Heart Failure Challenge in T2DM

Introduction Heart failure is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.1 There are 463 million patient with diabetes mellitus all over the world .2 People with diabetes have a 2- to 5-fold higher risk of developing HF3, On the other hand more than 30% of patients with heart failure also have diabetes. Patients with heart failure and diabetes have a worse prognosis than those without diabetes4. UKPDs, Accord and advance trials showed that Intensive glycaemic control has not been shown to significantly impact the risk of HF.5,6 SGLT2 inhibitor is a new class of drugs to treat diabetes by inhibiting SGT2 decreases glucose reabsorption and increases urinary glucose excretion, improving glucose control in the diabetic patient.7 At 2015 EMPA-REG OUTCOME trial showed that Empagliflozin in addition to reduction of HBa1c, reduced the 3MAC by 14%, CV death by 38% and HHF by 35%. Is these cardiovascular benefit were a chance? 8 Then DECLARE-TMI58, CNVAS and VIRTIS trials showed that Dapagliflizon, Canagliflozin and ertuglifozin respectively in addition to reduction of HBa1c, reduce HHFso it is a class effect. 9,10,11 Because in these trials starting treatment at the preclinical stage may prevent HF progression and improve outcomes. Objective We have 3 questions to be answered: There are 4 trials to answer these Questions DAPA HF, DELIVER, EMPEROR-Reduced and EMPEROR –Preserved. DAPA-HF and EMPEROR –Reduced include patients with HF with reduced ejection fraction, diabetic and non-diabetic the result of both was reduce the risk of worsening HF or death from cardiovascular causes regardless of the presence or absence of DM. 10,11 Conclusion The results of these trials FDA Approves Dapagliflozin for low EF-Heart Failure in diabetic and Non-diabetic. FDA had granted Fast Track status for empagliflozin. Waiting the result of other trials.12

SGLT2 Inhibitors: Physiology and Pharmacology

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

Lipid Accumulation Product Combined With Urine Glucose Excretion Improves the Efficiency of Diabetes Screening in Chinese Adults

BackgroundTo compare the efficacy of lipid accumulation product (LAP) and urine glucose excretion (UGE) in predicting diabetes and evaluate whether the combination of LAP and UGE would help to improve the efficacy of using LAP alone or UGE alone in identifying diabetes.MethodsData from 7485 individuals without prior history of diabetes who participated in a cross-sectional survey in Jiangsu, China, were analyzed. Each participant underwent an oral glucose-tolerance test. Operating characteristic curves (ROC) and logistic regression analyses were used to evaluate the performance of LAP and UGE in identification of newly diagnosed diabetes (NDM) and prediabetes (PDM).ResultsFor subjects with NDM, the area under the ROC curve was 0.72 for LAP and 0.85 for UGE, whereas for PDM, these values were 0.62 and 0.61, respectively. Furthermore, LAP exhibited a comparable sensitivity with UGE in detecting NDM (76.4% vs 76.2%, p = 0.31). In predicting PDM, LAP showed a higher sensitivity than UGE (66.4% vs 42.8%, p < 0.05). The combination of LAP and UGE demonstrated a significantly higher sensitivity than that of LAP alone and UGE alone for identification of NDM (93.6%) and PDM (80.1%). Moreover, individuals with both high LAP and high UGE had significantly increased risk of NDM and PDM than those with both low LAP and low UGE.ConclusionsThe combination of LAP and UGE substantially improved the efficacy of using LAP and using UGE alone in detecting diabetes, and may be a novel approach for mass screening in the general population.

A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats

Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.

Nonlinear ODE mathematical analysis of the insulin-glucose model in the presence of a condition in glycemia function H(G).

This work aims to analyze a fifth-order nonlinear ordinary differential equations that describe the glucoregulatory model system based on intravenous injection of glucose via in-vivo experimentation in rats reported previously in the literature. A mathematical analysis shows that existence of an invariant plane condition associated with insulin can determine a type 1 or type 2 diabetes classification. The bounded positive invariant domain (BPID) by applying the Lyapunov direct method establishes a mathematical preamble where maximum cell population is associated to an upper bound set given by a localizing function by applying the LCIS (Localizing Compact Invariant Set) method. Furthermore, an equilibrium point's existing condition is defined if U(t) is an invariant plane and H(G) exists. Also are discussed parameter conditions for renal glucose excretion (k5) and the rate constant of glucose absorption (ka) as a case of study when glycemia function presents existence conditions with or without insulin variable.

Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class

Sodium-glucose co-transporter 2 (SGLT2) inhibitors facilitate urine glucose excretion by reducing glucose reabsorption, leading to ameliorate glycemic control. While the main characteristics of type 2 diabetes mellitus are insufficient insulin secretion and insulin resistance, SGLT2 inhibitors have some favorable effects on pancreatic β-cell function and insulin sensitivity. SGLT2 inhibitors ameliorate fatty liver and reduce visceral fat mass. Furthermore, it has been noted that SGLT2 inhibitors have cardio-protective and renal protective effects in addition to their glucose-lowering effect. In addition, several kinds of SGLT2 inhibitors are used in patients with type 1 diabetes mellitus as an adjuvant therapy to insulin. Taken together, SGLT2 inhibitors have amazing multifaceted effects that are far beyond prediction like some emerging magical medicine. Thereby, SGLT2 inhibitors are very promising as relatively new anti-diabetic drugs and are being paid attention in various aspects. It is noted, however, that SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection. In addition, we should bear in mind the possibility of diabetic ketoacidosis, especially when we use SGLT2 inhibitors in patients with poor insulin secretory capacity.