SGLT2 inhibitors and the kidney: Effects and mechanisms.

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.

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.

Gitelman syndrome: an analysis of the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities.

Gitelman syndrome is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter in the early distal convoluted tubules. The review presents the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities observed in patients with Gitelman syndrome. The syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. The knowledge of the pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of other tubular diseases.

Phosphate imbalance in patients with heart failure.

Patients with heart failure often exhibit electrolyte abnormalities, such as hyponatremia or hypokalemia/hyperkalemia. Although not as common as the other electrolyte disturbances observed in patients with heart failure, phosphate imbalance is also of high importance in this population. The aim of this review is to present the mechanisms of low or high phosphate serum levels in patients with heart failure and its role in the pathogenesis and progression of heart dysfunction. Hypophosphatemia in patients with heart failure may be the result of co-existing electrolyte and acid-base abnormalities, pharmacological treatments, decreased intestinal absorption or secondary to sympathetic nervous system activation and co-morbidities, such as diabetes mellitus or heavy alcohol consumption. Hypophosphatemia can affect multiple organ systems including the cardiovascular system. Depletion of phosphate can lead to ventricular arrhythmias and elimination of ATP synthesis, resulting in reversible myocardial dysfunction. Hyperphosphatemia, observed mainly in patients with chronic kidney failure, is also associated with cardiac hypertrophy, which may worsen cardiac contractility and heart failure. Studies have also shown an association of high-normal serum phosphate levels with vascular and valvular calcification. Therefore, serum phosphate imbalances may exhibit a causal role in the pathogenesis and progression of heart failure.

Pharmacological management of diabetic dyslipidemia.

INTRODUCTION: Diabetes mellitus is associated with increased cardiovascular disease (CVD) risk. Areas covered: Main goal of hypolipidemic treatment in diabetic patients is low-density lipoprotein cholesterol (LDL-C) lowering with the use of statins. Addition of ezetimibe is useful in diabetic patients who cannot achieve their LDL-C target. However, many diabetic patients have increased residual CVD risk, which is mainly attributed to high triglycerides and low high-density lipoprotein (HDL-C) values. The addition of fenofibrate targets these variables and possibly reduces residual CVD risk, but a possible beneficial effect has been shown only in a pre-specified subgroup analysis in patients with high triglycerides and low HDL-C values. The newer proprotein convertase subtilisin/kexin type 9 inhibitors lower substantially LDL-C levels, but data from specifically designed trials in diabetic patients are not currently available. Although the cholesterol ester transfer protein (CETP) inhibitors have shown harmful effects or lack of efficacy in completed clinical trials, the newer CETP inhibitors have promising effects on lipid profile and carbohydrate metabolism, but their effects on CVD risk and safety profile have not been assessed. Expert commentary: Clinicians have a range of pharmacological options to reduce the CVD risk of diabetic patients.

MANAGEMENT OF ENDOCRINE DISEASE: Hypothyroidism-associated hyponatremia: mechanisms, implications and treatment.

BACKGROUND: Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels (<135 mmol/L). SUMMARY: The aim of this short review is the presentation of the mechanisms of hyponatremia and of the available data regarding its implications and treatment in patients with hypothyroidism. Hypothyroidism is one of the causes of hyponatremia, thus thyroid-stimulating hormone determination is mandatory during the evaluation of patients with reduced serum sodium levels. The main mechanism for the development of hyponatremia in patients with chronic hypothyroidism is the decreased capacity of free water excretion due to elevated antidiuretic hormone levels, which are mainly attributed to the hypothyroidism-induced decrease in cardiac output. However, recent data suggest that the hypothyroidism-induced hyponatremia is rather rare and probably occurs only in severe hypothyroidism and myxedema. Other possible causes and superimposed factors of hyponatremia (e.g. drugs, infections, adrenal insufficiency) should be considered in patients with mild/moderate hypothyroidism. Treatment of hypothyroidism and fluid restriction are usually adequate for the management of mild hyponatremia in patients with hypothyroidism. Patients with possible hyponatremic encephalopathy should be urgently treated according to current guidelines. CONCLUSIONS: Severe hypothyroidism may be the cause of hyponatremia. All hypothyroid patients with low serum sodium levels should be evaluated for other causes and superimposed factors of hyponatremia and treated accordingly.

Use of intravenous fluids/solutions: a narrative review.

OBJECTIVE: Intravenous fluids are broadly categorized into colloids and crystalloids. The aim of this review is to present under a clinical point of view the characteristics of intravenous fluids that make them more or less appropriate either for maintaining hydration when enteral intake is contraindicated or for treating hypovolemia. METHODS: We considered randomized trials and meta-analyses as well as narrative reviews evaluating the effects of colloids or crystalloids in patients with hypovolemia or as maintenance fluids published in the PubMed and Cochrane databases. RESULTS: Clinical studies have not shown a greater clinical benefit of albumin solutions compared with crystalloid solutions. Furthermore, albumin and colloid solutions may impair renal function, while there is no evidence that the administration of colloids reduces the risk of death compared with resuscitation with crystalloids in patients with trauma, burns or following surgery. Among crystalloids, normal saline is associated with the development of hyperchloremia-induced impairment of kidney function and metabolic acidosis. On the other hand, the other commonly used crystalloid solution, the Ringer's Lactate, has certain indications and contraindications. These matters, along with the basic principles of the administration of potassium chloride and bicarbonate, are meticulously discussed in the review. CONCLUSIONS: Intravenous fluids should be dealt with as drugs, as they have specific clinical indications, contraindications and adverse effects.

L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study.

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. L-Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of L-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive L-carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the L-carnitine/simvastatin group [-19.4%, from 52 (20-171) to 42 (15-102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [-6.7%, from 56 (26-108) to 52 (27-93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B and TAG were observed in both groups. Co-administration of L-carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.

Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise.

Hyponatremia (Na(+) <135 mmol/l) is the most common electrolyte disorder. Cirrhosis represents a rather frequent cause of hyponatremia mainly due to systemic and splanchnic vasodilation resulting in decreased effective arterial blood volume, which leads to excessive non-osmotic secretion of antidiuretic hormone. However, hyponatremia of multifactorial origin may be seen in patients with liver diseases. The review focuses on the factors and pathogenetic mechanisms of decreased sodium levels other than the hemodynamic compromise of cirrhosis in patients with liver diseases. The mechanisms and causal or contributing role of pseudohyponatremia, hyperglycemia, infections, drugs and toxins as well as of endocrine disorders, renal failure and cardiac disease in patients with liver disease are meticulously discussed. Hyponatremia of multifactorial origin is frequently observed in patients with liver diseases, and special efforts should be made to delineate the underlying causative and precipitating factors as well as the risk factors of the osmotic demyelination syndrome in order to properly manage this serious electrolyte disorder and avoid treatment pitfalls.

Pitavastatin and carbohydrate metabolism: what is the evidence?

Statins are the cornerstone of hypolipidemic treatment but recently have been associated with increased risk of developing diabetes mellitus. However, the risk of incident diabetes is not the same among statins. Pitavastatin lowers low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol but also seems to be neutral in terms of risk of incident diabetes. Clinical and experimental evidence shows that pitavastatin increases adiponectin levels and reduces oxidative stress, effects that seem to be implicated in the beneficial effect of the drug on carbohydrate metabolism variables. Pitavastatin is a useful hypolipidemic drug, which is promising for patients with increased diabetes risk or established diabetes.

Ten common pitfalls in the evaluation of patients with hyponatremia.

Hyponatremia is the most common electrolyte disorder in hospitalized patients associated with increased morbidity and mortality. On the other hand, inappropriate treatment of hyponatremia (under- or mainly overtreatment) may also lead to devastating consequences. The appropriate diagnosis of the causative factor is of paramount importance for the proper management and avoidance of treatment pitfalls. Herein, we describe the most common pitfalls in the evaluation of the hyponatremic patient, such as failure to exclude pseudohyponatremia or hypertonic hyponatremia (related to glucose, mannitol or glycine), to properly assess urine sodium concentration and other laboratory findings, to diagnose other causes of hyponatremia (cerebral salt wasting, reset osmostat, nephrogenic syndrome of inappropriate antidiuresis, prolonged strenuous exercise, drugs) as well as inability to measure urine osmolality or delineate the diagnosis and cause of the syndrome of inappropriate antidiuretic hormone secretion. Clinicians should be aware of these common clinical practice pitfalls, which could endanger patients with hyponatremia.

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.

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.

Distinct effects of fixed combinations of valsartan with either amlodipine or hydrochlorothiazide on lipoprotein subfraction profile in patients with hypertension.

The effect of antihypertensive drugs on lipoprotein subfraction profile is still under investigation. In this study the effects of fixed combination of valsartan with either amlodipine (V-A) or hydrochlorothiazide (V-H) on low-density-lipoprotein (LDL) and high-density-lipoprotein (HDL) subfraction profile of patients with stage 2 or 3 hypertension were assessed. A total of 60 drug-naive patients were randomized to either V-A (160/5 mg, n=30) or V-H (160/12.5 mg, n=30). At baseline as well as 16 weeks post-treatment analysis of the LDL and HDL subfraction profile was conducted by using LDL Lipoprint System. Both V-A and V-H effectively reduced blood pressure (BP) to similar levels. An increase in the cholesterol concentration of small-dense LDL subfractions (by 18.2%, P<0.05) was observed in the V-H group, whereas this parameter remained unchanged in the V-A group. Therefore, mean LDL particle size was decreased in the V-H group (from 267 ± 5 to 266 ± 5Å, P<0.05). HDL-Cholesterol (HDL-C) levels were reduced by 4.7% (P<0.05) in the V-H group, mirrored by a reduction in the cholesterol mass of small and intermediate HDL particles. In conclusion, despite similar reductions in BP, V-H combination may adversely affect serum lipids as well as LDL and HDL subfraction profile as compared with V-A.

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). 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 < 0.05 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%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. CONCLUSIONS: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.

Lysis syndrome during therapy of visceral leishmaniasis.

INTRODUCTION: Lysis syndrome is a constellation of metabolic disorders usually seen after the initiation of chemotherapy for rapidly proliferating malignancies (tumor lysis syndrome). Reported herein is a tumor lysis-like syndrome after the initiation of anti-infective therapy for visceral leishmaniasis. PATIENTS AND METHODS: Ten consecutive patients with visceral leishmaniasis were administered liposomal amphotericin B. Levels of serum uric acid, phosphate, creatinine, blood urea nitrogen, potassium, calcium, and magnesium were evaluated prior to as well as 4 and 30 days following the initiation of treatment. RESULTS: During the 4th post-treatment day significant increases in the levels of serum uric acid, phosphate, creatinine, and blood urea nitrogen were seen, while the levels of calcium, potassium, and magnesium were not significantly altered. Patients were treated by hydration, urine alkalization, and administration of allopurinol as needed. A recovery of metabolic abnormalities was recorded 1 month later, although some patients had evidence of residual injury. CONCLUSION: A lysis syndrome may complicate the treatment of visceral leishmaniasis. Awareness of this complication can lead to the initiation of prophylactic treatment as well as to early recognition and management of this syndrome in susceptible patients.

Effects of thyroid dysfunction on lipid profile.

Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is beneficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypocholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients.

High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia.

The aim of the study was to compare the efficacy of high-dose rosuvastatin, low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega-3 fatty acids with regard to the lipid profile in patients with mixed hyperlipidemia. The primary endpoint was changes in non-high density lipoprotein-cholesterol (non-HDL-C) levels. Study participants were randomly allocated to receive rosuvastatin 40 mg (n = 30, R group), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, RF group) or rosuvastatin 10 mg plus n-3 fatty acids 2 g (n = 30, RN group). Non-HDL-C levels were reduced in all groups: in R group by 54%, in RF group by 42% and in RN group by 42%. Significant reductions in total cholesterol (TC), low density lipoprotein (LDL)-C and triglyceride levels were observed in all groups. The reductions in total and LDL-C were greatest in the R group while a more pronounced reduction of triglycerides in the RF group compared with that in the R and the RN group was observed. HDL-C levels were significantly increased only in the RF group. In conclusion, high doses of rosuvastatin and small doses of rosuvastatin plus either fenofibrate or n-3 fatty acids exhibit favorable effects on both LDL-C and non-HDL-C levels. However, rosuvastatin monotherapy more potently reduces these parameters. The combination of rosuvastatin plus fenofibrate leads to a greater decrease in triglyceride levels and a greater increase in HDL-C levels compared with the other two treatments. While awaiting the results of ongoing trials high doses of rosuvastatin may represent the treatment of choice in individuals with mixed dyslipidemia.

The (TAAAA)n polymorphism of the SHBG gene in men with the metabolic syndrome.

OBJECTIVE: Low serum Sex Hormone-Binding Globulin (SHBG) has been proposed as an indicator of the Metabolic Syndrome (MS) and cardiovascular disease in men. On the other hand, the (TAAAA)n repeat polymorphism in the SHBG gene has been shown to affect SHBG levels. The possible role of this polymorphism in the MS was examined in the present study. DESIGN: The study population consisted of 83 men with MS aged 54.9±14.8 years and 166 healthy men of the same age. The diagnosis of MS was based on the criteria proposed by the National Cholesterol Education Program - Third Adult Treatment Panel (NCEP-ATP III). The waist circumference was recorded and blood samples were obtained after overnight fasting for biochemical and hormonal tests. The SHBG(TAAAA)N polymorphism was genotyped in peripheral blood leucocytes. RESULTS: Genotype analysis for the (TAAAA)n polymorphism of the SHBG gene in the patients and controls identified 6 alleles having 6-11 TAAAA repeats. Patients with MS had more frequently short-allele genotypes (with 6/6, 6/7, 6/8, 7/7, 7/8 or 8/8 tandem repeats) compared to controls (53% vs. 39.8%, p=0.047). In the entire study population, men homozygous for the 6 TAAAA repeat allele had lower SHBG levels (p=0.01) and higher waist circumference (p=0.006) than men heterozygous or non-carriers of this allele. CONCLUSION: Short SHBG(TAAAA)N allele genotypes may play a role in the development of the MS. The mechanism of this contribution remains unclear.