Ertugliflozin

合成路线和反应条件： 恩格列净的合成涉及多个步骤，从用三苯甲基保护中间体化合物中伯醇部分开始，在吡啶存在下进行。 然后用对甲苯磺酸进行脱保护 . 该过程还涉及使用具有式 III、式 IV 和式 VII 的化合物，这些化合物用合适的保护基进行保护，以确保高纯度和高收率 .

工业生产方法： 恩格列净的工业生产遵循类似的合成路线，但规模更大。该过程涉及使用先进的技术和设备，以确保高收率和高纯度。 尽量减少使用吡啶等危险化学品，以确保安全并符合工业标准 .

Degradation Reactions Under Stress Conditions

Ertugliflozin exhibits stability under thermal, photolytic, neutral, and alkaline hydrolysis conditions but degrades in acidic and oxidative environments. These reactions were studied as per ICH guidelines (Q1A–Q1E) to identify degradation products (DPs) and their mechanisms .

Key Degradation Pathways:

• Acid Hydrolysis (1N HCl at 60°C for 48 h) :
  • Forms four degradation products (DP-1 to DP-4) via:
    • Ritter reaction (DP-1: acetonitrile reacts with protonated formaldehyde).
    • Benzyl ether cleavage (DP-2: acid-mediated elimination of the ethoxybenzyl group).
    • Esterification (DP-3: reaction with acetic acid from sugar decomposition).
    • Chlorination (DP-4: SN2 displacement of hydroxymethyl group by chloride) .
• Oxidative Hydrolysis (30% H₂O₂ at RT for 48 h) :
  • Generates DP-5 via oxidative cleavage of the aryl ethoxy group to phenol .

Structural Characterization of Degradation Products

All five degradation products were characterized using UHPLC-MS , HRMS , NMR (1D/2D) , and IR spectroscopy . Key data include:

Data from

Metabolic Reactions

This compound is primarily metabolized via glucuronidation (86%) and minor oxidative pathways (12%) :

• UGT1A9/UGT2B7-mediated glucuronidation : Forms inactive metabolites M5a (2-O-β-glucuronide) and M5c (3-O-β-glucuronide).
• CYP3A4-mediated oxidation : Produces hydroxy (M1/M3) and desethyl (M2) metabolites .

Synthetic Reactions

The commercial synthesis of this compound involves:

• Cocrystallization : this compound is stabilized as a 1:1 cocrystal with L-pyroglutamic acid to enhance solubility and stability .
• Key intermediates : Protection/deprotection steps using formaldehyde and acetonitrile under acidic conditions .

Stability in Formulations

• pH-dependent solubility : Sparingly soluble in water (0.64–0.74 mg/mL at physiological pH) .
• Humidity-induced dissociation : The cocrystal partially converts to amorphous this compound under high humidity but remains bioequivalent .

Interaction with Analytical Reagents

This compound reacts with formaldehyde and dichloromethane during stress testing, leading to DP-1 and DP-4 formation .

Clinical Efficacy in Type 2 Diabetes Management

Ertugliflozin has demonstrated significant reductions in HbA1c levels across various studies. In a pivotal phase 3 trial, participants showed a mean reduction in HbA1c of 0.6% to 0.9% compared to placebo after 52 weeks of treatment .

Key Clinical Trials

• VERTIS Trials : These trials evaluated the efficacy and safety of this compound in patients with T2DM and established cardiovascular disease. The results indicated that this compound was noninferior to placebo concerning major adverse cardiovascular events, but it did show trends toward reduced hospitalization for heart failure .
• Long-term Efficacy : A study assessing long-term outcomes reported sustained reductions in HbA1c over two years, with patients on higher doses (15 mg) showing more significant improvements compared to lower doses (5 mg) .

Cardiovascular Benefits

This compound has been associated with cardiovascular benefits beyond glycemic control. The VERTIS CV trial highlighted that this compound reduced the risk of hospitalization for heart failure by approximately 30% compared to placebo .

Cardiovascular Outcomes Summary

Renal Outcomes

Recent studies have also explored the renal protective effects of this compound. It has shown promise in improving renal outcomes in patients with chronic kidney disease (CKD) and T2DM, demonstrating a reduction in the progression of kidney disease markers .

Renal Outcomes Summary

Safety Profile

While this compound is generally well-tolerated, some adverse effects have been noted, including an increased risk of genital mycotic infections and urinary tract infections . However, these side effects are manageable and do not outweigh the benefits seen in glycemic control and cardiovascular health.

Combination Therapy

This compound can be used as monotherapy or in combination with other antidiabetic agents such as metformin or sitagliptin. Clinical trials have shown that such combinations can lead to enhanced glycemic control while minimizing the risk of hypoglycemia associated with insulin or sulfonylureas .

恩格列净通过抑制肾脏中的钠-葡萄糖协同转运体 2 (SGLT2) 发挥作用。 这种抑制阻止了肾小球滤液中葡萄糖的重吸收，导致尿液中葡萄糖排泄增加，血葡萄糖水平降低 . 参与此过程的分子靶标包括位于肾脏近端小管中的 SGLT2 蛋白 .

恩格列净是 SGLT2 抑制剂类药物的一部分，其中还包括卡格列净、达格列净和恩格列净。 与这些化合物相比，恩格列净在降低血糖水平方面显示出类似的疗效，但其安全性 and 副作用可能不同 . 例如，已发现恩格列净比其他一些 SGLT2 抑制剂导致尿路感染的风险更低 .

• 卡格列净
• 达格列净
• 恩格列净
• 贝格列净

Ertugliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that plays a significant role in the management of type 2 diabetes mellitus (T2DM). This compound enhances glycemic control by promoting urinary glucose excretion, thereby lowering blood glucose levels. This article delves into the biological activity of this compound, highlighting its pharmacokinetics, mechanisms of action, clinical efficacy, and safety profile based on diverse research findings.

This compound selectively inhibits SGLT2, a protein responsible for the reabsorption of glucose in the kidneys. By blocking this transporter, this compound increases urinary glucose excretion and decreases blood glucose levels. The selectivity of this compound for SGLT2 over SGLT1 is significant, with an IC50 value of 0.877 nM for SGLT2 compared to 1960 nM for SGLT1, indicating a greater than 2000-fold selectivity .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties:

• Bioavailability : Approximately 100% when administered orally.
• Peak Concentration : Achieved within 1-2 hours post-dose.
• Half-life : Approximately 16.6 hours in T2DM patients, supporting once-daily dosing.
• Metabolism : Primarily metabolized by UGT1A9 and UGT2B7 through O-glucuronidation into inactive metabolites .

Clinical Efficacy

This compound has been evaluated in multiple clinical trials assessing its efficacy as monotherapy and in combination with other antidiabetic agents. Key findings include:

• VERTIS-CV Trial : Demonstrated a reduction in hospitalizations for heart failure among patients treated with this compound compared to placebo .
• Long-term Studies : A 104-week study showed significant reductions in HbA1c levels (up to -0.84% at week 104) and improvements in fasting plasma glucose (FPG) and body weight .

Table 1: Summary of Key Clinical Trials Involving this compound

Safety Profile

While this compound is generally well-tolerated, it is associated with some adverse effects:

• Genital Mycotic Infections : Higher incidence reported among patients treated with this compound compared to placebo.
• Diabetic Ketoacidosis : Rare cases have been documented, particularly in patients with underlying conditions such as Latent Autoimmune Diabetes of Adulthood (LADA) .
• Bone Mineral Density : Minimal changes observed; however, some reductions were noted at the hip region after long-term use .

Case Studies

Several case studies have highlighted the real-world efficacy and safety of this compound:

• Case Study on Cardiovascular Outcomes : A patient with established cardiovascular disease showed improved cardiovascular outcomes after initiating treatment with this compound alongside standard diabetes management.
• Long-term Management Case : A patient inadequately controlled on metformin alone achieved target HbA1c levels after adding this compound to their regimen over a period of six months.

Basic Research Questions

Q. What are the primary efficacy endpoints of ertugliflozin in phase III clinical trials, and how were they statistically validated?

this compound demonstrated clinically meaningful reductions in HbA1c, body weight, and systolic blood pressure across the VERTIS phase III trials (e.g., VERTIS CV, VERTIS SU, VERTIS MET). These outcomes were assessed using mixed-model repeated measures (MMRM) and last observation carried forward (LOCF) imputation for missing data. For example, in VERTIS SU, placebo-adjusted HbA1c reductions were −0.69% (5 mg) and −0.76% (15 mg) at 18 weeks, with p < 0.001 . Secondary endpoints like fasting plasma glucose and blood pressure changes were analyzed using logistic regression and log-rank tests for time-to-event outcomes .

Q. How was cardiovascular safety established for this compound in high-risk type 2 diabetes (T2DM) populations?

The VERTIS CV trial (N=8,246) demonstrated non-inferiority of this compound versus placebo for major adverse cardiovascular events (MACE; HR 0.97, 95.6% CI 0.85–1.11). The trial design included a double-blind, placebo-controlled protocol with pooled 5 mg/15 mg dosing and a pre-specified non-inferiority margin of 1.3. Secondary outcomes, such as cardiovascular death or heart failure hospitalization, showed a non-significant trend toward benefit (HR 0.88, 95.8% CI 0.75–1.03) .

Q. What methodologies are used to evaluate this compound’s renal effects in long-term studies?

Post hoc analyses of pooled data from VERTIS MET and VERTIS SU trials (N=1,237) assessed renal outcomes over 104 weeks. Changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were analyzed using linear mixed-effects models. This compound showed a 19% relative risk reduction in composite renal endpoints (e.g., eGFR decline, ESKD) compared to non-ertugliflozin treatments, with adjustments for baseline covariates like UACR category .

Advanced Research Questions

Q. How do contradictory findings between cardiovascular and renal outcomes inform mechanistic hypotheses for this compound?

While this compound did not show superiority in MACE reduction, its renal benefits (e.g., 19% risk reduction in composite renal endpoints) suggest distinct pathways. Mediation analyses from empagliflozin trials propose mechanisms such as hematocrit elevation (indicating plasma volume reduction) and metabolic effects (e.g., uric acid reduction). These findings highlight the need for targeted studies on hemodynamic versus metabolic mediators in this compound’s organ protection .

Q. What statistical approaches address missing data in this compound trials, and how do they impact validity?

Trials like VERTIS SU used multiple imputation based on a constrained longitudinal data analysis (cLDA) model for missing HbA1c data at week 18. Sensitivity analyses comparing LOCF and MMRM methods confirmed robustness, with consistent HbA1c reductions (placebo-adjusted LS mean: −0.6% to −0.7%) across methodologies . However, residual bias from unmeasured confounders in imputation models remains a limitation .

Q. How do subgroup analyses by baseline HbA1c, age, or eGFR influence the interpretation of this compound’s efficacy?

In VERTIS CV sub-studies, this compound’s HbA1c reductions were consistent across subgroups (e.g., baseline HbA1c ≥8.5%: −0.8% vs. placebo). However, in patients with eGFR <60 mL/min/1.73 m², the glycemic effect attenuated, necessitating stratified dosing recommendations. These analyses used interaction tests with Bonferroni correction to control for Type I error .

Q. What evidence supports or refutes the association between this compound and amputations?

Pooled phase III data reported amputation rates of 2.0% (5 mg) and 2.1% (15 mg) versus 1.6% for placebo, with exposure-adjusted incidence rates of 5.0–6.8 vs. 4.3 per 1,000 patient-years. However, the VERTIS CV trial found no statistically significant increase (HR 1.14, 95% CI 0.75–1.74), suggesting confounding by baseline risk factors (e.g., peripheral artery disease) .

Q. Methodological Considerations

Q. How are composite renal endpoints defined and validated in this compound trials?

Renal endpoints in VERTIS trials included a clinically relevant hierarchy: ≥40% eGFR decline, end-stage kidney disease (ESKD), or renal death. These were adjudicated by blinded endpoint committees using standardized criteria. Sensitivity analyses excluding non-adjudicated events confirmed consistency in effect sizes .

Q. What are the limitations of indirect treatment comparisons (ITCs) for this compound versus other SGLT2 inhibitors?

ITCs in the 2018 PBAC report highlighted heterogeneity in trial designs (e.g., background therapies, follow-up duration) and inappropriate handling of multi-arm trials. For example, this compound showed non-inferiority to dapagliflozin in HbA1c reduction but had wider CIs due to fewer trials, limiting reliability .

Q. How do post hoc and prespecified analyses differ in interpreting this compound’s heart failure outcomes?

Prespecified analyses in VERTIS CV showed no significant reduction in heart failure hospitalization (HR 0.88, p=0.11), but sensitivity analyses using fixed-effect models suggested clinically meaningful benefits. This discrepancy underscores the importance of pre-registered statistical plans to avoid Type I error inflation .