Empagliflozin

Target of Action

Empagliflozin primarily targets the sodium-glucose co-transporter-2 (SGLT2) . SGLT2 is the predominant transporter responsible for the reabsorption of glucose from the glomerular filtrate back into the circulation . It is primarily located in the kidney and plays a crucial role in maintaining glucose homeostasis .

Mode of Action

This compound acts as an inhibitor of SGLT2 . By inhibiting SGLT2, this compound prevents glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine . This leads to a reduction in blood glucose levels, which is beneficial for managing type 2 diabetes mellitus .

Biochemical Pathways

This compound’s action on SGLT2 affects several biochemical pathways. One of the key pathways involves the NLRP3 inflammasome and MyD88-related pathways . Inhibition of these pathways by this compound has been associated with anti-apoptotic and anti-fibrotic effects . Additionally, this compound has been shown to impact pathways related to cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets .

Result of Action

This compound has several molecular and cellular effects. It has been shown to ameliorate myocardial extracellular matrix remodeling, cardiomyocyte stiffness, and concentric hypertrophy . Additionally, this compound has been found to inhibit microglia activation and neuroinflammation resulting from injury . It also improves pancreatic beta-cell function by reducing pancreatic beta-cell burden and glucotoxicity .

Action Environment

The action of this compound can be influenced by various environmental factors. For instance, renal function can impact the efficacy of this compound, as its mechanism of action is contingent on the renal excretion of glucose . Therefore, this compound may be held in cases of acute kidney injury . Furthermore, the drug’s blood pressure-lowering effects have been associated with its action in non-diabetic hypertensive rats .

Synthetic Routes and Reaction Conditions: Empagliflozin is synthesized through a multi-step process involving several key intermediates. One common synthetic route involves the following steps:

Formation of Intermediate I: The initial step involves the reaction of 4-chloro-3-(4-(tetrahydrofuran-3-yloxy)benzyl)phenyl with a suitable glucosyl donor to form Intermediate I.

Formation of Intermediate II: Intermediate I undergoes further reactions, including protection and deprotection steps, to yield Intermediate II.

Final Coupling: Intermediate II is then coupled with a suitable glucosyl donor under basic conditions to form this compound

Industrial Production Methods: Industrial production of this compound typically involves large-scale synthesis using optimized reaction conditions to ensure high yield and purity. The process includes:

Refluxing: The reaction mixture is refluxed to facilitate the formation of the desired product.

Purification: The crude product is purified using techniques such as recrystallization and chromatography to obtain this compound with high purity

Types of Reactions: Empagliflozin undergoes various chemical reactions, including:

Oxidation: this compound can undergo oxidative degradation under certain conditions, leading to the formation of degradation products.

Hydrolysis: The compound is susceptible to hydrolysis, especially under acidic and basic conditions.

Common Reagents and Conditions:

Oxidative Degradation: Reagents such as hydrogen peroxide or other oxidizing agents can induce oxidative degradation.

Hydrolysis: Acidic or basic conditions, such as hydrochloric acid or sodium hydroxide, can facilitate hydrolysis.

Major Products Formed:

Oxidative Degradation Products: Various oxidation products can be formed, depending on the specific conditions and reagents used.

Hydrolysis Products: Hydrolysis can lead to the formation of smaller fragments and degradation products.

Empagliflozin is a relatively new drug that inhibits the sodium–glucose cotransporter 2 (SGLT2), increasing urinary glucose excretion . Originally used to induce a hypoglycemic effect in patients with type 2 diabetes mellitus (T2DM), this compound has demonstrated other beneficial effects, including nephroprotection and as a breakthrough in treating heart failure (HF) . Studies have shown benefits in patients with and without T2DM .

Scientific Research Applications

A study evaluated this compound initiated in-hospital for acute heart failure . The primary outcome was clinical benefit, assessed using a hierarchical composite of death from any cause, the number of heart failure events, time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days . More patients treated with this compound had clinical benefit compared with placebo . Clinical benefit was seen for both acute de novo and decompensated chronic heart failure and regardless of ejection fraction or diabetes status . this compound was well tolerated, with fewer serious adverse events than placebo . These results extend and complement those of EMPEROR-Reduced and EMPEROR-Preserved by focusing on patients hospitalized for acute heart failure across the range of ejection fraction .

Renal Protection: this compound significantly reduces the relative risk of developing or worsening nephropathy by 39% compared to placebo . The relative risk reduction for progression to macroalbuminuria between the this compound and placebo groups was 38% . The risk of doubling plasma creatinine levels was reduced by 44% in the this compound group, and the relative risk of starting renal replacement therapy (RRT) was significantly 55% lower .

Alzheimer's Disease: A five-drug combination consisting of Tofacitinib, Niraparib, Baricitinib, this compound, and Doxercalciferol can serve as a promising drug combination for AD treatment . this compound, an SGLT2 inhibitor, regulates the insulin signaling pathway linking diabetes and AD . this compound can target EGFR in the MAPK, FOXO, and Rap1 signaling pathways via SLC5A1 .

Improved Cardiac Function: this compound administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality . this compound significantly ameliorated adverse LV remodeling, decreased LV volumes and LV hypertrophy, reduced neurohormonal activation, and improved cardiac systolic function compared with the control group . Moreover, this compound also improved diastolic function in this HFrEF model .

Improved Clinical Stability: this compound reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction . this compound reduced the total number of heart failure hospitalizations that required intensive care and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention . Patients assigned to this compound were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up .

Data Table

Empagliflozin is part of the SGLT2 inhibitor class of drugs. Other similar compounds in this class include:

Canagliflozin: Another SGLT2 inhibitor used to manage type 2 diabetes.

Dapagliflozin: This compound is also used to treat type 2 diabetes and has been approved for use in heart failure.

Ertugliflozin: Another SGLT2 inhibitor with similar mechanisms of action but different pharmacokinetic properties.

Uniqueness of this compound: this compound is unique in its high selectivity for SGLT2 over SGLT1, which contributes to its efficacy and safety profile. It has also been shown to have significant cardiovascular and renal benefits, making it a valuable option for patients with type 2 diabetes and comorbid conditions .

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily used in the management of type 2 diabetes mellitus (T2DM). Its biological activity extends beyond glycemic control, showing significant cardiovascular benefits and effects on cardiac metabolism. This article reviews the biological activity of this compound, supported by recent studies, clinical trials, and case studies.

This compound works by inhibiting the SGLT2 protein in the kidneys, leading to reduced glucose reabsorption and increased glucose excretion. This mechanism not only lowers blood glucose levels but also has secondary effects on cardiovascular health.

• Cardiac Energy Metabolism : Recent studies indicate that this compound enhances cardiac energy status by increasing ATP levels in both cytosolic and mitochondrial compartments within cardiomyocytes. In a study involving db/db mice, this compound treatment resulted in a significant increase in mitochondrial ATP levels, which was associated with improved cardiac function during ischemic conditions .
• Cardioprotection : this compound has been shown to provide cardioprotective effects, particularly in models of heart failure. It improves recovery capacity in ischemic-reperfusion scenarios and maintains ATP levels during stress conditions .

Clinical Evidence

This compound's efficacy has been validated through various clinical trials:

• EMPULSE Trial : This double-blind trial evaluated this compound in patients hospitalized for acute heart failure. Results indicated that this compound significantly improved clinical outcomes compared to placebo, with a stratified win ratio of 1.36 (p = 0.0054), demonstrating its potential benefits even when initiated during hospitalization .
• Long-term Cardiovascular Outcomes : In patients with chronic heart failure, this compound reduced the risk of cardiovascular death and heart failure hospitalization. The drug was well tolerated, with serious adverse events occurring less frequently than in the placebo group .

Case Studies

Several case studies highlight the biological activity of this compound:

• Case Study on Cardiac Remodeling : A study focused on patients with T2DM and coronary artery disease found that this compound treatment led to a reduction in left ventricular mass over time, suggesting beneficial remodeling effects on the heart .
• Impact on Diabetic Patients : Research involving diabetic patients showed that this compound effectively reduced fasting plasma glucose and glycated hemoglobin levels while also improving markers of cardiovascular health, such as blood pressure and weight management .

Summary of Findings

The following table summarizes key findings from recent studies regarding the biological activity of this compound: