmHg and may play a prominent role in the beneficial effects of empagliflozin in the EMPA-REG OUTCOME (empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients) trial [3]. It has been shown that BP reduction is a class effect of SGLT2 inhibitors, since they induce a considerable decrease in SBP and a lesser decrease in DBP compared with other glucose-lowering drugs, without any differences among the different agents within this group of antidiabetic drugs [4]. The BP reduction with these drugs exhibited a statistically significant dose dependency only for canagliflozin (−3.9 and −5.3 mmHg with 100 and 300 mg/d, respectively, for SBP and −2.1 and −2.5 mmHg with 100 and 300 mg/d, respectively, for DBP) [4]. Additionally, a meta-analysis of studies with empagliflozin, dapagliflozin, and canagliflozin showed a positive effect on sitting BP [5]. Importantly, although orthostatic dizziness has been reported with these agents, it has been emphasized that the SGLT2 inhibitor-induced BP reduction is not associated with orthostatic hypotension (relative risk compared with control treatment 0.72; 95% confidence interval 0.47–1.09) and this finding has been verified by the recent results of the EMPA-REG OUTCOME trial [3,4]. A number of possible mechanisms, which may be interrelated, have been proposed for the BP reduction with SGLT2 inhibitors (Table 1). 1.1. Hemodynamic mechanisms

SGLT2 inhibitors-induced electrolyte abnormalities: An analysis of the associated mechanisms

AIMS Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that affect serum electrolytes levels. The aim of this review is the detailed presentation of the associated mechanisms of the SGLT2 inhibitors-induced electrolyte abnormalities. MATERIALS AND METHODS Eligible trials and relevant articles published in PubMed (last search in July 2017) are included in the review. RESULTS SGLT2 inhibitors induce small increases in serum concentrations of magnesium, potassium and phosphate. The small increase in serum phosphate concentration may result in reduced bone density and increased risk of bone fractures, mainly seen with canagliflozin, but recent meta-analyses did not show increased risk of bone fractures with SGLT2 inhibitors. CONCLUSION The increases in serum electrolytes levels may play a role in the cardiovascular protection that has been recently reported with empagliflozin and canagliflozin.