Nonalcoholic Fatty Pancreas Disease: Role in Metabolic Syndrome, "Prediabetes," Diabetes and Atherosclerosis.

Fat accumulation in the pancreas associated with obesity and the metabolic syndrome (MetS) has been defined as "non-alcoholic fatty pancreas disease" (NAFPD). The aim of this review is to describe the association of NAFPD with obesity, MetS, type 2 diabetes mellitus (T2DM) and atherosclerosis and also increase awareness regarding NAFPD. Various methods are used for the detection and quantification of pancreatic fat accumulation that may play a significant role in the differences that have been observed in the prevalence of NAFPD. Endoscopic ultrasound provides detailed images of the pancreas and its use is expected to increase in the future. Obesity and MetS have been recognized as NAFPD risk factors. NAFPD is strongly associated with non-alcoholic fatty liver disease (NAFLD) and it seems that the presence of both may be related with aggravation of NAFLD. A role of NAFPD in the development of "prediabetes" and T2DM has also been suggested by most human studies. Accumulation of fat in pancreatic tissue possibly initiates a vicious cycle of beta-cell deterioration and further pancreatic fat accumulation. Additionally, some evidence indicates a correlation between NAFPD and atherosclerotic markers (e.g., carotid intima-media thickness). Weight loss and bariatric surgery decreases pancreatic triglyceride content but pharmacologic treatments for NAFPD have not been evaluated in specifically designed studies. Hence, NAFPD is a marker of local fat accumulation possibly associated with beta-cell function impairment, carbohydrate metabolism disorders and atherosclerosis.

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.

Renoprotective Effects of SGLT2 Inhibitors: Beyond Glucose Reabsorption Inhibition.

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.

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.

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.

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.

Cholesteryl ester transfer protein inhibitors: challenges and perspectives.

INTRODUCTION: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction. AREAS COVERED: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review. Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.

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.

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.

Leptin and adiponectin levels in patients with ankylosing spondylitis. The effect of infliximab treatment.

BACKGROUND: Adipose tissue-derived leptin and adiponectin control hunger, energy expenditure, insulin sensitivity, endothelial function, reproduction and immunity and are thought to play a role in autoimmune diseases. However, their role in ankylosing spondylitis (AS) is not clearly defined. Tumour necrosis factor ΤNF-α is a potential modulator of adipocytokines. The effect of longterm anti-TNF-α treatment on plasma levels of leptin and adiponectin has not been assessed so far. OBJECTIVES: To assess the effect of a 6-month anti-TNF-α treatment on serum leptin and adiponectin levels in AS patients. METHODS: Thirty men with AS were included in the study. Thirty age- and weight-matched men served as controls. Clinical and biochemical parameters were assessed and serum levels of leptin and adiponectin were measured with enzyme immunoassay methods prior to and after the 6-month treatment with infliximab. RESULTS: Mean age and disease duration of AS patients were 40.6±13.7 and 13.4±8.4 years, respectively. At baseline, AS patients exhibited significantly higher adiponectin (15.4±8.3 vs. 8.6±4.2 µg/ml, p<0.05), but no difference in leptin levels (7.2±2.9 vs. 8.9±6.4 ng/ml, p=NS). Adipocytokines did not correlate with any disease parameter. Body weight of the patients did not change significantly over the 6-month period. Serum levels of leptin and adiponectin did not change significantly after the 6-month treatment. CONCLUSIONS: Adiponectin levels were significantly higher in AS patients compared with controls. Infliximab treatment did not change serum levels of leptin and adiponectin suggesting that the anti-TNF-α treatment may not modulate significantly their levels.

Combination of fenofibrate with non-statin drug regimens.

OBJECTIVE: We present the available data on the effects of combined therapy of fenofibrate with drugs affecting lipid metabolism other than statins. METHODS: We consider studies evaluating the effects of combined therapy of fenofibrate with bile acid sequestrants (BAS), ezetimibe, niacin, n-3 fatty acids, plant sterols, orlistat, rimonabant, metformin and glitazones. RESULTS: Combination of BAS (especially colesevelam) with fenofibrate had additional effects on metabolic parameters in patients with mixed hyperlipidemia. Combination of ezetimibe with fenofibrate may be a useful approach to improve the overall lipid profile of patients with mixed hyperlipidemia. There is a further reduction in triglyceride levels when n-3 fatty acids are administered with fenofibrate in patients with severe hypertriglyceridemia. Combined fenofibrate and orlistat treatment further improves metabolic parameters in overweight/obese patients with metabolic syndrome. The fenofibrate/thiazolidinedione combination is an alternative for diabetic patients intolerant to statins, though differences exist between pioglitazone and rosiglitazone. CONCLUSIONS: For patients who cannot tolerate statins there are useful combinations of fenofibrate with other drugs affecting lipid metabolism. These combinations improve several metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular events.