Blood pressure and cardiovascular disease in the Asia Pacific region

Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

SGLT2 inhibitors: are they safe?

Background/aims SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). Methods CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. Results Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1β, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. Conclusion Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

/pdf/effects-of-the-sglt-2-inhibitor-canagliflozin-on-adenine-44ymge832t.pdf

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats

The lack of mechanically effective contraction of the left atrium (LA) during atrial fibrillation (AF) disturbs blood flow, increasing the risk of thrombosis and ischemic stroke. Thrombosis is most likely in the left atrial appendage (LAA), a small narrow sac where blood is prone to stagnate. Slow flow promotes the formation of erythrocyte aggregates in the LAA, also known as rouleaux, causing viscosity gradients that are usually disregarded in patient-specific simulations. To evaluate these non-Newtonian effects, we built atrial models derived from 4D computed tomography scans of patients and carried out computational fluid dynamics simulations using the Carreau-Yasuda constitutive relation. We examined six patients, three of whom had AF and LAA thrombosis or a history of transient ischemic attacks (TIAs). We modeled the effects of hematocrit and rouleaux formation kinetics by varying the parameterization of the Carreau-Yasuda relation and modulating non-Newtonian viscosity changes based on residence time. Comparing non-Newtonian and Newtonian simulations indicates that slow flow in the LAA increases blood viscosity, altering secondary swirling flows and intensifying blood stasis. While some of these effects are subtle when examined using instantaneous metrics like shear rate or kinetic energy, they are manifested in the blood residence time, which accumulates over multiple heartbeats. Our data also reveal that LAA blood stasis worsens when hematocrit increases, offering a potential new mechanism for the clinically reported correlation between hematocrit and stroke incidence. In summary, we submit that hematocrit-dependent non-Newtonian blood rheology should be considered when calculating patient-specific blood stasis indices by computational fluid dynamics. 

/pdf/scp-non-newtonian-scp-blood-rheology-impacts-left-atrial-t110lvqo.pdf

<scp>Non‐Newtonian</scp> blood rheology impacts left atrial stasis in <scp>patient‐specific</scp> simulations

This research sought to ascertain the relationship between hematocrit (HCT) and mortality in patients with sepsis. Methods: A retrospective analysis was conducted on the clinical data of septic patients who were hospitalized between 2008 and 2019 in an advanced academic medical center in Boston, Massachusetts, registered in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, We analyzed basic information including gender, age, race, and types of the first admission, laboratory indicators including HCT, platelets, white blood cells, albumin, bilirubin, hemoglobin, and serum creatinine, and 30-day mortality. A Cox proportional hazards regression model was utilized to analyze the relationship between HCT and 30-day mortality in patients with sepsis. Results: This research recruited 2057 patients who met the research requirements from 2008 to 2019. According to the HCT level, it was classified into the low HCT level, the regular HCT level, and the high HCT level. The 30-day mortality rate was 62.6%, 27.5%, and 9.9% for patients with the low HCT level, the regular HCT level, and the high HCT level, respectively (p < 0.05). The multivariate Cox proportional hazard regression model analysis displayed that compared with patients with the regular HCT level, the 30-day mortality of patients with the low HCT level increased by 58.9% (hazard ratio = 1.589, 95% confidence interval (CI) = 1.009–2.979, p < 0.05). Conclusion: The low HCT level is an independent risk factor for the increase of the 30-day mortality in patients with sepsis and can be used as a significant predictor of the clinical outcome of sepsis.

/pdf/association-between-hematocrit-and-the-30-day-mortality-of-3nnjbon9.pdf

Association between hematocrit and the 30-day mortality of patients with sepsis: A retrospective analysis based on the large-scale clinical database MIMIC-IV

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.

Hematocrit and Stroke: A Forgotten and Neglected Link?

Background Diabetic nephropathy is a crucial microvascular complication of diabetes mellitus that is associated with elevated cardiovascular risk. SGLT-2 inhibitors are a new class of hypoglycemic drugs that positively affect several risk factors of cardiorenal damage. Objectives The study aimed to review and critically discuss available data on the association of SGLT-2 inhibitors treatment with kidney function, progress of diabetic kidney disease, and renal related outcomes, as well to unveil potential mechanisms of action that mediate such effects. Method We conducted a comprehensive search of the literature on the renal related effects of SGLT-2 inhibitors, to compose a narrative mini-review. Results The administration of SGLT-2 inhibitors was observed to exert beneficial effects on a wide cluster of risk factors of chronic kidney disease, such as hyperglycemia, blood pressure, serum uric acid, and body weight. Data from the first two large, randomized, clinical trials of SGLT-2 inhibitors conducted to address the renal related outcomes of SGLT-2 inhibitors suggest substantial benefits on estimated glomerular filtration rate decline and albuminuria. Conclusion The initial data suggest clinically meaningful benefits of the SGLT-2 inhibitors in diabetic patients in relevance with chronic kidney disease. Future, well-designed randomised clinical trials need to be further investigated such as nephroprotective outcomes, that if confirmed, could lead to new perspectives in the management of diabetic nephropathy.

Sodium-glucose Cotransporter 2 Inhibitors: Nephroprotective Impact on Diabetic Kidney Disease

Background Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the general population. The disease ranges from simple steatosis, to non-alcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. Several drugs are used in daily clinical practice to manage the disease. However, data on their efficacy in liver histology are not consistent. Aim We discuss current treatment options for NAFLD and NASH and preliminary results from novel drugs under investigation. Results Among various drugs assessed for the management of NAFLD and NASH, only pioglitazone and vitamin E have provided consistent benefits on liver histology, and are recommended by the European and American guidelines. Statins were shown to produce clinically meaningful results in patients with NAFLD or NASH. Other drugs such as metformin and polyunsaturated fatty acids that are being used in clinical practice off-label have provided benefits on terms of hepatic biochemical and diabetesrelated markers; data on liver histology with these drugs are scarce and from small studies. Several new approaches to reduce inflammation, steatosis or fibrosis have shown promising results in experimental models of NAFLD or NASH lesions and are being evaluated in humans. Conclusion Pioglitazone and vitamin E are the only drugs providing consistent benefits and are currently recommended for NASH. Various pathogenetic pathways are being targeted to reduce steatosis, inflammation and fibrosis and early data on several novel drugs are very promising. On-going human trials will unveil their true impact.

Current and Potential Future Pharmacological Approaches for Non- Alcoholic Fatty Liver Disease.

Background Mineralocorticoid receptor antagonists are a second-line class of antihypertensive drugs, which have been accounted for as the optimal add-on therapy in the triple algorithm for the management of resistant hypertension. Objectives To assess the effects of mineralocorticoid receptor antagonists in the treatment of patients with essential hypertension and resistant hypertension. Method We conducted a meticulous review of the literature and comprehensive identification of the clinical trials assessing the efficacy of mineralocorticoid receptor antagonists in individuals with primary and resistant hypertension. Results MRAs have been thoroughly tested in several clinical studies in relevance to blood pressure lowering effects, over the last six decades. Accumulating data observed that MRAs resulted in a significant reduction in blood pressure level in patients with resistant hypertension. In addition, spironolactone was found to beneficially affect the management of resistant hypertension. Conclusion Mineralocorticoid receptor antagonists exert a significant antihypertensive effect. Future welldesigned randomized controlled studies are greatly needed to address crucial clinical aspects in the field.

Mineralocorticoid Receptor Antagonists in Essential and Resistant Hypertension

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Hematocrit and Stroke: A Forgotten and Neglected Link?

Sodium-glucose Cotransporter 2 Inhibitors: Nephroprotective Impact on Diabetic Kidney Disease

Current and Potential Future Pharmacological Approaches for Non- Alcoholic Fatty Liver Disease.

Mineralocorticoid Receptor Antagonists in Essential and Resistant Hypertension