Chrysoula Boutari

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome

AIM To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. METHODS This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. RESULTS The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group. CONCLUSION These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve MetS within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?

Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Current therapeutic strategies have not provided constant beneficial cardiovascular-related results. Sodium–glucose co-transporters 2 (SGLT-2) inhibitors have emerged as a novel antidiabetic class of drugs that exert favourable results in a variety of other cardiovascular risk factors too, such as increased blood pressure and body weight. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study was the first trial that evaluated cardiovascular outcomes in patients with diabetes with the use of empagliflozin, a member of this new class of drugs. Empagliflozin was associated with remarkable reduction of cardiovascular morbidity and mortality and all-cause death. On the contrary, stroke incidence was slightly increased, although the result did not reach statistical significance. It could be assumed that a drug providing such beneficial effects on cardiovascular outcomes, would have also the same impact in stroke risk. This finding could theoretically be attributed to ‘play of chance’. However, an increase of haematocrit was observed in EMPA-REG and other SGLT-2 inhibitors studies. Accumulating evidence suggests a direct association between increased haematocrit and stroke risk. Could this ‘stroke paradox’ be a result of the increased haematocrit levels noted with SGLT-2 inhibitors? The aim of this review is to critically assess both possibilities, given that increased stroke rates (if indeed true) should not be neglected and unattended.

Predictive value of the ankle brachial index in patients with acute ischemic stroke.

BACKGROUND Peripheral arterial disease (PAD) is frequently present in patients with acute ischemic stroke. However, there are limited data regarding the association between ankle brachial index (ABI) ≤ 0.90 (which is diagnostic of PAD) or > 1.40 (suggesting calcified arteries) and the severity of stroke and in-hospital outcome in this population. We aimed to evaluate these associations in patients with acute ischemic stroke. PATIENTS AND METHODS We prospectively studied 342 consecutive patients admitted for acute ischemic stroke (37.4 % males, mean age 78.8 ± 6.4 years). The severity of stroke was assessed with the National Institutes of Health Stroke Scale (NIHSS)and the modified Rankin scale (mRS) at admission. The outcome was assessed with the mRS and dependency (mRS 2 - 5) at discharge and in-hospital mortality. RESULTS An ABI ≤ 0.90 was present in 24.6 % of the patients whereas 68.1 % had ABI 0.91 - 1.40 and 7.3 % had ABI > 1.40. At admission, the NIHSS score did not differ between the 3 groups (10.4 ± 10.6, 8.3 ± 9.3 and 9.3 ± 9.4, respectively). The mRS score was also comparable in the 3 groups (3.6 ± 1.7, 3.1 ± 1.8 and 3.5 ± 2.3, respectively). At discharge, the mRS score did not differ between the 3 groups (2.9 ± 2.2, 2.3 ± 2.1 and 2.7 ± 2.5, respectively) and dependency rates were also comparable (59.5, 47.6 and 53.3 %, respectively). In-hospital mortality was almost two-times higher in patients with ABI ≤ 0.90 than in patients with ABI 0.91 - 1.40 or > 1.40 but this difference was not significant (10.9, 6.6 and 6.3 %, respectively). CONCLUSIONS An ABI ≤ 0.90 or > 1.40 does not appear to be associated with more severe stroke or worse in-hospital outcome in patients with acute ischemic stroke.

Hematocrit and Stroke: A Forgotten and Neglected Link?

&NA; Stroke is considered among the most common causes of mortality and disability, leading to dramatic socioeconomic consequences. From a pathophysiologic perspective, enhanced blood viscosity due to increased hematocrit might be associated with stroke through impaired cerebral blood perfusion. This association has remained rather neglected during previous decades, but newly emerged as an epicenter of scientific interest due to the unexpected elevation of stroke rates with sodium‐glucose cotransporter‐2 inhibitors, a new class of hypoglycemic drugs with otherwise dramatic cardiovascular benefits. The purpose of this article is to review available data on the relation between stroke and hematocrit values. Data from large observational studies point toward an increased risk for stroke in individuals with elevated hematocrit. Data also suggest that the coexistence of increased hematocrit values and hypertension significantly enhance the risk of cerebrovascular events compared with each condition alone. Additionally, high hematocrit values seem related to worse survival outcomes in post‐stroke patients. Collectively, the association between hematocrit and stroke seems to be strong and independent in high hematocrit values (>0.50) in both previously healthy individuals and post‐stroke patients, but remains less clarified in patients with normal hematocrit values.

Effect of Prior Treatment with Different Statins on Stroke Severity and Functional Outcome at Discharge in Patients with Acute Ischemic Stroke

Previous studies have suggested that prior treatment with statins is associated with improved outcome of acute ischemic stroke (IS) (1,2). However, there are no studies comparing the effects of different statins on IS outcome. We evaluated the effects of prior treatment with statins in 378 consecutive patients (age 78·8 ± 6·5 years) admitted for IS. Overall, 110 patients (29·1%) were taking a statin before admission. At admission, the National Institutes of Health Stroke Scale (NIHSS) score did not differ between patients who were on a statin and those who were not (8·5 ± 9·5 and 9·1 ± 9·7, respectively; P = NS). The modified Rankin scale (mRS) score at discharge was lower in patients who were on a statin than in those who were not (2·2 ± 2·2 and 2·8 ± 2·2, respectively; P = 0·020). Adverse outcome (mRS at discharge ≥2) was less frequent in patients who were on a statin (46·5 vs. 64·5% in those who were not; P = 0·003). In binary logistic regression analysis, predictors of adverse outcome were older age, current smoking, history of stroke, and higher NIHSS score at admission, whereas prior treatment with statins was associated with favorable outcome (Table 1). When the type of statin was entered in the multivariate model, prior treatment with simvastatin (n = 46, median dose 20 mg/day) was associated with a favorable outcome [odds ratio (OR) 0·21, 95% confidence interval (CI) 0·06–0·69, P = 0·011], whereas prior treatment with atorvastatin (n = 45, median dose 20 mg/day) (OR 0·94, 95% CI 0·29–3·01, P = NS) or with all other statins combined (rosuvastatin, pravastatin, or fluvastatin, n = 11, 7, and 1, respectively) (OR 0·19, 95% CI 0·03–1·36, P = NS) was not. In conclusion, treatment with simvastatin prior to stroke appears to be more beneficial than prior treatment with atorvastatin. Given the smaller lipidlowering potency of simvastatin compared with the same dose of atorvastatin (3), lipid-lowering-independent neuroprotective effects might explain the better outcome observed in simvastatin-treated patients (4,5).

Nonalcoholic Fatty Liver Disease vs. Nonalcoholic Steatohepatitis: Pathological and Clinical Implications

The implications and prognosis of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are substantially different. The aim of the present review is to describe and compare the pathological and clinical implications of these two conditions. Patients with NASH have a higher risk of progressing to cirrhosis than patients with NAFL but without steatohepatitis, who tend to have a non-progressive disease and only a minority progresses to NASH. Patients with NASH also are at greater risk to develop hepatocellular cancer (HCC) and NASH is the third commonest cause of HCC. In contrast, only few cases of HCC have been reported in patients with isolated NAFL. Given that nonalcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, it is also strongly related to cardiovascular disease (CVD). Again, it appears that patients with NASH have higher cardiovascular risk than patients with NAFL. Finally, all-cause mortality is also higher in patients with NASH than in patients with NAFL; mortality rates in the latter patients do not differ from the general population. In conclusion, NAFL and NASH have different prognosis and therefore it is imperative to develop accurate, noninvasive methods that will identify the presence of steatohepatitis in this population.

SGLT-2 Inhibitors and Cardiovascular Risk in Diabetes Mellitus: A Comprehensive and Critical Review of the Literature

BACKGROUND Diabetes mellitus is a major cardiovascular risk factor. Despite the vast pharmaceutical armamentarium, current therapeutic options for the treatment of type 2 diabetes mellitus were unable to provide consistent cardiovascular benefits, apart for metformin. The newest antidiabetic class of drugs, the SGLT-2 inhibitors, seem to provide significant survival benefits. The aim of this review is to present available data that will clarify whether SGLT-2 inhibitors could precipitate in reducing cardiovascular risk in diabetes mellitus. METHODS A comprehensive literature search was performed to identify available data from clinical and experimental studies evaluating the impact of SGLT-2 inhibitors in cardiovascular risk factors and outcomes. RESULTS Along with a mild antihyperglycemic effect, SGLT-2 inhibitors seem to possess multi-dimensional properties, affecting positively several recognized cardiovascular risk factors such as increased blood pressure, arterial stiffness, body weight and dyslipidemia. Furthermore, preliminary data point towards additional benefits, including reduction of albuminuria in diabetic nephropathy, and reduction of oxidative markers and fatty liver disease in experimental models. The efficacy and safety profile of empagliflozin, an SGLT-2 inhibitor, was evaluated in the EMPA-REG outcome study, and the results were quite impressive. Further credence comes from the analysis of pooled data of SGLT-2 inhibitors trials that have shown similar results. CONCLUSION SGLT-2 Inhibitors seem to be related with ameliorating effects on multiple cardiovascular risk factors. The first data from the EMPA-REG outcome study are indeed very promising. Several ongoing cardiovascular studies with this novel class of drugs will shed light and enforce or question current enthusiasm.

Effect of low (5 mg) vs high (20-40 mg) rosuvastatin dose on 24h arterial stiffness, central haemodynamics, and non-alcoholic fatty liver disease in patients with optimally controlled arterial hypertension

OBJECTIVE Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). METHODS Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. RESULTS Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. CONCLUSION Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference.

Canagliflozin and Hypertension: Is It the Optimal Choice for All Hypertensive Patients?

To the Editor: We have read with great interest the study by Townsend and colleagues, which provided important clinical data on the effect of canagliflozin on blood pressure (BP). Patients with type 2 diabetes are typically a group with difficult-to-control hypertension, most often in need of combination treatment to achieve BP control. The study efficiently demonstrated that canagliflozin seems to actually be an antihypertensive drug, which is in agreement with the results of several studies of impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on BP. Of note, the study demonstrated almost similar 24-hour ambulatory BP monitoring (ABPM) and office BP reductions, in contrast with data supporting that antihypertensive treatment leads to an ABPM reduction that is usually two-thirds of the office BP decrease. A meta-analysis of 44 studies assessing response to antihypertensive treatment with office and 24-hour BP measurements concluded that the average reductions in 24-hour systolic BP and diastolic BP were 36.5% and 36.8% less than the reduction in the office systolic BP and diastolic BP values, respectively. Therefore, the SGLT2 inhibitor not only demonstrated a decrease in BP but exceeded the expectations for its possible antihypertensive action. The importance of these findings are obvious and we would kindly ask the investigators to provide us with further data that could clarify several important topics on the management of hypertensive patients. First, it would be of interest to provide any differences in the efficacy of canagliflozin according to ethnicity (Hispanic/Latino vs other), especially in African American populations. It is known that patients of African ancestry exhibit greater tendency to retain sodium and have volume-dependent BP elevation. Therefore, diuretics are among the most effective BP-lowering drugs in African Americans. Second, diuretics are very useful in the management of hypertension in obese patients. A subanalysis of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial revealed that the combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor provided similar outcome benefits across the baseline adiposity status (lean, overweight, and obese). On the other hand, the combination of a diuretic with an angiotensin-converting enzyme inhibitor was associated with significantly greater benefits in obese patients than in overweight and especially in lean patients. Subsequently, a subanalysis according to baseline body mass index would specify any plausible effects of the diuretic action of the drug on BP in overweight or obese compared with lean patients (body mass index ≤25, 25–30, and >30 kg/m). Third, it is clear that canagliflozin demonstrates an important diuretic effect. Useful information could emerge through the detection of any differences in the efficacy of the drug according to baseline antihypertensive classes used, and especially whether the SGLT2 inhibitor was equally effective in patients already on therapy with diuretics and/or renin-angiotensin system inhibitors. Finally, considering the mechanism of action of canagliflozin, the simultaneous administration of the SGLT2 inhibitor with other antihypertensive agents could explain the occurrence of several adverse events. Did orthostasis, volume depletion, and renal function deterioration occur in patients already treated with diuretics or renin-angiotensin system inhibitors? The additional BP-lowering effect of canagliflozin raises high hopes for the future of this antidiabetic class of drugs. Further understanding of their impact in different subgroups is essential to help physicians individualize treatment options for their patients. Therefore, we would be deeply obliged to the authors for performing the suggested subanalyses.

Novel Drugs for Hypertension and Heart Failure: Struggling for a Place Under the Sun.

Backgound: Current drug therapy for the management of arterial hypertension and heart failure has provided substantial benefits but has also some limitations. LCZ696, a dual inhibitor of angiotensin receptor blockers and neprilysin, and finerenone, a non-steroidal mineralocorticoid receptor antagonist, are two recently developed novel agents for the management of these conditions. METHODS This review aims to present the pathophysiological basis for the use of these two novel drugs, critically discuss available clinical data, and provide future perspectives. RESULTS LCZ696 seems a very promising antihypertensive agent, that additionally generates clinically meaningful benefits in patients with heart failure with reduced injection fraction and raises expectations for the management of patients with heart failure with preserved ejection fraction. Finerenone aims to be safer than current aldosterone antagonists and has been so far tested in patients with heart failure and in patients with albuminuria. First available data are very promising for the efficacy of the drug, while it provides a better safety profile than current mineralocorticoid antagonists. CONCLUSION LCZ696 and finerenone are two novel drugs for the management of arterial hypertension and heart failure. First available data point toward important clinical benefits from their use. Future large trials further investigating the cardiovascular profile of these agents will establish the use of these drugs.