pf-04971729 and Diabetes-Mellitus--Type-2

The global prevalence of type 2 diabetes mellitus (T2DM) is growing yearly. The efficacy of ertugliflozin (ERT), a recently licensed anti-diabetic drug, has been widely reported. However, additional evidence-based data is required to ensure its safety. In particular, convincing evidence on the effects of ERT on renal function and cardiovascular outcomes is needed.. We searched PubMed, Cochrane Library, Embase, and Web of Science for randomized placebo-controlled trials of ERT for T2DM published up to August 11, 2022. Cardiovascular events here mainly refer to acute myocardial infarction and angina pectoris (AP) (including stable AP and unstable AP). The estimated glomerular filtration rate (eGFR) was used to measure renal function. The pooled results are risk ratios (RRs) and 95% confidence intervals (CIs). Two participants worked independently to extract data.. We searched 1516 documents and filtered the titles, abstracts, and full text, 45 papers were left. Seven trials met the inclusion criteria and were ultimately included in the meta-analysis. The meta-analysis found that ERT reduced eGFR by 0.60 mL·min-1·1.733 m-2 (95% CI: -1.02--0.17, P = .006) in patients with T2DM when used for no more than 52 weeks and these differences were statistically significant. Compared with placebo, ERT did not increase the risk of acute myocardial infarction (RR 1.00, 95% CI: 0.83-1.20, P = .333) and AP (RR 0.85, 95% CI: 0.69-1.05, P = .497). However, the fact that these differences were not statistically significant.. This meta-analysis shows that ERT reduces eGFR over time in people with T2DM but is safe in the incidence of specific cardiovascular events.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Kidney; Myocardial Infarction

To evaluate the effectiveness and safety of the novel sodium-glucose cotransporter inhibitor, ertugliflozin, compared with a placebo or other antihyperglycemic agents for type 2 diabetes patients.. We carried out a meta-analysis of randomized controlled trials to assess the benefits and harms of ertugliflozin. Online database searches were carried out in PubMed, EMBASE, WEB OF SCIENCE and Cochrane from inception up to 11 March 2021. Our end-points were glycated hemoglobin, fasting plasma glucose and bodyweight. We analyzed the results using a random effects model, computed weighted mean differences and risk ratios.. A total of 10 randomized controlled trials with 13,223 patients met the inclusion criteria. Compared with a placebo, the weighted mean differences in glycated hemoglobin were -0.77% (95% confidence interval [CI] -0.86 to -0.68%) for ertugliflozin 5 mg, and -0.82% (95% CI -1.01 to -0.63%) for ertugliflozin 15 mg. Ertugliflozin 5 mg daily was also associated with bodyweight loss (weighted mean difference -1.87 kg, 95% CI -2.12 to -1.6). When compared with a placebo, ertugliflozin significantly reduced fasting plasma glucose by -1.62 mmol/L (weighted mean difference, 95% CI -1.82 to -1.42 for 5 mg ertugliflozin). Yet, we observed a rising risk for genital mycotic infections (risk ratio 4.34, 95% CI 2.78-6.76). The results were similar for the 15 mg ertugliflozin group.. Ertugliflozin effectively reduces glycated hemoglobin levels and provides extra clinical benefits including bodyweight and fasting plasma glucose. Common adverse effects, including genital mycotic infections and so on, were reviewed.

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Genital Diseases; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Mycoses; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

To evaluate dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, and sotagliflozin according to their effect on the glycated hemoglobin A1c (HbA1c) level in patients with type 2 diabetes mellitus.. The Web of Science, PubMed, Cochrane Library, EMBASE, and Clinical Trials databases were electronically searched to collect randomized controlled trials of patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used to perform the meta-analysis and to create plots.. Finally, 27 studies were selected and included in this study. The meta-analysis results showed that sodium-dependent glucose transporter (SGLT) inhibitors significantly reduced the HbA1c level in patients with type 2 diabetes mellitus. However, these results were highly heterogeneous, so we conducted a subgroup analysis. The results of the subgroup analysis suggested that by dividing populations into different subgroups, the heterogeneity of each group could be reduced.. SGLT inhibitors had a good effect on the HbA1c level in patients with type 2 diabetes mellitus, but there might be differences in the efficacy of SGLT inhibitors in different populations. It is hoped that more studies will be conducted to evaluate the efficacy and safety of SGLT inhibitors in different populations.. CRD42020185025.

Topics: Benzhydryl Compounds; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Canagliflozin; Diabetes Mellitus, Type 2; Glucosides; Glycated Hemoglobin; Glycosides; Humans; Sodium-Glucose Transporter 2 Inhibitors; Time Factors

Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Development; Humans; Models, Biological; Network Pharmacology; Regression Analysis; Sodium-Glucose Transporter 2 Inhibitors

Post-hoc analysis of the efficacy and safety of ertugliflozin in East/Southeast (E/SE) Asian patients with type 2 diabetes mellitus (T2DM).. Efficacy evaluations used data from randomized, double-blind, phase 3 studies: a pool of two 26-week placebo-controlled studies and one 52-week active-comparator (glimepiride) study. Least squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events based on pooled data (broad pool) from seven phase 3 studies (including studies in the efficacy analysis).. Among 161 E/SE Asian patients in the placebo pool (ertugliflozin, n = 106), ertugliflozin reduced HbA1c, FPG, BW and SBP from baseline at week 26. The placebo-adjusted changes from baseline for ertugliflozin 5 and 15 mg were: HbA1c, -0.9% and -1.0%; BW, -2.1 and -1.9 kg; and SBP, -3.3 and -3.5 mmHg, respectively. Among 174 E/SE Asian patients in the active-comparator study (ertugliflozin, n = 118), HbA1c changes from baseline at week 52 were -0.6%, -0.6% and -0.7% for ertugliflozin 5 mg, 15 mg and glimepiride, respectively. Ertugliflozin 5 and 15 mg reduced BW from baseline by -4.3 and -4.1 kg, respectively, and SBP by -7.4 and -9.3 mmHg, respectively, compared with glimepiride. Safety findings were generally consistent with overall ertugliflozin safety data published to date.. Treatment with ertugliflozin was associated with reductions in HbA1c, FPG, BW and SBP, and was generally well tolerated in E/SE Asian patients with T2DM. ClinicalTrials.gov identifier: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, NCT02226003.

Topics: Blood Glucose; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (T

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

To assess the efficacy and safety of ertugliflozin in older patients with type 2 diabetes (T2D).. This is a post hoc analysis of patients with T2D aged less than 65 years and those aged 65 years or older who participated in randomized, double-blind, phase III studies of ertugliflozin. Efficacy was evaluated in a pooled analysis of three placebo-controlled studies (ertugliflozin monotherapy and add-on therapy). Safety was evaluated in a pooled analysis of seven placebo- and active-controlled studies (including those used for efficacy). Least-squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).. In participants aged less than 65 years, the placebo-adjusted mean changes from baseline in HbA1c, BW and SBP with ertugliflozin 5 and 15 mg at week 26 were -0.9% and -1.0%, -1.9 and -1.8 kg, and -3.7 and -3.6 mmHg, respectively; in participants aged 65 years or older they were -0.6% and -0.8%, -1.9 and -2.2 kg, and -2.7 and -3.4 mmHg, respectively. The incidences of AEs, serious AEs, discontinuations and deaths in participants aged less than 65 years and those aged 65 years or older were generally similar across the treatment groups. In patients aged 65 years or older the incidences of volume depletion AEs and genital mycotic infection were higher with ertugliflozin than with non-ertugliflozin.. Ertugliflozin improved glycaemic control, BW and SBP in younger and older individuals with T2D and was generally well tolerated in both groups.

Topics: Aged; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

To assess the safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with conventional therapy at different periods.. We searched PubMed, Embase, and The Cochrane Library from inception to September 23, 2020. A total of six studies involving 4120 patients were included.. Compared with the control group, 15 mg and 5 mg of ertugliflozin were associated with higher risks of genital mycotic infections (GMIs) at 26 weeks (. This meta-analysis of randomized controlled trials indicates that ertugliflozin is tolerated by T2DM, but the risk of GMIs is noteworthy, especially among females in the high-dose group.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.

Topics: Animals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucosides; Humans; Hypoglycemic Agents; Molecular Structure; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship

The purpose of this article is to review the pharmacological aspects of ertugliflozin and its clinical trials, which led to Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes mellitus (T2DM).. A MEDLINE/PubMed (May 2013 to October 2018) search was conducted using the following keywords: ertugliflozin, sodium glucose co-transporter 2 inhibitor, SGLT2 inhibitor, type 2 diabetes mellitus, hyperglycemia. Study Selection and Data Extraction Quantify: We included English-language articles evaluating ertugliflozin pharmacology, pharmacokinetics, efficacy, and safety in humans for blood glucose reduction in human subjects.. Ertugliflozin has been FDA approved and considered both safe and efficacious for the treatment of T2DM with hemoglobin A. With the number of patients with diabetes growing, additional safe and effective treatment options available for clinicians and patients is important. Ertugliflozin appears to be an effective and safe therapy as both single and add-on therapy.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Combining antihyperglycemic agents in order to rapidly and safely achieve the best possible glycemic control is the standard of care today for the management of type 2 diabetes. Agents should ideally have mechanisms of actions that are complementary and that improve glycemic control without unacceptable gain in body weight or hypoglycemia. Areas covered: Ertugliflozin and metformin hydrochloride (ertugliflozin/metformin, SEGLUROMET) is a recently approved fixed-dose combination tablet containing the sodium-glucose co-transporter 2 (SGLT-2) inhibitor ertugliflozin and metformin. This review summarizes key characteristics of ertugliflozin and metformin, as well as the efficacy and safety results of co-administration of these agents in the ertugliflozin clinical development program. This information comes from the ertugliflozin/metformin prescribing information as well as published clinical trials obtained through a PubMed search. Expert commentary: SGLT-2 inhibitors are an important class of antihyperglycemic agents that are efficacious as monotherapy and in combination with other antihyperglycemic agents. Given their favorable effects on glycemia control as well as 'extra-glycemic' parameters such as body weight and blood pressure, they are ideal agents for appropriate patients with type 2 diabetes. The fixed-dose combination of ertugliflozin with metformin is an effective combination that is conveniently administered and may improve medication adherence and persistence.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Treatment Outcome

Sodium/glucose cotransporter 2 (SGLT2) is exclusively expressed in the S1 and S2 segments of proximal convoluted tubules and accounts for roughly 90% of glucose reabsorption. Ertugliflozin, a highly selective and reversible SGLT2 inhibitor, is the latest addition to the gliflozin class of SGLT2 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). It was granted approval by the U.S. Food and Drug Administration (FDA) in December 2017 for treatment of T2DM as a monotherapy, and as part of two separate fixed-dose combination therapies with sitagliptin (Steglujan) and metformin (Segluromet). Ertugliflozin demonstrated roughly 100% bioavailability following a single dose of 15 mg. It also has a longer half-life (16.6 hours) than presently available gliflozins, which translates into single daily dosing and dose reduction allowing for patient compliance. This review will focus on the preclinical pharmacology, pharmacokinetics, clinical efficacy and safety of ertugliflozin.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Ertugliflozin (Steglatro™) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (Segluromet™) and ertugliflozin and sitagliptin (Steglujan™) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM.

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Drug Approval; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; United States; United States Food and Drug Administration

The sodium glucose cotransporter 2 (SGLT2) inhibitors canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin represent a novel class of medications to manage type 2 diabetes through urinary excretion of glucose. These drugs block glucose reabsorption by the kidneys to increase glucosuria. These drugs provide hemoglobin A1C reduction, promote weight loss, and remain hypoglycemic-neutral when not used in combination with insulin or secretagogues. Canagliflozin and empagliflozin have shown cardiovascular benefit. The potential to reduce the risk of cardiovascular death in patients with type 2 diabetes, along with the benefit of weight reduction, makes these new agents useful tools for the primary care provider.

Topics: Benzhydryl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Canagliflozin; Diabetes Mellitus, Type 2; Glucose; Glucosides; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Type 2 diabetes mellitus (T2DM) is a growing and serious global health problem. Inhibition of the sodium--glucosecotransporter-2 (SGLT2) can increase urinary glucose excretion and decrease plasma glucose levels in an insulin-independent manner. Ertugliflozin is a highly selective inhibitor of SGLT2, and was approved in the US for the treatment of adults with T2DM. Areas covered: In this paper, the mechanism of action, pharmacokinetics, clinical efficacy, safety, etc., of ertugliflozin have been introduced. Expert commentary: Ertugliflozin offers a novel, therapeutic approach to T2DM. Advantages of ertugliflozin include reduction in glycated hemoglobin, weight loss and blood pressure lowering with a low risk of hypoglycemia. The main adverse effects likely to be seen are genital fungal infections. Studies show that there is no increased risk of cardiovascular disease, but studies focusing on longer duration outcome are still essential.

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Sodium-dependent glucose transporter 2 (SGLT2) inhibitors are novel, potent oral anti-diabetic agents in a β-cell function-independent manner, inhibiting SGLT2-mediated renal glucose reabsorption and thus increasing urinary glucose excretion. Ertugliflozin (Steglatro

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and β-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients.

Topics: Administration, Oral; Animals; Blood Glucose; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

1. Several sodium-glucose cotransporter-2 (SGLT-2) inhibitors are in clinical use for the management of type 2 diabetes. The objectives of the current review were: (a) to provide a comparative pharmacokinetics including absorption, distribution, metabolism and excretory (ADME) profiles of three SGLT-2 inhibitors namely: sergliflozin, remogliflozin and ertugliflozin; (b) to provide some perspectives on possible developmental issues. 2. Based on the half-life (t

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glucosides; Half-Life; Humans; Hypoglycemic Agents; Pyrazoles; Sodium-Glucose Transporter 2

The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA.. In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA.. In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA.. gov identifier: NCT01986881.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Sleep Apnea, Obstructive; Sodium-Glucose Transporter 2 Inhibitors

To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study.. Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo).. In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Fibrosis; Glucose; Heart Failure; Humans; Middle Aged; Sodium; Sodium-Glucose Transporter 2 Inhibitors

VERTIS CV evaluated the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD).. The aim of these analyses was to assess the insulin requirements of VERTIS CV patients over the trial duration.. Patients received ertugliflozin 5 mg, 15 mg, or placebo once daily; mean follow-up was 3.5 years. Time to insulin initiation in patients who were insulin naïve at baseline, change in insulin dose in patients receiving baseline insulin, and hypoglycemia incidence in both patient groups were assessed.. In VERTIS CV, mean duration of type 2 diabetes was 13.0 years; glycated hemoglobin was 8.2%. Among 4348 (53%) insulin-naïve patients, the likelihood of insulin initiation was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: hazard ratio [HR] 0.70, 95% CI 0.58-0.84; ertugliflozin 15 mg: HR 0.64, 95% CI 0.53-0.78). Time to insulin initiation was delayed with ertugliflozin; the estimated delay in reaching a 10% cumulative incidence of new insulin initiations vs placebo was 399 days with ertugliflozin 5 mg and 669 days with ertugliflozin 15 mg. Among 3898 (47%) patients receiving baseline insulin, the likelihood of requiring a ≥20% increase in insulin dose was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: HR 0.62, 95% CI 0.52-0.75; ertugliflozin 15 mg: HR 0.51, 95% CI 0.41-0.62). The incidence of hypoglycemia events was not increased with ertugliflozin treatment.. In VERTIS CV patients, ertugliflozin reduced the likelihood of insulin initiation, delayed the time to insulin initiation by up to ∼1.8 years, and reduced insulin dose requirements vs placebo, without increasing hypoglycemia events.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Metformin; Sodium-Glucose Transporter 2 Inhibitors

VERTIS CV was a randomised, double-blind, placebo-controlled, parallel-group, multicentre cardiovascular outcomes trial that evaluated the cardiovascular efficacy and safety of ertugliflozin in adults with type 2 diabetes and atherosclerotic cardiovascular disease. The primary objective of VERTIS CV was to show non-inferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). The analyses reported here aimed to assess cardiorenal outcomes, kidney function, and other safety outcomes with ertugliflozin in older adults with type 2 diabetes and atherosclerotic cardiovascular disease compared with younger participants.. VERTIS CV was done at 567 centres in 34 countries. Participants (aged ≥40 years) with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned (1:1:1) to once-daily ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo in addition to background standard-of-care treatment. Random assignment was done with the use of an interactive voice-response system. The study outcomes were major adverse cardiovascular events, hospitalisation for heart failure or cardiovascular death, cardiovascular death, hospitalisation for heart failure, prespecified kidney composite outcomes, kidney function, and other assessments of safety. Cardiorenal outcomes, kidney function, and safety outcomes were evaluated by baseline age (≥65 years and <65 years [prespecified] and ≥75 years and <75 years [post hoc]). The study is registered with ClinicalTrials.gov, NCT01986881.. Between Dec 13, 2013, and July 31, 2015, and between June 1, 2016, and April 14, 2017, 8246 adults with type 2 diabetes and atherosclerotic cardiovascular disease were recruited to the study and randomly assigned. 2752 patients were assigned to ertugliflozin 5 mg, 2747 patients to ertugliflozin 15 mg, and 2747 patients to placebo. 8238 participants received at least one dose of ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. 4145 (50·3%) of 8238 participants were aged 65 years and older, including 903 (11·0%) participants aged 75 years and older. 5764 (70·0%) of 8238 participants were male and 2474 (30·0%) were female, and 7233 (87·8%) of 8238 participants were White, 497 (6·0%) were Asian, 235 (2·9%) were Black, and 273 (3·3%) were classified as other. The mean estimated glomerular filtration rate (eGFR) was lower and the type 2 diabetes duration longer for those aged 65 years and older versus those younger than 65 years, and for those aged 75 years and older versus those younger than 75 years. Cardiovascular outcomes were more common in the older age subgroups than in the younger age subgroups. Similar to the overall VERTIS CV cohort, ertugliflozin did not increase the risk of major adverse cardiovascular events, cardiovascular death or hospitalisation for heart failure, cardiovascular death alone, or the kidney composite outcome (using doubling of serum creatinine, dialysis or transplantation, or kidney death), and reduced the risk of hospitalisation for heart failure and the exploratory kidney composite outcome (using a 40% sustained eGFR decrease, dialysis or transplantation, or kidney death) in the older age subgroups (p. The effects of ertugliflozin on cardiorenal outcomes, kidney function, and safety outcomes were generally similar across age subgroups. These results have the potential to help clinical decision making by providing a longer-term evaluation of the cardiorenal safety and overall tolerability of ertugliflozin in a large population of older adults.. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA in collaboration with Pfizer Inc, New York, NY, USA.

Topics: Aged; Aged, 80 and over; Arteriolosclerosis; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Kidney; Myocardial Infarction; Renal Dialysis; Sodium-Glucose Transporter 2; Standard of Care; Treatment Outcome

Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes in adults. In its natural form, ertugliflozin exists as an amorphous solid with physicochemical properties that prevent commercial manufacture. The commercial product was developed as an immediate-release tablet, consisting of an ertugliflozin-L-pyroglutamic acid cocrystal of 1 : 1 molar stoichiometry as the active pharmaceutical ingredient. The ertugliflozin cocrystal may partially dissociate when exposed to high humidity for extended periods, leading to the formation of free amorphous ertugliflozin. Therefore, a study was conducted to estimate the relative bioavailability of ertugliflozin when administered in non-commercial formulated tablets containing the amorphous form vs. the cocrystal form.. In this phase 1, open-label, randomized, two-period, two-sequence, single-dose crossover study, 16 healthy subjects received 15 mg immediate-release ertugliflozin in its amorphous and cocrystal forms under fasted conditions, separated by a washout period of ≥ 7 days. Blood samples were collected post-dose for 72 hours to determine plasma ertugliflozin concentrations.. Mean ertugliflozin plasma concentration-time profiles were nearly superimposable following administration of the amorphous and cocrystal forms. The 90% confidence intervals for the geometric mean ratios for AUC. Any dissociation of ertugliflozin to the amorphous form that occurs in tablets containing the cocrystal will not have any clinically meaningful impact on the oral bioavailability of ertugliflozin.

Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Bridged Bicyclo Compounds, Heterocyclic; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Sodium-Glucose Transporter 2 Inhibitors; Tablets; Therapeutic Equivalency

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown.. Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes.. For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome.. In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods.. NCT01986881.

Topics: Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Heart Failure; Humans; Kidney; Serum Albumin; Uric Acid

Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) "dip" with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated.. Patients were categorized into tertiles based on change in eGFR at week 6: >+1.00 mL/min/1.73 m2 (tertile 1), >-5.99 and ≤+1.00 (tertile 2), and ≤-6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline-week 6) and chronic periods (week 6-30 days after last dose of trial medication).. In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m2/year; weeks 6-156) were -0.76 (-1.03, -0.50), -0.29 (-0.51, -0.07), and -0.05 (-0.26, 0.17) in tertiles 1, 2, and 3, respectively (p value <0.001), and approximately -1.5 mL/min/1.73 m2/year across tertiles in the placebo group (p value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were -0.77, -0.71, and -0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All pinteraction values were <0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups.. With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Hypoglycemic Agents

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Sodium-Glucose Transporter 2 Inhibitors

In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881).. Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed.. Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR.. ClinicalTrials.gov NCT01986881.

Topics: Aged; Albuminuria; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

To assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled by insulin.. VERTIS CV was the cardiovascular outcome study for ertugliflozin. Patients were randomly assigned to placebo, or ertugliflozin 5 mg or 15 mg once daily. We report the results of a substudy in patients on a stable dose of insulin ≥20 units/d. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to 18 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), body weight (BW), the proportion of patients with HbA1c <53 mmol/mol (<7%), systolic blood pressure (SBP), diastolic blood pressure and insulin dose.. Of 8246 patients randomized in VERTIS CV, 1065 were included in the substudy (68.2% men, mean [SD] age 64.8 [7.8] years, T2DM duration 16.7 [9.0] years, HbA1c 8.4 [1.0]%). At week 18, the least squares (LS) mean change from baseline in HbA1c was significantly greater with ertugliflozin 5 mg and 15 mg versus placebo (placebo-adjusted LS mean change -0.58%, 95% confidence interval [CI] -0.71, -0.44 and -0.65%, 95% CI -0.78, -0.51, respectively; P < 0.001 for both). Ertugliflozin significantly reduced FPG, BW and SBP. In women, the incidence of genital mycotic infections was higher with ertugliflozin (3.5%) versus placebo (0.0%). The incidence of symptomatic hypoglycaemia was similar across treatment groups.. Ertugliflozin added to insulin improved glycaemic control, BW and SBP versus placebo at 18 weeks in patients with T2DM and ASCVD.

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus.. Data from three placebo-controlled, randomized, Phase 3 studies were pooled. Patients with baseline BMI ≥ 25 (1,377/1,544; 89%) were assessed with a stratification by BMI subgroup.. At week 26, reductions from baseline in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, body weight (BW), and systolic blood pressure (SBP) were greater with ertugliflozin versus placebo. For placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, least squares mean change was 0.1%, -0.8%, and -0.9% for HbA1c and -1.2 kg, -3.1 kg, and -3.2 kg for BW. HbA1c reductions were consistent across BMI subgroups. For ertugliflozin 5 mg and 15 mg, least squares mean change (placebo adjusted) in absolute BW was -1.4 kg and -1.2 kg for BMI 25 to < 30, -1.8 kg and -1.9 kg for BMI 30 to < 35, and -2.5 kg and -2.9 kg for BMI ≥ 35. Percent BW changes were similar across BMI subgroups. Incidence of adverse events was 52.5%, 44.6%, and 50.1% with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.. Meaningful reductions in HbA1c, fasting plasma glucose, BW, and SBP were observed with ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. Ertugliflozin improved HbA1c and SBP and reduced BW across BMI subgroups. Ertugliflozin was generally well tolerated.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Obesity; Overweight; Sodium-Glucose Transporter 2 Inhibitors

Topics: Adult; Aged; Black People; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Middle Aged; Mycoses; Sodium-Glucose Transporter 2 Inhibitors; White People

Topics: Aged; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Follow-Up Studies; Glycated Hemoglobin; Humans; Middle Aged; Outcome Assessment, Health Care; Sodium-Glucose Transporter 2 Inhibitors

The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.. In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.. A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).

Topics: Aged; Atherosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Hospitalization; Humans; Male; Middle Aged; Placebos; Sodium-Glucose Transporter 2 Inhibitors

In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes.. VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events.. In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.

Topics: Aged; Atherosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Heart Failure; Humans; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of adults with type 2 diabetes mellitus, is expected to be coadministered with sitagliptin, metformin, glimepiride, and/or simvastatin. Four separate open-label, randomized, single-dose, crossover studies were conducted in healthy adults to assess the potential pharmacokinetic interactions between ertugliflozin 15 mg and sitagliptin 100 mg (n = 12), metformin 1000 mg (n = 18), glimepiride 1 mg (n = 18), or simvastatin 40 mg (n = 18). Noncompartmental pharmacokinetic parameters derived from plasma concentration-time data were analyzed using mixed-effects models to assess interactions. Coadministration of sitagliptin, metformin, glimepiride, or simvastatin with ertugliflozin had no effect on area under the plasma concentration-time profile from time 0 to infinity (AUC

Topics: Adolescent; Adult; Bridged Bicyclo Compounds, Heterocyclic; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Female; Glucuronosyltransferase; Healthy Volunteers; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Sulfonylurea Compounds; UDP-Glucuronosyltransferase 1A9; Young Adult

To evaluate the long-term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin.. A 104-week Phase III, randomized double-blind study with a 26-week placebo-controlled period (Phase A) and a 78-week period (Phase B) where blinded glimepiride was added to non-rescued placebo participants with fasting fingerstick glucose ≥6.1 mmol/L. Results through week 104 are reported.. Mean (standard error) change in HbA1c from baseline was -0.7% (0.07) and -1.0% (0.07) at week 52; -0.6% (0.08) and -0.9% (0.08) at week 104 for ertugliflozin 5 and 15 mg. At week 52, 34.8% and 36.6% participants had HbA1c <7.0%, and 24.6% and 33.7% at week 104, for ertugliflozin 5 and 15 mg. Ertugliflozin reduced fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP) from baseline through week 104. The incidence of female genital mycotic infections (GMIs) was higher with ertugliflozin, and symptomatic hypoglycaemia was lower for ertugliflozin versus placebo/glimepiride. Minimal bone mineral density (BMD) changes were observed, similar to placebo/glimepiride, except at total hip where reduction in BMD was greater with ertugliflozin 15 mg versus placebo/glimepiride: difference in least squares means (95% CI) -0.50% (-0.95, -0.04) at week 52 and -0.84% (-1.44, -0.24) at week 104.. Ertugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non-clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. ClinicalTrials.gov Identifier: NCT02033889.

Topics: Aged; Blood Glucose; Bone Density; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mycoses; Reproductive Tract Infections; Sulfonylurea Compounds; Vulvovaginitis

Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC. In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period.. The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC. There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.

Topics: Adolescent; Adult; Bridged Bicyclo Compounds, Heterocyclic; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Healthy Volunteers; Humans; Male; Metformin; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Young Adult

Phase III, randomized, double-blind study evaluating the efficacy and safety of ertugliflozin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, including evaluation in the China subpopulation.. A 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c <7.0%. Hypotheses for the primary endpoint and FPG and BW secondary endpoints were tested in the China subpopulation.. At week 26, least squares mean (95% CI) change from baseline HbA1c was significantly greater with ertugliflozin 5- and 15 mg versus placebo: -1.0% (-1.1, -0.9), -0.9% (-1.0, -0.8), -0.2% (-0.3, -0.1), respectively. Ertugliflozin significantly reduced FPG, BW and SBP. Reductions in DBP with ertugliflozin were not significant. At week 26, 16.2%, 38.2% and 40.8% of patients had HbA1c <7.0% with placebo, ertugliflozin 5- and 15 mg, respectively. 59.3%, 56.5% and 53.3% of patients experienced adverse events with placebo, ertugliflozin 5- and 15 mg, respectively. Incidence of symptomatic hypoglycaemia was higher for ertugliflozin 15 mg vs placebo. Results in the China subpopulation were consistent.. Ertugliflozin significantly improved glycaemic control and reduced BW and SBP in Asian patients with T2DM. Ertugliflozin was generally well-tolerated. Results in the China subpopulation were consistent with the overall population. ClinicalTrials.gov: NCT02630706.

Topics: Aged; Asia, Eastern; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Metformin; Middle Aged; Philippines; Sodium-Glucose Transporter 2 Inhibitors

We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%-10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks).. This was a double-blind, 26-week, multicentre study with ongoing 78-week extension (ClinicalTrials.gov identifier: NCT02033889). A total of 621 participants were randomized 1:1:1 to placebo, or ertugliflozin 5 or 15 mg/d. The primary endpoint was change from baseline at week 26 in HbA1c. Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP) and number of participants with HbA1c <7.0% (53 mmol/mol). Pre-specified adverse events (AEs) of special interest and percent change from baseline in bone mineral density (BMD) were also assessed at week 26.. At week 26, the placebo-adjusted least-squares mean change from baseline HbA1c (8.1%) was -0.7% and -0.9% for ertugliflozin 5 and 15 mg, respectively (both P < .001), to final means of 7.3% and 7.2%, respectively. The odds of HbA1c <7.0% were significantly greater in both ertugliflozin groups vs placebo. Ertugliflozin significantly reduced FPG, body weight, SBP and DBP vs placebo. The incidence of genital mycotic infections was higher in the ertugliflozin groups (female subjects: placebo, 0.9%; ertugliflozin 5 mg, 5.5%; ertugliflozin 15 mg, 6.3% [P = .032]; male subjects: 0%; 3.1%; 3.2%, respectively), as was the incidence of urinary tract infections and symptomatic hypoglycaemia. The incidence of hypovolaemia AEs was similar across groups. Ertugliflozin had no adverse impact on BMD at week 26.. Ertugliflozin added to metformin in patients with inadequately controlled T2DM improved glycaemic control, reduced body weight and BP, but increased the incidence of genital mycotic infections.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Bone Density; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Weight Loss; Young Adult

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.. In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m. Ertugliflozin added to metformin and sitagliptin was well-tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.

Topics: Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

To evaluate the efficacy and safety of ertugliflozin and sitagliptin co-administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.. In this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.. At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (-1.5%) and E15/S100 (-1.5%) than with individual agents (-1.0%, -1.1% and -1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin-treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups.. In patients with uncontrolled type 2 diabetes while using metformin, co-administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.

Topics: Aged; Body Mass Index; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Overweight; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors

This phase III, multicentre, randomized study (ClinicalTrials.gov; NCT01958671) evaluated the efficacy and safety of ertugliflozin monotherapy in adults with inadequately controlled type 2 diabetes (glycated haemoglobin [HbA1c], 7.0% to 10.5% [53-91 mmol/mol]) despite diet and exercise.. The 52-week study comprised a 26-week, double-blind, placebo-controlled period (Phase A) during which 461 participants received placebo, ertugliflozin 5 mg/d or ertugliflozin 15 mg/d. This was followed by a 26-week active-controlled period (Phase B) during which participants in the placebo group who had not received glycaemic rescue therapy had blinded metformin added. Results to Week 52 are reported. Because of the use of metformin in Phase B, no statistical comparisons of efficacy were made between the ertugliflozin and placebo/metformin groups at Week 52.. The mean (standard error) change from baseline to Week 52 in HbA1c was -0.9% (0.1) and -1.0% (0.1) in the ertugliflozin 5 and 15 mg groups, respectively. The proportions of participants with HbA1c <7.0% at Week 52 were 25.6% and 28.5%, respectively. Ertugliflozin reduced fasting plasma glucose, body weight and systolic blood pressure (SBP). The incidence of genital mycotic infections (GMIs) in females was significantly higher in both ertugliflozin groups (5 mg, 26.9%; 15 mg, 29.0%) vs the placebo/metformin group (9.9%), and in males was significantly higher in the 15 mg group (7.8%) vs the placebo/metformin group (1.2%). Ertugliflozin was not associated with increased incidence of urinary tract infections, symptomatic hypoglycaemia or hypovolaemia adverse events compared with placebo/metformin.. Ertugliflozin treatment over 52 weeks improved glycaemic control and reduced body weight and SBP, but increased GMIs.

Topics: Adolescent; Adult; Aged; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise Therapy; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Weight Loss; Young Adult

Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose.. This was a Phase I, open-label, single-dose study in healthy individuals (n = 8) and those with moderate hepatic impairment (n = 8). Eligible participants were men or women aged 18 to 75years with a body mass index of 18.0 to 40.5 kg/m. The adjusted least squares geometric meanratios for total ertugliflozin AUC. Moderate hepatic impairment had no clinically relevant effect on the PK and safety profiles of ertugliflozin. The results of this study support a recommendation for no dose adjustment of ertugliflozin in patients with mild or moderate hepatic impairment. Ertugliflozin was well tolerated when administered tohealthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347.

Topics: Area Under Curve; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Female; Humans; Liver Diseases; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline.. Patients ≥40 years old with T2DM (HbA1c 7.0-10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy.. 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients.. The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD.

Topics: Adult; Aged; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Incidence; Male; Middle Aged; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Survival Rate; Treatment Outcome; United States

Ertugliflozin is a highly selective and potent inhibitor of the sodium-glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium-glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ≥90 mL/min) and type 2 diabetes mellitus subjects with mild (60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) renal impairment (n = 36). Blood and urine samples were collected predose and over 96 hours postdose for pharmacokinetic evaluation and measurement of urinary glucose excretion over 24 hours. Log-linear regression analyses indicated predicted mean area under the concentration-time curve values for mild, moderate, and severe renal function groups that were ≤70% higher relative to subjects with normal renal function. Generally consistent results were obtained with categorical analysis based on analysis of variance. The increase in ertugliflozin exposure in subjects with renal impairment is not expected to be clinically meaningful. Regression analysis of change from baseline in urinary glucose excretion over 24 hours vs estimated glomerular filtration rate showed a decrease in urinary glucose excretion with declining renal function. A single 15-mg dose of ertugliflozin was well tolerated in all groups.

Topics: Aged; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Glucose; Glucosides; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Renal Insufficiency; Sodium-Glucose Transporter 2

To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes.. This was a 52-week, double-blind, multicentre, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (phase A), followed by a 26-week active-controlled treatment period (phase B) in 461 men and women, aged ≥18 years with inadequate glycaemic control (glycated haemoglobin [HbA1c] concentration 7.0% to 10.5% [53-91 mmol/mol], inclusive) despite diet and exercise. Results from phase A are reported in the present paper. The primary endpoint was the change in HbA1c from baseline to week 26.. At week 26, the placebo-adjusted least squares mean HbA1c changes from baseline were -0.99% and -1.16% for the ertugliflozin 5 and 15 mg doses, respectively ( P  < .001 for both doses). The odds of having HbA1c <7.0% (53 mmol/mol) were significantly greater in the ertugliflozin 5 and 15 mg groups compared with the placebo group. Both doses of ertugliflozin significantly lowered fasting plasma glucose and 2-hour postprandial glucose levels and body weight. The placebo-adjusted differences in changes from baseline in systolic blood pressure were not statistically significant. A higher incidence of genital mycotic infections occurred in men and women treated with ertugliflozin compared with placebo. There was no significant difference between treatments in the proportion of participants with symptomatic hypoglycaemia or adverse events associated with urinary tract infection or hypovolaemia.. Ertugliflozin 5 and 15 mg treatment for 26 weeks provides effective glycaemic control, reduces body weight and is generally well tolerated, when used as monotherapy.

Topics: Anti-Obesity Agents; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunity, Mucosal; Incidence; Male; Membrane Transport Modulators; Mycoses; Overweight; Reproductive Tract Infections; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.. A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored.. Ertugliflozin (1-25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) -0.45% (1 mg) to -0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (-0.76%; p = 0.0001)], FPG (LSM -1.17 to -1.90 mmol/l; p < 0.0001) and body weight (-1.15 to -2.15%; p < 0.0001). The LSM SBP decreased by -3.4 to -4.0 mmHg from baseline with ertugliflozin 5-25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo.. Ertugliflozin (1-25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Genital Diseases, Female; Genital Diseases, Male; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mycoses; Sitagliptin Phosphate; Sodium-Glucose Transport Proteins; Urinary Tract Infections

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

Topics: Aldosterone; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Female; Glycosuria; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Hypoglycemic Agents; Male; Renin

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Sodium-Glucose Transporter 2 Inhibitors

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Muscles; Sodium-Glucose Transporter 2 Inhibitors

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Muscles; Sodium-Glucose Transporter 2 Inhibitors

To assess selected cardiorenal outcomes with ertugliflozin according to use of baseline glucose-lowering agent.. VERTIS CV was a cardiovascular (CV) outcome trial for ertugliflozin versus placebo, conducted in patients with type 2 diabetes and established atherosclerotic CV disease. The primary outcome was time to the first event of CV death, myocardial infarction or stroke (major adverse CV events [MACE]), with other CV outcomes also assessed. Outcomes were analysed using Cox proportional hazards models stratified by baseline use of metformin, insulin, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, with interaction testing to assess for treatment effect modification. Changes from baseline in glycaemic, metabolic and haemodynamic variables were also assessed.. Of 8246 randomized patients, at baseline 6286 (76%) were on metformin, 3898 (47%) were on insulin, 3383 (41%) were on SUs and 911 (11%) were on DPP-4 inhibitors, alone or in combination therapy (67% used >1 glucose-lowering agent at baseline). For each glucose-lowering agent evaluated, no evidence for effect modification was observed for MACE by baseline use of metformin (with: hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.790, 1.073; without: 1.13, 95% CI 0.867, 1.480), insulin (with: HR 0.91, 95% CI 0.765, 1.092; without: 1.06, 95% CI 0.867, 1.293), SUs (with: HR 1.11, 95% CI 0.890, 1.388; without: 0.90, 95% CI 0.761, 1.060) or DPP-4 inhibitors (with: HR 0.77, 95% CI 0.502, 1.173; without: 1.00, 95% CI 0.867, 1.147) (all P. In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes were consistent across subgroups of patients stratified by baseline glucose-lowering agent.. gov identifier: NCT01986881.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose; Humans; Hypoglycemic Agents; Insulin; Metformin; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

A growing number of antidiabetic agents have demonstrated cardiovascular and renal benefits in cardiovascular outcome trials (CVOTs), despite such trials being principally required to rule out excess cardiovascular risk.. This article addresses the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial, its background, design, results, and implications. In patients at least 40 years of age with atherosclerotic cardiovascular disease (ASCVD), the VERTIS-CV trial demonstrated ertugliflozin was non-inferior to placebo for major adverse cardiovascular events, though not superior. Ertugliflozin significantly reduced hospitalization for heart failure compared to placebo. The composite renal outcome was not significantly different between groups. Ertugliflozin was generally well tolerated with a safety profile commensurate with other sodium-glucose co-transporter-2 inhibitors (SGLT-2) inhibitors.. In patients with type 2 diabetes and ASCVD, ertugliflozin appears safe with a noted non-significant trend toward improved renal outcomes. Approximately 23.7% of patients in the VERTIS-CV trial had heart failure, the highest among SGLT-2 inhibitor CVOTs. The VERTIS-CV trial reaffirms the reduction in heart failure hospitalizations as a likely class effect of SGLT-2 inhibitors. While the trial supports the use of ertugliflozin beyond glycemic control, agents with confirmed superiority for improved cardiovascular outcomes and mortality may be preferred.

Topics: Atherosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). A population pharmacokinetic (popPK) model was developed to characterize the pharmacokinetics (PK) of ertugliflozin and quantify the influence of intrinsic (eg, body weight, age, sex, race, estimated glomerular filtration rate [eGFR], T2DM) and extrinsic (eg, food) covariates on the PK parameters of ertugliflozin. The analysis was conducted using data from 15 clinical studies (phases 1-3) enrolling healthy subjects and patients with T2DM, which included 13,691 PK observations from 2276 subjects and was performed using nonlinear mixed-effects modeling. A 2-compartment popPK model with first-order absorption and a lag time and first-order elimination, described the plasma concentration-time profile of ertugliflozin after single and multiple dosing in healthy subjects and in patients with T2DM. Apparent clearance increased with increasing body weight and eGFR, was slightly lower in patients with T2DM and females, and was slightly higher in Asians. Apparent central volume of distribution increased with increasing body weight and was higher in females and Asians. Administration of ertugliflozin with food decreased the absorption rate constant (k

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Biological Availability; Bridged Bicyclo Compounds, Heterocyclic; Case-Control Studies; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Models, Biological; Sodium-Glucose Transporter 2 Inhibitors; Tissue Distribution; Young Adult

Topics: Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glucose; Humans; Renal Insufficiency, Chronic; Sodium; Sodium-Glucose Transporter 2

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Sodium-Glucose Transporter 2 Inhibitors

Background Inhibitors of the sodium-glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium-glucose linked transporter 2 inhibition on mitochondrial function, high-energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high-fat, high-sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High-energy phosphates were assessed by

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Dietary Sucrose; Energy Metabolism; Gene Expression Regulation; Hypertrophy, Left Ventricular; Male; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

Topics: Adult; Aged; Asia, Eastern; Asia, Southeastern; Asian People; Bridged Bicyclo Compounds, Heterocyclic; China; Diabetes Mellitus, Type 2; Ethnicity; Female; Humans; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

To identify potential predictors and mediators of changes in β-cell function in response to ertugliflozin treatment in people with type 2 diabetes mellitus (T2DM).. Data from patients with T2DM randomized to ertugliflozin (5 or 15 mg; observations from both doses were pooled) or placebo in four phase 3 clinical studies (clinicaltrials.gov: NCT01958671, NCT02226003, NCT02036515, NCT02099110) were pooled and analysed. Change from baseline in β-cell function at week 26 was assessed, and its potential predictors and mediators were analysed using linear and multiple regression analyses.. Compared with placebo, ertugliflozin improved β-cell function when assessed by mean percent change from baseline in homeostatic model assessment of β-cell function (HOMA-%β; ertugliflozin: 14.7%, 95% confidence interval [CI] 12.3, 17.1; placebo: -0.4%, 95% CI -3.4, 2.5], but not when assessed by change in C-peptide index following a mixed meal tolerance test. Change in HOMA-%β correlated with change from baseline in glycated haemoglobin (HbA1c) and treatment with ertugliflozin, and weakly with change from baseline in body weight. In the ertugliflozin group, change in HOMA-%β correlated with baseline fasting plasma glucose (FPG; r = 0.235, P < 0.001), baseline HbA1c (r = 0.138, P < 0.001), baseline homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.162, P < 0.01), and baseline HOMA-%β (r = -0.321, P < 0.001) in linear regression analyses. Multiple regression analyses yielded similar results.. In people with T2DM, ertugliflozin treatment improved fasting β-cell function, but no effect on postprandial β-cell function was observed in this analysis. Improvement in HOMA-%β was predicted by high baseline FPG, HbA1c, HOMA-IR, and low baseline HOMA-%β, and mediated by ertugliflozin treatment, and improved HbA1c and body weight.

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Insulin Resistance; Sodium-Glucose Transporter 2 Inhibitors

Ertugliflozin is a new sodium-glucose cotransporter type 2 inhibitor (SGLT2i) that is indicated in the treatment of type 2 diabetes. It has been investigated in the large phase 3 development programme VERTIS, in monotherapy and in association with different antidiabetic medications, including insulin. The add-on of ertugliflozin to metformin (VERTIS MET) and the association ertugliflozin-sitagliptin (VERTIS-SITA, VERTIS FACTORIAL, VERTIS SITA2) showed a significant reduction in glycated haemoglobin, without hypoglycaemia, together with a diminution of body weight and arterial blood pressure. As expected, more genital mycotic infections were observed, the only adverse event consistently reported. The cardiovascular safety of ertugliflozin has been demonstrated in VERTIS CV. Ertugliflozin is commercialized with two doses 5 mg and 15 mg. This SGLT2i is also available in fixed-dose combinations, ertugliflozin-metformin and ertugliflozin-sitagliptin. The three presentations offer a greater flexibility to the practitioner to optimize therapeutic choices for a complex disease where the treatment should be individualized according to the patient profile.. L’ertugliflozine est un nouvel inhibiteur des cotransporteurs sodium-glucose de type 2 (iSGLT2) indiqué dans le traitement du diabète de type 2. Il a été investigué dans un vaste programme de développement de phase 3 appelé VERTIS, en monothérapie et en association avec divers autres médicaments antidiabétiques, y compris l’insuline. L’association de l’ertugliflozine à la metformine (VERTIS MET) et l’association ertugliflozine-sitagliptine (VERTIS SITA, VERTIS FACTORIAL, VERTIS SITA2) ont montré une réduction significative du taux d’hémoglobine glyquée, sans hypoglycémie, avec une perte de poids et une diminution de la pression artérielle. Comme attendu, il y a eu davantage d’infections génitales mycotiques, la seule manifestation indésirable systématiquement rapportée. La sécurité cardiovasculaire de l’ertugliflozine a été démontrée dans VERTIS CV. L’ertugliflozine est commercialisée aux deux dosages de 5 mg et 15 mg. Elle est également disponible en combinaisons fixes, ertugliflozine-metformine et ertugliflozine-sitagliptine. Les trois présentations offrent une plus grande flexibilité au praticien dans ses choix thérapeutiques pour une maladie complexe où le traitement doit être individualisé selon le profil du patient.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin

This study evaluated the characteristics of new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) in clinical practice to assess the applicability of the findings from clinical trials (Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial, Canagliflozin Cardiovascular Assessment Study (CANVAS) program and the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial) and multinational observational studies (CVD-REAL Nordic study and CVD-REAL 2 study).. We conducted a retrospective cohort study using the largest electronic medical records database from seven hospitals in Taiwan. We included adult patients with type 2 diabetes initiating canagliflozin, dapagliflozin and empagliflozin between 1 January 2018 and 31 August 2019. We compared the patient characteristics with SGLT2i to examine the data representativeness of clinical trials and to evaluate channeling uses between canagliflozin, dapagliflozin and empagliflozin.. We identified a cohort of 11 650 patients newly initiating SGLT2i, 49.9% of whom received empagliflozin. However, only 18.7%, 19.2%, 50.4% and 57.3% of real-world SGLT2i new users were included in the EMPA-REG OUTCOME trial, VERTIS-CV trial, DECLARE-TIMI 58 trial and CANVAS program, respectively. Reasons for exclusion were largely reduced cardiovascular disease risks in real-world patients, namely 72.8%, 73.6% and 34.2% for EMPA-REG OUTCOME trial, VERTIS-CV trial and DECLARE-TIMI 58 trial and CANVAS program, respectively. However, hemoglobin A1c out of range accounted for the most frequent reason (25.0%) for exclusion of real-world patients from the CANVAS program. We found channeling uses in different SGLT2i, for example, more patients receiving empagliflozin (15.3%) and canagliflozin (19.6%) had poorer renal functions (eg, estimated glomerular filtration rate <60 mL/min/1.73 m. The findings provide clear evidence that results from current studies may be less applicable to real-world patients. Further studies are required to support the concept of real-world cardiovascular event protection through SGLT2i.

Topics: Adult; Aged; Aged, 80 and over; Benzhydryl Compounds; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Canagliflozin; Cardiovascular Diseases; Clinical Trials as Topic; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glucosides; Glycated Hemoglobin; Humans; Male; Middle Aged; Observational Studies as Topic; Practice Patterns, Physicians'; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors

With the growth in co-development deals between pharmaceutical companies and the increased use of contract research organizations (CROs) in drug development, more and more employees are encountering projects that require working across different companies. Navigating the mix of corporate cultures as well as variations in standards and procedures can lead to unanticipated challenges and delays. The development of ertugliflozin, a recently approved medicine for type 2 diabetes mellitus, involved both co-development and CRO engagement across 4 companies. Challenges to combining processes and systems across the 4 companies were encountered and resolved. Early decisions for adoption of standards and processes as well as the organization of committees and communication pathways were key to the success of this ambitious program. Here we share our experiences and lessons learned with respect to the analysis and reporting of clinical trial results.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials Data Monitoring Committees; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Industry; Humans; Outsourced Services

The efficacy of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, for glycemic and blood pressure (BP) control has been demonstrated in phase 3 studies. To further evaluate the effects of ertugliflozin on BP and other hemodynamic parameters, an analysis was conducted on the pooled patient populations from these studies.. This was a post hoc analysis of data from three phase 3 studies (NCT01958671, NCT02033889, and NCT02036515) of adults with type 2 diabetes mellitus who received placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg. Outcomes at 26 weeks were analyzed for the pooled population and according to relevant baseline factors, including BP.. Of the 1544 patients included (placebo, n = 515; ertugliflozin 5 mg, n = 519; ertugliflozin 15 mg, n = 510), most (67.4-69.0%) had hypertension at baseline. Mean baseline BP was similar across treatment groups (placebo, 129.7/78.0 mmHg; ertugliflozin 5 mg, 131.0/78.4 mmHg; ertugliflozin 15 mg, 130.5/78.4 mmHg). At Week 26, placebo-adjusted least squares (LS) mean changes (95% confidence intervals [CI]) from baseline in systolic BP (SBP) were - 3.7 mmHg (- 5.1, - 2.3) for both ertugliflozin doses. Reductions were consistent across all baseline subgroups. At Week 26, more patients with a baseline SBP ≥ 130 mmHg had a SBP < 130 mmHg with ertugliflozin (38.7% both doses) than with placebo (24.0%), and more patients with a baseline SBP ≥ 140 mmHg attained a SBP < 140 mmHg with ertugliflozin (59.5% [5 mg] and 66.7% [15 mg]) than with placebo (43.8%). Placebo-adjusted LS mean changes (95% CI) in diastolic BP (DBP) with ertugliflozin 5 mg and 15 mg were - 1.8 mmHg (- 2.7, - 0.9) and - 1.6 mmHg (- 2.5, -  0.7), respectively, and in pulse rate were - 1.3 beats per minute (bpm) (- 2.2, - 0.3) and - 1.5 bpm (- 2.5, - 0.6), respectively. Greater reductions in pulse pressure, mean arterial pressure, and double product were observed with ertugliflozin than with placebo. Incidence of adverse event-related osmotic diuresis was low, but greater with ertugliflozin (2.9% [5 mg], 2.4% [15 mg]) than placebo (1.0%).. Ertugliflozin treatment led to reductions in SBP, DBP, and pulse rate relative to placebo. Reductions in SBP were generally consistent across the subgroups evaluated. Trial registration NCT01958671; NCT02033889; NCT02036515.

Topics: Aged; Antihypertensive Agents; Biomarkers; Blood Glucose; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome

This pooled analysis assessed the efficacy of ertugliflozin versus placebo as monotherapy or with other antihyperglycaemic agents across patient subgroups defined by demographic and disease characteristics.. At Week 26, placebo-adjusted least squares mean changes from baseline in glycated haemoglobin with ertugliflozin 5 and 15 mg were -0.8% (95% confidence interval: -0.9, -0.7) and -0.9% (-1.0, -0.8), respectively. Reductions were consistent across subgroups. Placebo-adjusted least squares mean changes in body weight were -1.8 kg (-2.2, -1.4) for both ertugliflozin doses; for systolic blood pressure, these were -3.4 mmHg (-4.8, -2.0) and -3.5 mmHg (-4.9, -2.0) for ertugliflozin 5 and 15 mg, respectively. Higher proportions of patients receiving ertugliflozin had glycated haemoglobin <7.0%, weight loss ⩾5% and systolic blood pressure <130 mmHg versus placebo. Ertugliflozin and placebo safety profiles were similar, including incidences of hypoglycaemia, urinary tract infection and hypovolaemia. Genital mycotic infection and adverse events related to osmotic diuresis were more common with ertugliflozin.. Ertugliflozin demonstrated efficacy as monotherapy or with other antihyperglycaemic agents in patients with different demographic and disease characteristics and was generally well tolerated.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Drug Costs; Drug Interactions; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Glucose; Glycosuria; Humans; Hypoglycemic Agents; Kidney; Macaca mulatta; Male; Mice, Inbred ICR; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes mellitus (T2DM) is a growing and serious global health problem. Pharmacological inhibition of the sodium-glucose cotransporter-2 (SGLT2; SLC5A2) increases urinary glucose excretion, decreasing plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 have recently become available for clinical therapy of T2DM.. The patent claims a new class of SGLT2 inhibitors: derivatives of dioxa-bicyclo[3.2.1]octane-2,3,4-triol (including ertugliflozin; PF-04971729). The invention describes the design, synthesis and pharmacological tests related to ertugliflozin, which could ultimately lead to efficacious therapy for T2DM alone or in combination with other anti-diabetic agents.. Ertugliflozin is likely to be of great clinical significance in the near future. Continued analysis of ertugliflozin derivatives to now validate safe and efficacious treatment of T2DM in a larger number of clinical subjects over an extended period is needed to further support clinical utility. Identification, and discussion, of likely contra-indications is also needed.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Patents as Topic; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors