Ertugliflozin

Inhibition of Renal Glucose Reabsorption via SGLT2

Ertugliflozin exerts its primary glucose-lowering effect by selectively inhibiting SGLT2, a protein predominantly found in the proximal convoluted tubules of the kidneys. SGLT2 is responsible for the vast majority of glucose reabsorption from the glomerular filtrate back into the bloodstream.

This compound is characterized by its high molecular selectivity for SGLT2 over SGLT1. SGLT1, while also involved in glucose transport, is primarily located in the small intestine and a smaller portion of the renal tubules (S3 segment). This compound demonstrates a selectivity ratio of greater than 2,000-fold for SGLT2 compared to SGLT1 in vitro frontiersin.orgnih.govdovepress.com. This pronounced selectivity is crucial as it allows this compound to effectively reduce renal glucose reabsorption without significantly interfering with intestinal glucose absorption mediated by SGLT1, thereby minimizing gastrointestinal side effects researchgate.net.

Table 1: SGLT Isoform Selectivity of Key SGLT2 Inhibitors

Under normal physiological conditions, nearly all filtered glucose is reabsorbed by the kidneys, with minimal amounts excreted in the urine. SGLT2 in the S1 and S2 segments of the proximal tubule reabsorbs approximately 90% of filtered glucose, while SGLT1 in the S3 segment handles the remainder researchgate.netresearchgate.netdrugbank.com. This compound inhibits SGLT2, thereby reducing the reabsorption capacity of the proximal tubule. This leads to an increase in urinary glucose excretion (glucosuria) and a lowering of the renal threshold for glucose (RTG) drugbank.comnih.govmdpi.comeuropa.eueuropa.euscottishmedicines.org.uk. The RTG, normally around 10 mmol/L (180 mg/dL), is reduced to approximately 2.2 mmol/L (40 mg/dL) by SGLT2 inhibitors mdpi.com. This mechanism is independent of insulin secretion and sensitivity, making it effective even with impaired beta-cell function or insulin resistance mdpi.comexplorationpub.com. The efficacy of this compound in promoting urinary glucose excretion is dependent on adequate glomerular filtration rate (GFR), with reduced efficacy observed in moderate renal impairment and likely absent in severe renal impairment europa.euresearchgate.neteuropa.eu.

Table 2: Impact of SGLT2 Inhibition on Renal Glucose Handling

Beyond Glycemic Regulation: Pleiotropic Mechanisms

The therapeutic benefits of this compound extend significantly beyond its direct impact on blood glucose levels, encompassing a range of pleiotropic effects that influence cardiovascular and renal hemodynamics, as well as cardiac metabolism.

The increased urinary glucose excretion induced by this compound has a consequential osmotic effect, leading to increased water and sodium excretion (osmotic diuresis and natriuresis) dovepress.comdiabetesjournals.orgsmw.chimrpress.comfrontiersin.orgmdpi.com. This diuresis results in a reduction of extracellular fluid volume and circulating blood volume, estimated to be around 7% smw.ch. These changes contribute to a decrease in preload and left ventricular (LV) filling pressures, which is particularly relevant in conditions like heart failure smw.chimrpress.com.

Furthermore, the natriuretic effect and volume contraction can lead to a modest reduction in blood pressure, typically in the range of 3-4 mmHg for systolic blood pressure and 1-2 mmHg for diastolic blood pressure dovepress.comsmw.chmdpi.comnih.gov. While these diuretic and natriuretic effects can be significant acutely, studies suggest they may attenuate over time with continued treatment, potentially due to compensatory mechanisms in distal tubular sodium handling frontiersin.orgnih.govmdpi.com. The inhibition of sodium reabsorption in the proximal tubule also increases sodium delivery to the macula densa, activating tubuloglomerular feedback (TGF). This can lead to afferent arteriolar vasoconstriction, reducing intraglomerular pressure and mitigating glomerular hyperfiltration, a process beneficial for kidney protection explorationpub.commdpi.com.

Table 3: Hemodynamic Effects Associated with this compound

Emerging research indicates that this compound exerts direct beneficial effects on the myocardium, influencing cardiac energetics and function independent of its glycemic effects. Studies in animal models of diabetic cardiomyopathy have demonstrated that this compound can prevent or reverse pathological cardiac remodeling, including hypertrophy and diastolic dysfunction mdpi.comnih.govresearchgate.netresearchgate.netahajournals.orgnih.gov.

These cardioprotective effects are associated with improvements in myocardial energetics. This compound has been shown to normalize or improve the phosphocreatine (PCr) and PCr/ATP ratio, key indicators of cellular energy status, in hearts exhibiting impaired energetics mdpi.comresearchgate.netnih.gov. Furthermore, this compound has been linked to a reduction in elevated myocardial intracellular sodium ([Na+]i), a factor implicated in mitochondrial dysfunction and impaired ATP synthesis in failing hearts researchgate.netnih.gov. By reducing [Na+]i, this compound may indirectly improve mitochondrial calcium handling and ATP production researchgate.net.

This compound also appears to modulate myocardial metabolism by promoting the expression of genes involved in oxidative phosphorylation (OXPHOS) and fatty acid metabolism, thereby enhancing the heart's capacity to utilize fuel efficiently nih.govahajournals.org. These metabolic adaptations can support increased systolic function and contribute to improved cardiac performance, even in non-diabetic states nih.govahajournals.org.

A significant pleiotropic effect observed with this compound is its capacity to reverse diastolic dysfunction. In preclinical models of diabetic cardiomyopathy, this compound treatment prevented the development of diastolic dysfunction, as evidenced by improvements in parameters such as the E/A ratio and Em velocity measured by echocardiography researchgate.net. This reversal is hypothesized to be mediated by the drug's ability to improve myocardial energetics, reduce intracellular sodium overload, and potentially modulate mitochondrial function mdpi.comresearchgate.netnih.gov. By restoring more favorable myocardial energy metabolism and reducing cellular stress, this compound contributes to improved cardiac relaxation and filling, key components of diastolic function.

Table 4: Myocardial Energetics and Function Markers in Preclinical Models

Compound Names

this compound

Glucose

Sodium

Adenosine

Angiotensinogen

Angiotensin-converting enzyme (ACE)

Glucagon-like peptide-1 (GLP-1)

Peptide YY (PYY)

Phosphocreatine (PCr)

Adenosine deaminase

Glucagon

Hydrogen Peroxide (H2O2)

ATP

Pharmacodynamics

Ertugliflozin exerts its primary pharmacodynamic effect by inhibiting the SGLT2 transporter in the renal proximal tubules drugbank.comclinicaltrials.eutijer.org. This inhibition reduces the reabsorption of glucose from the glomerular filtrate back into the bloodstream, leading to an increase in urinary glucose excretion (UGE) europa.eudrugbank.comclinicaltrials.eutijer.orgnih.gov. Dose-response modeling indicates that both the 5 mg and 15 mg doses achieve near-maximal inhibition of renal glucose reabsorption, resulting in substantial UGE europa.eu. The increase in UGE is dose-dependent, meaning higher doses lead to greater glucose excretion europa.eudrugbank.com. This increased excretion of glucose contributes to the reduction in blood glucose levels. It is important to note that UGE decreases with worsening renal function nih.govresearchgate.net.

This compound effectively modulates glucose homeostasis in patients with T2DM through its glucose-lowering mechanism.

Clinical trials have consistently demonstrated that this compound significantly reduces fasting plasma glucose (FPG) levels compared to placebo dovepress.comnih.govresearchgate.netfrontiersin.orgnih.govnih.gov. In placebo-controlled studies, reductions in FPG have been observed with both 5 mg and 15 mg doses. For instance, the VERTIS MONO trial reported placebo-adjusted mean reductions in FPG of 26.69 mg/dL with the 5 mg dose and 38.25 mg/dL with the 15 mg dose at week 26 dovepress.com. Similar reductions were noted in other trials, such as the VERTIS SITA2 study, with reductions of 30.07 mg/dL and 37.55 mg/dL for the 5 mg and 15 mg doses, respectively dovepress.com. Meta-analyses of pooled data indicate weighted mean differences in FPG reduction of -1.62 mmol/L for the 5 mg dose compared to placebo, and substantial reductions were also observed in studies involving patients on insulin or a combination of metformin and sulfonylurea nih.govresearchgate.netfrontiersin.orgnih.govnih.gov.

Table 2: Mean Change in Fasting Plasma Glucose (FPG) from Baseline with this compound Treatment

This compound demonstrates significant efficacy in lowering glycated hemoglobin (HbA1c) levels, a key marker of long-term glycemic control, in patients with T2DM dovepress.comnih.govresearchgate.netfrontiersin.orgnih.govnih.govtandfonline.comdoi.orgtg.org.aunih.govnih.gov. Across various clinical trials, treatment with this compound resulted in substantial reductions in HbA1c compared to placebo. For example, in the VERTIS MONO trial, mean changes from baseline in HbA1c were -0.99% for the 5 mg dose and -1.16% for the 15 mg dose, both significantly greater than the change observed with placebo dovepress.com. Similarly, the VERTIS SITA2 study reported placebo-adjusted mean HbA1c reductions of -0.68% for the 5 mg dose and -0.76% for the 15 mg dose dovepress.com. Pooled analyses and meta-analyses confirm these findings, showing weighted mean differences in HbA1c reduction of -0.77% for the 5 mg dose and -0.82% for the 15 mg dose compared to placebo researchgate.netfrontiersin.orgnih.gov. In East/Southeast Asian patients, placebo-corrected reductions of -0.9% and -1.0% were observed for the 5 mg and 15 mg doses, respectively doi.org. These reductions in HbA1c are generally maintained over longer treatment periods nih.govnih.govdoi.org.

Table 3: Mean Change in Glycated Hemoglobin (HbA1c) from Baseline with this compound Treatment

Beyond direct glucose lowering, this compound, like other SGLT2 inhibitors, can positively influence glucose homeostasis by improving beta-cell function and insulin sensitivity dovepress.comtijer.orgtandfonline.com. Pooled analyses of phase 3 studies indicate that this compound treatment led to an improvement in fasting beta-cell function, as assessed by the homeostatic model assessment of beta-cell function (HOMA-%β). Specifically, a mean percentage change from baseline of 14.7% was observed with this compound, compared to a -0.4% change with placebo nih.govdiabetesjournals.org. However, no significant effect on postprandial beta-cell function was detected when measured by the C-peptide index nih.gov.

The improvement in fasting beta-cell function with this compound was found to be predicted by higher baseline fasting plasma glucose (FPG), HbA1c, and homeostatic model assessment of insulin resistance (HOMA-IR) values, as well as lower baseline HOMA-%β nih.gov. This compound has also been associated with a reduced likelihood of initiating insulin therapy and has been shown to extend the time to insulin initiation by up to 1.8 years tandfonline.com. These findings suggest that this compound contributes to a more favorable metabolic environment in patients with T2DM.

Compound Name List:

this compound

Glycemic Control in Type 2 Diabetes Mellitus

Ertugliflozin has demonstrated consistent efficacy in improving glycemic control across different treatment settings in patients with T2DM. Its mechanism of action, which leads to increased glucose excretion in the urine, contributes to reductions in HbA1c and FPG, as well as associated benefits such as weight loss and blood pressure reduction. The clinical trials have provided detailed data on its effectiveness when used alone or in conjunction with other glucose-lowering therapies.

Cardiovascular Outcomes in Type 2 Diabetes Mellitus

Renal Outcomes in Type 2 Diabetes Mellitus

This compound has shown significant benefits in preserving renal function and reducing markers of kidney damage in patients with T2DM. These effects are consistent with the broader class effects of SGLT2 inhibitors.

Effects on Other Clinically Relevant Parameters

Beyond its direct impact on glycemic control and renal parameters, this compound influences other clinically relevant physiological measures, including body weight and blood pressure.

Body Weight: this compound treatment has been associated with significant reductions in body weight. Pooled analyses from clinical trials reported a weighted mean difference of -2.35 kg compared to placebo nih.gov. Other data suggest an approximate 2.5 kg reduction in body weight medscape.comspringermedizin.de.

Blood Pressure: this compound also demonstrated beneficial effects on blood pressure. Significant reductions were observed in systolic blood pressure (SBP), with a weighted mean difference of -3.64 mmHg compared to placebo nih.gov, and approximately 3 mmHg reduction in other reports medscape.comspringermedizin.de. Diastolic blood pressure (DBP) also showed significant reductions, with a weighted mean difference of -1.13 mmHg compared to placebo nih.gov.

Table 5: Effects on Other Clinically Relevant Parameters

Genitourinary Tract-Related Events

Genitourinary tract infections are a known class effect of SGLT2 inhibitors due to increased urinary glucose excretion.

Genital mycotic infections, such as yeast infections, were reported more frequently in patients treated with ertugliflozin compared to placebo. In pooled analyses of placebo-controlled trials, the incidence of female genital mycotic infections ranged from 9.1% to 12.2% in women treated with this compound (5 mg and 15 mg, respectively), compared to 3% in the placebo group europa.euwikidoc.org. In males, the incidence was 3.7% to 4.2% with this compound compared to 0.4% with placebo europa.euwikidoc.org. These infections were more common in uncircumcised males europa.eu. Discontinuation due to genital mycotic infections was low, occurring in 0.6% of females and 0.2% of males treated with this compound, compared to 0% in the placebo groups europa.euwikidoc.org.

The incidence of urinary tract infections (UTIs) was generally similar between this compound and placebo groups in most clinical trials. In the VERTIS CV trial, UTIs occurred in 12.2% and 12.0% of patients treated with this compound 5 mg and 15 mg, respectively, compared to 10.2% in the placebo group pfizer.com. Across seven other phase 3 clinical trials, the incidences of UTIs were 4% and 4.1% for this compound 5 mg and 15 mg groups, respectively, and 3.9% for placebo europa.eu. Most reported UTIs were mild or moderate, with no serious cases reported in some pooled analyses europa.eu. However, post-marketing reports have indicated serious UTIs, including urosepsis and pyelonephritis, requiring hospitalization in patients treated with SGLT2 inhibitors . Temporary interruption of this compound may be considered when treating pyelonephritis or urosepsis europa.eu.

Volume Depletion-Related Adverse Events

This compound, like other SGLT2 inhibitors, can lead to osmotic diuresis, potentially causing intravascular volume contraction.

Adverse events associated with osmotic diuresis, such as thirst and increased urination, were reported more frequently in patients receiving this compound compared to placebo. In pooled placebo-controlled studies, thirst occurred in 1.3% and 1.0% of patients treated with this compound 5 mg and 15 mg, respectively, versus 0.2% in the placebo group europa.eunih.govnih.gov. Similarly, increased urination was reported in 2.7% and 2.4% of patients on this compound 5 mg and 15 mg, respectively, compared to 1.0% on placebo europa.eunih.govnih.gov.

The incidence of adverse events related to volume depletion, including dehydration, postural dizziness, presyncope, syncope, hypotension, and orthostatic hypotension, was generally low (<2%) and not significantly different between this compound and placebo groups in pooled placebo-controlled trials europa.eueuropa.eu. However, a higher incidence of volume depletion-related adverse events was observed in specific subgroups, including patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², those aged 65 years or older, and patients taking diuretics europa.eunih.goveuropa.eunps.org.au. In elderly patients (≥65 years), the incidence of volume depletion adverse events was higher with this compound compared to younger patients sci-hub.se.

Diabetic Ketoacidosis (DKA) Incidence

Diabetic ketoacidosis (DKA) is a rare but serious adverse event associated with SGLT2 inhibitors. In pooled clinical trials, there were three cases of DKA reported, all in patients receiving this compound 15 mg, with no cases reported in the placebo group nih.govnih.gov. In the VERTIS CV trial, DKA occurred in 0.3% and 0.4% of patients in the this compound 5 mg and 15 mg groups, respectively, compared to 0.1% in the placebo group pfizer.com.

Compound Names:

Data Tables

Table 1: Incidence of Genital Mycotic Infections in Pooled Placebo-Controlled Trials

Source: europa.euwikidoc.org

Table 2: Incidence of Urinary Tract Infections in Pooled Clinical Trials

Source: europa.eupfizer.com

Table 3: Incidence of Thirst and Increased Urination in Pooled Placebo-Controlled Studies

Source: europa.eunih.govnih.gov

Table 4: Incidence of Volume Depletion-Related Adverse Events in Pooled Placebo-Controlled Trials

Source: sci-hub.sefda.gov

Table 5: Incidence of Diabetic Ketoacidosis (DKA) in Clinical Trials

Source: pfizer.comnih.govnih.gov

Indirect Comparisons with Other SGLT2 Inhibitors

Given the absence of direct head-to-head randomized controlled trials (RCTs) comparing all SGLT2 inhibitors, indirect comparisons, primarily through network meta-analyses (NMAs), provide valuable insights into their relative efficacy. These analyses synthesize data from various trials to estimate comparative effects.

Network meta-analyses have indicated nuanced differences in glycemic control among SGLT2 inhibitors. Studies suggest that ertugliflozin, particularly at a 15 mg dose, may offer greater reductions in glycated hemoglobin (HbA1c) compared to specific doses of dapagliflozin and empagliflozin in certain treatment contexts.

When used as an add-on therapy to diet and exercise, this compound 15 mg demonstrated a greater HbA1c reduction than dapagliflozin 10 mg (mean difference [MD] -0.36%, 95% credible interval [CrI] -0.65 to -0.08) and empagliflozin 25 mg (MD -0.31%, 95% CrI -0.58 to -0.04) nih.govresearchgate.net.

In patients treated with metformin, this compound 5 mg was found to be more effective than dapagliflozin 5 mg (MD -0.22%, 95% CrI -0.42 to -0.02) researchgate.net.

Similarly, this compound 15 mg showed greater efficacy than dapagliflozin 10 mg (MD -0.26%, 95% CrI -0.46 to -0.06) and empagliflozin 25 mg (MD -0.23%, 95% CrI -0.44 to -0.03) when added to metformin researchgate.net.

In drug-naive patients, this compound 5 mg monotherapy showed no significant difference in HbA1c reduction compared to other low-dose SGLT2 inhibitors nih.govresearchgate.netresearchgate.net.

Across various patient populations, this compound demonstrated comparable HbA1c reduction efficacy to canagliflozin nih.govresearchgate.net.

Compared to placebo, this compound (at 5 mg or 15 mg doses) resulted in a weighted mean difference (WMD) of -0.641% in HbA1c reduction frontiersin.orgresearchgate.net.

Table 1: Comparative HbA1c Reduction (Indirect Comparisons via Network Meta-Analysis)

While direct comparative data on cardiovascular and renal outcomes between this compound and other SGLT2 inhibitors are less abundant than glycemic control data, some findings from NMAs provide comparative insights. One analysis suggested that empagliflozin might be associated with a lower risk of primary outcomes compared to this compound in patients without chronic kidney disease (CKD) tandfonline.com. In broader comparisons of SGLT2 inhibitors as a class against GLP-1 receptor agonists in real-world data, SGLT2 inhibitors demonstrated a favorable profile regarding the reduction in heart failure development ccjm.org.

Specific to this compound, studies indicate a significant reduction in hospitalizations for heart failure compared to placebo (Hazard Ratio [HR] 0.70, 95% Confidence Interval [CI] 0.54–0.90) nih.govresearchgate.net. When used in combination with metformin, this compound showed a potential, though not statistically significant, reduction in major adverse cardiovascular events (MACE) (HR 0.92, 95% CI 0.79–1.07) nih.govresearchgate.net. For patients with pre-existing heart failure, this compound demonstrated a significant decrease in heart failure exacerbations (HR 0.53, 95% CI 0.33–0.84) nih.govresearchgate.net.

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Comparisons with Other Antihyperglycemic Agent Classes

Comparisons between SGLT2 inhibitors as a class and other antihyperglycemic agents, such as GLP-1 receptor agonists (GLP-1 RAs), have been explored using real-world data. These analyses suggest that while cardiovascular outcomes were largely equivalent between SGLT2 inhibitors and GLP-1 RAs, SGLT2 inhibitors showed a distinct advantage in reducing the incidence of heart failure development ccjm.org. This compound's specific comparative effectiveness against other classes like metformin, DPP-4 inhibitors, or sulfonylureas is less detailed in the provided snippets, beyond its inclusion in broader class comparisons or safety studies.

Real-World Data and Observational Study Analyses

Real-world evidence (RWE) is crucial for understanding the performance of medications in routine clinical practice. However, some RWE studies may have limitations in fully capturing the data for newer agents like this compound due to smaller sample sizes or insufficient follow-up periods ccjm.org. Nevertheless, observational studies and post-authorization safety studies are contributing to the understanding of this compound's profile.

One such initiative is a post-authorization safety study designed to assess the risk of diabetic ketoacidosis (DKA) in patients with T2DM treated with this compound, comparing it against patients treated with other antihyperglycemic agents. This study utilizes real-world data from comprehensive databases europa.eu. While specific comparative outcomes from these RWE analyses are still emerging, they aim to complement findings from clinical trials by reflecting outcomes in broader, more diverse patient populations.

Table 2: Comparative Effects of this compound (vs. Placebo/Other Therapies)

Compound List:

this compound

Dapagliflozin

Empagliflozin

Canagliflozin

Metformin

Sitagliptin

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)

Efficacy and Safety in Elderly Patients

Clinical studies have assessed the performance of ertugliflozin in older adults, generally defined as those aged 65 years and older. Pooled analyses of Phase III studies indicate that this compound provides meaningful improvements in glycemic control, body weight, and systolic blood pressure (SBP) in this demographic.

In a pooled analysis of patients aged 65 years or older, this compound treatment demonstrated the following placebo-adjusted mean changes from baseline at week 26:

Efficacy and Safety in Patients with Renal Impairment

This compound has been evaluated in patients with varying degrees of renal function, including those with moderate renal impairment and Stage 3 chronic kidney disease (CKD). Studies have indicated that this compound can offer benefits in glycemic control and body weight management even in these patient populations.

In patients with Stage 3 CKD, pooled analyses showed that this compound (5 mg or 15 mg) compared to placebo resulted in modest, placebo-adjusted reductions in HbA1c and body weight at week 26. Specifically, HbA1c reductions were approximately -0.78% to -0.80%, and body weight reductions were around -1.74 kg to -2.04 kg. nih.govbmj.com These reductions in HbA1c were consistent across different body mass index (BMI) subgroups, suggesting that the glycemic efficacy of this compound is not significantly influenced by baseline BMI in this population. nih.gov Furthermore, this compound treatment was associated with a maintenance of estimated glomerular filtration rate (eGFR) and a reduction in urine albumin-to-creatinine ratio (UACR) in patients with baseline albuminuria. bmj.comd-nb.info

Efficacy and Safety in Patients with Established Heart Failure

The VERTIS CV trial and its subsequent analyses have provided insights into the cardiovascular effects of this compound, with a notable impact on heart failure (HF) outcomes. This compound demonstrated a significant reduction in hospitalizations for heart failure (HHF) among patients with T2DM and established atherosclerotic cardiovascular disease.

Key findings from the VERTIS CV trial indicate:

this compound significantly reduced the risk of first HHF compared to placebo (Hazard Ratio [HR]: 0.70; 95% Confidence Interval [CI]: 0.54–0.90; P=0.006). ahajournals.org

In patients with a history of heart failure, this compound significantly decreased the exacerbations of heart failure (HR: 0.53; 95% CI: 0.33–0.84; P < 0.01). mdpi.comresearchgate.netnih.gov

The benefit of this compound in reducing HHF was consistent across patients with and without a prior history of HF. ahajournals.org

The risk reduction for first HHF appeared numerically greater in patients with reduced ejection fraction (EF ≤45%) compared to those with preserved EF (>45%). ahajournals.org

this compound also reduced total HHF events (Rate Ratio [RR]: 0.70; 95% CI: 0.56–0.87). ahajournals.org

While this compound did not significantly reduce the composite endpoint of major adverse cardiovascular events (MACE) or cardiovascular death in the VERTIS CV trial, its significant impact on reducing heart failure hospitalizations aligns with the known class effects of SGLT2 inhibitors. tandfonline.comajmc.com

Considerations in Pediatric Patients (Ongoing Research)

The prevalence of type 2 diabetes mellitus is increasing in the pediatric population, necessitating the evaluation of effective and safe treatment options. This compound, approved for adults with T2DM, is currently under investigation for its efficacy and safety in pediatric patients.

A Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical study is evaluating this compound in pediatric participants aged 10 to 17 years with T2DM who are on metformin, with or without insulin. hra.nhs.ukveeva.comjdch.commerckclinicaltrials.comchop.edu The primary hypothesis of this ongoing research is that the addition of this compound to existing therapy will lead to a greater reduction in hemoglobin A1c (HbA1c) compared to placebo after 24 weeks of treatment. hra.nhs.ukveeva.comjdch.commerckclinicaltrials.comchop.edu As this research is ongoing, specific efficacy and safety data for this population are not yet available. This compound is not approved for use in pediatric patients by regulatory bodies such as the FDA. hra.nhs.ukchop.edu

Efficacy and Safety in Overweight and Obese Patients

This compound has demonstrated efficacy in promoting weight loss and improving glycemic control in patients with T2DM who are overweight or obese (BMI ≥ 25 kg/m ²). Pooled analyses from Phase 3 studies and real-world data confirm these benefits across various BMI categories.

In pooled analyses of patients with overweight and obesity, this compound treatment at week 26 resulted in greater reductions in HbA1c and body weight compared to placebo.

These reductions in HbA1c were consistent across BMI subgroups (25 to <30, 30 to <35, and ≥35 kg/m ²), indicating that the glycemic efficacy of this compound is independent of baseline BMI. nih.govnih.govresearchgate.net Furthermore, absolute body weight reductions were observed across all BMI subgroups, and the percentage change in body weight was similar across these groups. nih.govnih.govresearchgate.net Specifically, the proportion of patients achieving a body weight reduction of ≥5% from baseline at week 26 was significantly higher with this compound (28.1% for 5 mg, 28.5% for 15 mg) compared to placebo (10.7%). nih.govfirstwordpharma.com this compound was generally well-tolerated in this patient group. nih.govnih.govresearchgate.net

Racial and Ethnic Group-Specific Response and Safety

Pooled analyses of Phase 3 trials have investigated the efficacy and safety of this compound across different racial and ethnic subgroups, including White, Black, Asian, and other populations. These analyses suggest that this compound's efficacy and safety profile are generally consistent across these groups.

Myocardial Electrophysiology and Arrhythmia Prevention

The influence of ertugliflozin on cardiac electrophysiology and its potential to prevent arrhythmias are areas of active investigation. While some SGLT2 inhibitors have demonstrated a reduction in the risk of atrial arrhythmias, this compound has not shown a significant impact on these specific arrhythmias tandfonline.com. However, preclinical studies suggest potential mechanisms by which this compound might affect cardiac electrical activity. Research indicates that SGLT2 inhibition, including by this compound, may exert cardiovascular benefits by reducing elevated myocardial intracellular sodium, which could have implications for arrhythmia prevention nih.gov.

The ERASe trial is a phase 3b study specifically designed to evaluate this compound's effect on the total burden of ventricular arrhythmias in patients with heart failure who have implanted cardiac devices nih.gov. Although this compound did not significantly reduce levels of the heart failure biomarker NT-proBNP in heart failure patients, it has been noted to decrease the incidence of persistent ventricular tachycardia or ventricular fibrillation events tandfonline.com. Further research is ongoing to fully elucidate the long-term cardiovascular benefits of this compound, including its precise impact on cardiac electrophysiology and arrhythmia risk mdpi.com.

Microvascular Function and Endothelial Health

Investigations into this compound's specific effects on microvascular function and endothelial health are still evolving. In patients with type 2 diabetes and stage 3 chronic kidney disease, this compound treatment was associated with a reduction in the circulating levels of the tubular injury marker KIM-1, suggesting potential protective effects on renal tubules nih.govnih.gov. Conversely, this treatment was linked to an increase in plasma eotaxin-1 levels. Importantly, in this cohort, this compound did not show significant changes in other markers of inflammation, fibrosis, oxidative stress, or endothelial dysfunction nih.govnih.gov.

Bone Metabolism and Density Research

This compound's impact on bone metabolism and mineral density has been a focus of clinical evaluation. Pooled analyses from phase 3 trials indicate that this compound generally has no adverse effect on bone mineral density (BMD) at key sites, including the lumbar spine, femoral neck, total hip, and distal forearm, across various study durations tga.gov.audiabetesjournals.orgnih.govdoi.org. In the VERTIS MET study, even after 104 weeks, this compound showed no clinically meaningful impact on BMD, with only small reductions observed at the total hip in the 15 mg dose group within the postmenopausal subgroup (-1.17%) diabetesjournals.org.

Regarding bone turnover markers, studies found no significant differences from baseline in procollagen type 1 N-terminal propeptide (P1NP) or parathyroid hormone (PTH) levels between this compound and placebo groups diabetesjournals.org. A transient, minor increase in serum C-terminal telopeptide of type 1 collagen (CTX) was noted at 26 and 52 weeks with this compound compared to placebo, which attenuated by 104 weeks diabetesjournals.org. The incidence of adjudicated fractures was comparable across groups receiving this compound and those receiving non-ertugliflozin treatments diabetesjournals.org. Notably, unlike some other SGLT2 inhibitors such as canagliflozin, which have been linked to increased fracture risk and reduced total hip BMD, this compound has not demonstrated such associations jparathyroid.com.

Table 1: Bone Metabolism and Density Markers with this compound

Note: P1NP, PTH, and CTX values represent changes from baseline as reported in the study.

Adipose Tissue Remodeling and Metabolism

This compound has demonstrated effects on body weight and adipose tissue metabolism. Clinical studies have shown that this compound is associated with significant reductions in body weight, particularly in individuals who are overweight or obese. These weight reductions have been observed to be maintained for up to 104 weeks in longer-term studies nih.gov. For instance, in the VERTIS MET study, placebo-adjusted mean changes in body weight from baseline at 26 weeks were -1.76 kg for this compound 5 mg and -2.16 kg for this compound 15 mg doi.orgdovepress.com. In another trial, daily administration of this compound 5 mg and 15 mg resulted in body weight reductions of -3.0 kg and -3.4 kg, respectively, compared to glimepiride nih.gov.

Table 2: Body Weight Reduction with this compound (vs. Placebo)

Long-Term Cardiovascular and Renal Benefit Trajectories

Regarding renal benefits, ertugliflozin has been shown to reduce the urine albumin-to-creatinine ratio (UACR) and mitigate the decline in estimated glomerular filtration rate (eGFR) mdpi.comnih.govekb.eg. Exploratory analyses from the VERTIS CV trial suggested that this compound had a favorable placebo-adjusted eGFR slope mdpi.com. However, the long-term impact on composite renal endpoints and the durability of these effects require more extensive investigation. Understanding how these renal benefits evolve over many years will be crucial for defining this compound's role in preventing chronic kidney disease (CKD) progression.

Mechanistic Elucidation of Class-Specific versus Drug-Specific Effects

This compound belongs to the SGLT2 inhibitor class, which shares common mechanisms of action, including increased urinary glucose excretion, natriuresis, and potential effects on the renin-angiotensin-aldosterone system nih.govclinicaltrials.eumdpi.comnih.govfrontiersin.org. Many of the observed cardiovascular and renal benefits are considered class effects attributed to SGLT2 inhibition. However, subtle differences in drug properties, such as selectivity for SGLT2 over SGLT1, pharmacokinetic profiles, or interactions with other biological pathways, could lead to drug-specific effects. Future research should aim to disentangle these class-specific versus drug-specific mechanisms to better understand if this compound possesses unique attributes that differentiate its efficacy or safety profile from other agents in the same class. This could involve detailed in vitro and in vivo studies, as well as comparative clinical analyses.

Role in Non-Diabetic Heart Failure or Chronic Kidney Disease

While SGLT2 inhibitors have shown significant benefits in patients with heart failure (HF) and chronic kidney disease (CKD) regardless of diabetes status, the specific role of this compound in these non-diabetic populations remains an area for further investigation. Clinical trials like DAPA-CKD and EMPA-KIDNEY are evaluating SGLT2 inhibitors in patients with CKD, with or without diabetes, to confirm if renal protective effects are independent of glycemic control nih.gov. This compound has demonstrated a reduction in albuminuria and a slower decline in eGFR in patients with diabetic kidney disease (DKD), including those without albuminuria ekb.egresearchgate.net. However, dedicated trials specifically examining this compound's efficacy and safety in non-diabetic individuals with HF or CKD are needed to establish its therapeutic value in these patient groups.

Health Economic and Outcomes Research Implications

The integration of this compound into clinical practice necessitates robust health economic and outcomes research (HEOR). While clinical trial data provide efficacy and safety information, HEOR studies are crucial for assessing cost-effectiveness, real-world effectiveness, and patient-reported outcomes. Real-world evidence (RWE) can offer insights into long-term outcomes, treatment adherence, and effectiveness in diverse patient populations not fully represented in clinical trials purplelab.com. Future HEOR research should focus on comparative cost-effectiveness analyses against other SGLT2 inhibitors and alternative therapies, as well as evaluating the impact of this compound on healthcare resource utilization and quality of life in routine clinical practice.

Combination Therapies and Synergistic Effects with Novel Agents

This compound is currently used as an add-on therapy to existing diabetes medications like metformin and sitagliptin researchgate.netmerck.comdovepress.comnps.org.aucda-amc.caeuropa.eunih.gov. As new classes of antidiabetic and cardiovascular agents emerge, research into combination therapies involving this compound is essential. Understanding potential synergistic effects with novel agents, such as GLP-1 receptor agonists or other emerging treatments, could optimize glycemic control and cardiovascular/renal protection. Such studies would help define optimal treatment strategies for complex patient profiles and explore enhanced therapeutic outcomes beyond monotherapy or current combination regimens.

Research on Rare Adverse Events and Long-Term Surveillance

While this compound shares a similar safety profile with other SGLT2 inhibitors, ongoing long-term surveillance is vital for identifying and characterizing any rare adverse events that may not have been apparent in shorter-term clinical trials. The VERTIS CV trial, for instance, included a large patient population, but the duration of follow-up might still be insufficient to detect very infrequent events cda-amc.caeuropa.eu. Future research should focus on robust pharmacovigilance systems and post-marketing studies to monitor for any potential rare safety signals, including those related to cancer risk, as suggested by some meta-analyses tandfonline.com. Establishing comprehensive long-term surveillance strategies will ensure the continued safe and effective use of this compound.

Novel Therapeutic Applications Beyond Diabetes

While this compound is primarily indicated for the management of type 2 diabetes mellitus, ongoing research is exploring its potential benefits in other therapeutic areas. The mechanism of action of this compound, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor, suggests pleiotropic effects extending beyond glycemic control, particularly concerning cardiovascular and renal health.

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) .

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 .