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ObjectivesThe aim of this analysis was to describe nirmatrelvir/ritonavir real-world effectiveness in preventing hospitalization among high-risk US COVID-19 patients during SARS-CoV-2 Omicron predominance.DesignAn ongoing population-based cohort study with retrospective and prospective collection of electronic healthcare data in the United States.MethodsData for this analysis were collected from the US Optum® de-identified COVID-19 Electronic Health Record (EHR) dataset during December 22, 2021−June 8, 2022. Key eligibility criteria for inclusion in the database analysis were ≥12-years-old; positive SARS-CoV-2 test, COVID-19 diagnosis, or nirmatrelvir/ritonavir prescription; and high risk of severe COVID-19 based on demographic/clinical characteristics. Potential confounders between groups were balanced using propensity score matching (PSM). Immortal time bias was addressed.Outcome measuresHospitalization rates within 30 (primary analysis) or 15 (sensitivity analysis) days from COVID-19 diagnosis overall and within subgroups were evaluated.ResultsBefore PSM, the nirmatrelvir/ritonavir group (n=2811) was less racially diverse, older, and had higher COVID-19 vaccination rates and a greater number of comorbidities than the non-nirmatrelvir/ritonavir group (n=194,542). Baseline characteristics were well balanced across groups (n=2808 and n=10,849, respectively) after PSM. Incidence of hospitalization (95% CI) within 30 days was 1.21% (0.84%−1.69%) for the nirmatrelvir/ritonavir group and 6.94% (6.03%−7.94%) for the non-nirmatrelvir/ritonavir group, with a hazard ratio (95% CI) of 0.16 (0.11−0.22; 84% relative risk reduction). Incidence within 15 days was 0.78% (0.49%−1.18%) for the nirmatrelvir/ritonavir group and 6.54% (5.65%−7.52%) for the non-nirmatrelvir/ritonavir group; hazard ratio 0.11 (0.07−0.17; 89% relative risk reduction). Nirmatrelvir/ritonavir was effective in African American patients (hazard ratio, 0.35 [0.15−0.83]; 65% relative risk reduction). Relative risk reductions were comparable with overall results across ages and among vaccinated patients.ConclusionsReal-world nirmatrelvir/ritonavir effectiveness against hospitalization during the Omicron era supports EPIC-HR efficacy among high-risk patients. Future research should confirm these early real-world results and address limitations.

Supplemental Digital Content is available in the text., Background: 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. Methods: 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. Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75–1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54–0.90]; P=0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44–0.90]; no HF: HR, 0.79 [95% CI, 0.54–1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30–0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58–1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate

Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods: Adults with non–high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non–HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. Results: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58–69) years, 44% were female, the median non–HDL-C was 132.4 (interquartile range, 118.0–154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4–270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non–HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P P P 3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). Conclusions: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non–HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT04516291.

Aim To assess the efficacy and safety of ertugliflozin in older patients with type 2 diabetes (T2D). Materials and methods 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). Results 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. Conclusions Ertugliflozin improved glycaemic control, BW and SBP in younger and older individuals with T2D and was generally well tolerated in both groups.

Introduction This post hoc exploratory analysis examined the effects of ertugliflozin on liver enzymes in patients with type 2 diabetes mellitus (T2DM). Methods Data were pooled from seven randomized, double-blind VERTIS phase 3 trials that evaluated ertugliflozin (5 mg and 15 mg) versus non-ertugliflozin (placebo, glimepiride, or sitagliptin) treatment in patients with T2DM. Change from baseline at week 52 of treatment in alanine and aspartate aminotransferase (ALT and AST, respectively) serum levels (overall and categorized into tertiles by baseline ALT and AST), Fibrosis-4 Index (FIB-4), glycated hemoglobin (HbA1c), and body weight were evaluated, along with the association between changes in ALT and AST and changes in HbA1c and body weight by treatment. Results Baseline characteristics were balanced across treatment groups (ertugliflozin 5 mg, n = 1716; ertugliflozin 15 mg, n = 1693; non-ertugliflozin, n = 1450). At week 52 of treatment, serum levels of ALT and AST were reduced in patients in the ertugliflozin treatment groups (5 and 15 mg, respectively) compared with those in the non-ertugliflozin group. The comparator-adjusted mean (95% confidence interval [CI]) difference in change from baseline at week 52 for ALT was − 3.35 (− 4.40, − 2.31) IU/L for ertugliflozin 5 mg and − 4.08 (− 5.13, − 3.03) IU/L for ertugliflozin 15 mg; for AST, the respective values were − 1.81 (− 2.50, − 1.11) IU/L and − 2.12 (− 2.82, − 1.42) IU/L. The effects of ertugliflozin were detected across all baseline ALT and AST tertiles, with the highest tertile showing the greatest treatment differences. No meaningful differences were observed between treatment groups for FIB-4. Changes in ALT and AST showed a weak but statistically significant association with changes in HbA1c and body weight in all treatment groups. Conclusions Treatment with ertugliflozin resulted in a reduction in the levels of hepatic transaminases compared with the non-ertugliflozin group after 52 weeks of treatment. Changes in body weight and HbA1c contributed at least in part to the effects of ertugliflozin on liver enzymes. Trial Registration Clinicaltrials.gov registry numbers: NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

Objective: To assess the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N = 4859) and three placebo-controlled studies were used to assess efficacy (N = 1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was -0.8% (-1.0, -0.7) and -1.0% (-1.1, -0.8) with ertugliflozin 5 mg and 15 mg, respectively, in the White subgroup, -0.7% (-1.2, -0.2) and -0.8% (-1.3, -0.3) in the Black subgroup, and -0.8% (-1.1, -0.5) and -1.0% (-1.3, -0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5 mg, 15 mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.

Introduction The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator. Methods The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks. Results In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate

Aims/hypothesisThis study aimed to evaluate the effect of ertugliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.govNCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population.MethodsPost hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks.ResultsOverall, mean (SD) baseline eGFR was 88.2 (18.8) ml min−1(1.73 m)−2and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were −2.3, −2.7 and −0.7 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were −0.2, 0.1 and −2.0 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was −29.5% (−44.8, −9.8;p p 1c(mmol/mol [95% CI]) at week 104 were similar between treatment groups: −6.84 (−7.64, −6.03), −7.74 (−8.54, −6.94) and −6.84 (−7.65, −6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c(% [95% CI]) at week 104 were: −0.63 (−0.70, −0.55), −0.71 (−0.78, −0.64) and −0.63 (−0.70, −0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively.Conclusions/interpretationErtugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1cdid not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria.Trial registrationclinicaltrials.govNCT01999218 and NCT02033889.

OBJECTIVE This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. METHODS 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. RESULTS 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

Aim Post‐hoc analysis of the efficacy and safety of ertugliflozin in East/Southeast (E/SE) Asian patients with type 2 diabetes mellitus (T2DM). Materials and Methods 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). Results 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. Conclusions 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. https://ClinicalTrials.gov identifier: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, NCT02226003.

A fixed‐dose combination (FDC) of ertugliflozin, a selective sodium‐glucose cotransporter 2 inhibitor, and immediate‐release metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open‐label, randomized, 2‐period, single‐dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US‐ or EU‐sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration–time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.

Background: 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. Methods: Data from three phase III randomised, placebo-controlled, double-blind studies (NCT01958671, NCT02033889 and NCT02036515) with similar designs and populations were pooled ( N = 1544). Results: 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 Conclusion: Ertugliflozin demonstrated efficacy as monotherapy or with other antihyperglycaemic agents in patients with different demographic and disease characteristics and was generally well tolerated.

Objective 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 (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. Materials and methods 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. Results The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE24 for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC24 and UGE24 for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated. Conclusion 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.

AIM 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. MATERIALS AND METHODS 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

Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0–9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were −0.3% (−0.4, −0.2), −0.4% (−0.5, −0.3) and −0.4% (−0.5, −0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks. Trial registration:ClinicalTrials.gov identifier: NCT01999218.

AIM To evaluate the long-term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin. MATERIALS AND METHODS 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. RESULTS 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

Background 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. Methods 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. Results 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. Conclusion The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD.

Objective: To assess the efficacy and safety of ertugliflozin in Hispanic/Latino patients with type 2 diabetes (T2DM). Methods: Analysis of data from Hispanic/Latino patients who participated in randomized, double-blind phase III studies. Ertugliflozin efficacy was evaluated when initiated as a single agent (as monotherapy or add-on therapy) and when initiated in combination with sitagliptin. Least-squares mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight (BW), and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs). Results: Analyses included 1178 Hispanic/Latino patients. In a pooled analysis of three placebo-controlled studies where ertugliflozin was initiated as a single agent, the placebo-corrected change from baseline in HbA1c at week 26 for ertugliflozin 5 and 15 mg was −0.8 and −1.0%, respectively. In an active-comparator study, when initiated as a single agent, the change from baseline in HbA1c at week 52 was −0.5, −0.7, and −0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg, and glimepiride, respectively. In a placebo-controlled study, when initiated in combination with sitagliptin, the placebo-corrected change from baseline in HbA1c at week 26 for ertugliflozin 5 mg/sitagliptin and ertugliflozin 15 mg/sitagliptin was –1.3 and –1.6%, respectively. In an active-comparator study, when initiated in combination with sitagliptin, the change from baseline in HbA1c at week 26 was –1.4, −1.6, and –0.9 for ertugliflozin 5 mg/sitagliptin, ertugliflozin 15 mg/sitagliptin, and sitagliptin alone, respectively. Reductions in BW and SBP were observed with ertugliflozin as a single agent or combined with sitagliptin. The incidences of overall and prespecified AEs in Hispanic/Latino patients were generally consistent with the known safety profile of ertugliflozin. Conclusion: Ertugliflozin, administered as a single agent or as a combination with sitagliptin, improved HbA1c, BW, and SBP. Ertugliflozin was generally well-tolerated in Hispanic/Latino patients with T2DM. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.

Purpose 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. Methods 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 75 years with a body mass index of 18.0 to 40.5 kg/m2. Healthy individuals had normal hepatic function; patients with hepatic impairment had a Child-Pugh score of 7 to 9 points (moderate hepatic impairment). Blood samples were collected before dosing and during 96 hours after dosing for evaluation of PK parameters. Adverse events were monitored throughout the study. Findings The adjusted least squares geometric mean ratios for total ertugliflozin AUC0–∞ and Cmax in patients with moderate hepatic impairment compared with healthy individuals were 87.4% (90% CI, 68.1%–112.2%) and 78.7% (90% CI, 65.7%–94.2%), respectively. The AUC0–∞ and Cmax for unbound ertugliflozin were also similar between patients with moderate hepatic impairment and healthy individuals. Mean half-life estimates for ertugliflozin were similar (14.6 vs 13.8 hours) in patients with moderate hepatic impairment and healthy individuals. The number of participants with all-causality treatment-emergent adverse events was similar for both groups (2 of 8 patients with moderate hepatic impairment and 3 of 8 healthy individuals). Implications 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 to healthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347.

Purpose Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin. Methods Twelve healthy adult subjects were enrolled in this open-label, 2-period, fixed-sequence study and received ertugliflozin 15 mg on day 1 of period 1, followed by rifampin 600 mg once daily on days 1 to 10 in period 2. On day 8 of period 2, ertugliflozin 15 mg was coadministered with rifampin 600 mg. Plasma samples for ertugliflozin pharmacokinetic analysis were collected during 72 hours after dosing on day 1 of period 1 and day 8 of period 2 and analyzed using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis of concentration-time data. Natural log transformed AUC0–∞ and Cmax of ertugliflozin were analyzed using a mixed-effects model with treatment as a fixed effect and subject as a random effect. Findings After administration of ertugliflozin 15 mg alone or with rifampin, the Tmax was 1 hour. The mean t½ was 12.3 hours for ertugliflozin alone and 9.2 hours with steady-state rifampin. Geometric mean ratios for AUC0–∞ and Cmax were 61.2% (90% CI, 57.2%–65.4%) and 84.6% (90% CI, 74.2%–96.5%), respectively. Ertugliflozin was well tolerated when administered alone or with rifampin. Implications Coadministration of ertugliflozin with rifampin decreased ertugliflozin AUC0–∞ and Cmax by 39% and 15%, respectively. The effect of the reduced exposure was evaluated using the ertugliflozin dose-response model. The model predicted that a 5-mg ertugliflozin dose after coadministration with rifampin is expected to maintain clinically meaningful glycemic efficacy. Therefore, no dose adjustment of ertugliflozin is recommended when ertugliflozin is coadministered with a UGT and CYP inducer, such as rifampin.

Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with 14 C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa ) of ertugliflozin. Eight healthy adult men received 100-μg i.v. 14 C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14 C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high-performance liquid-chromatography tandem mass spectrometry (HPLC-MS/MS). 14 C-ertugliflozin plasma concentrations were determined using HPLC-accelerator mass spectrometry (AMS) and 14 C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o. /14 C-AUCi.v. )*(14 C-Dosei.v. /Dosep.o. )) and Fa ((14 C_Total_Urinep.o. /14 C_Total_Urinei.v. )* (14 C-Dosei.v. /14 C-Dosep.o. )) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

Introduction Ertugliflozin is an oral sodium-glucose cotransporter 2 inhibitor that is being developed to treat type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of co-initiation of ertugliflozin and sitagliptin compared with placebo in patients with T2DM inadequately controlled on diet and exercise. Methods In this phase III, randomized, double-blind, multicenter, placebo-controlled 26-week study (NCT02226003), patients with T2DM and glycated hemoglobin (HbA1c) 8.0–10.5% on diet/exercise were randomized 1:1:1 to ertugliflozin 5 mg once daily (QD) and sitagliptin 100 mg QD (E5/S100), ertugliflozin 15 mg QD and sitagliptin 100 mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26. Results The mean baseline HbA1c of the randomized patients (n = 291) was 8.9%. At week 26, both ertugliflozin/sitagliptin treatments provided significant reductions from baseline in HbA1c compared with placebo [least squares mean HbA1c change (95% confidence intervals) from baseline was − 0.4% (− 0.7, − 0.2), − 1.6% (− 1.8, − 1.4), and − 1.7% (− 1.9, − 1.5) for placebo, E5/S100, and E15/S100, respectively]. At week 26, 8.3%, 35.7%, and 31.3% of patients receiving placebo, E5/S100, and E15/S100, respectively, had HbA1c

Introduction This study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods This phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1c ≥ 7.0% and ≤ 9.0% on stable metformin ≥ 1500 mg/day 1:1:1 to ertugliflozin 15 or 5 mg once-daily (QD), or glimepiride (titrated from 1 mg QD). The primary hypothesis was that ertugliflozin 15 mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment difference Results Mean baseline HbA1c of randomized patients (N = 1326) was 7.8%. Mean and median doses of glimepiride were 3.0 mg/day throughout the study. At week 52, the least squares mean change (95% CI) from baseline in HbA1c was − 0.6% (− 0.7, − 0.5), − 0.6% (− 0.6, − 0.5), and − 0.7% (− 0.8, − 0.7) in the ertugliflozin 15 mg, ertugliflozin 5 mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15 mg and glimepiride of 0.1% (− 0.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups. Conclusions Ertugliflozin 15 mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride. Clinical Trial Registration Clinicaltrials.gov NCT01999218.

Introduction Ertugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52 weeks in patients with chronic kidney disease (CKD). Methods In this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0–10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR) ≥ 30 to

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 (

The propensity for CYP3A4 induction by 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999), an irreversible inactivator of myeloperoxidase, was examined in the present study. Studies using human hepatocytes revealed moderate increases in CYP3A4 mRNA and midazolam-1'-hydroxylase activity in a PF-06282999 dose-dependent fashion. At the highest tested concentration of 300 μM, PF-06282999 caused maximal induction in CYP3A4 mRNA and enzyme activity ranging from 56% to 86% and 47% t0 72%, respectively, of rifampicin response across the three hepatocyte donor pools. In a clinical drug-drug interaction (DDI) study, the mean midazolam Cmax and area under the curve (AUC) values following 14-day treatment with PF-06282999 decreased in a dose-dependent fashion with a maximum decrease in midazolam AUC0-inf and Cmax of ∼57.2% and 41.1% observed at the 500 mg twice daily dose. The moderate impact on midazolam pharmacokinetics at the 500 mg twice daily dose of PF-06282999 was also reflected in statistically significant changes in plasma 4β-hydroxycholesterol/cholesterol and urinary 6β-hydroxycortisol/cortisol ratios. Changes in plasma and urinary CYP3A4 biomarkers did not reach statistical significance at the 125 mg three times daily dose of PF-06282999, despite a modest decrease in midazolam systemic exposure. Predicted DDI magnitude based on the in vitro induction parameters and simulated pharmacokinetics of perpetrator (PF-06282999) and victim (midazolam) using the Simcyp (Simcyp Ltd., Sheffield, United Kingdom) population-based simulator were in reasonable agreement with the observed clinical data. Since the magnitude of the 4β-hydroxycholesterol or 6β-hydroxycortisol ratio change was generally smaller than the magnitude of the midazolam AUC change with PF-06282999, a pharmacokinetic interaction study with midazolam ultimately proved important for assessment of DDI via CYP3A4 induction.

Aims To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes. Materials and methods 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. Results 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

Ertugliflozin (ERTU), an SGLT2 inhibitor, improves glycemic control in adult patients (pts) with T2DM. Elderly pts with T2DM are underrepresented in clinical studies, often present with multiple co-morbidities and are more susceptible to adverse events (AEs). Pooled analyses based on 7 phase 3 studies from the VERTIS program evaluated the safety and efficacy of ERTU in subgroups of pts aged Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. B. Charbonnel: Consultant; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited. S.M. Patel: Stock/Shareholder; Spouse/Partner; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Merck & Co., Inc. M.A. Hickman: Employee; Self; Pfizer Inc. J. Liu: Employee; Self; Merck & Co., Inc. L. Tarasenko: Employee; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck & Co., Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

Background: ERTU is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of adults with type 2 diabetes mellitus (T2DM). As several SGLT2i are commercially available, MBMA of the HbA1c-lowering effect of these drugs was undertaken to assess their comparative effectiveness. Methods: MBMA quantified the time course of dose vs. HbA1c response of SGLT2i and evaluated the impact of covariates including baseline HbA1c, estimated glomerular filtration rate (eGFR) and background diabetes treatment on HbA1c efficacy. Of the 496 randomized controlled trials (RCTs) in the database, 94 RCTs representing >31,000 T2DM patients were with SGLT2i, including 5 RCTs for ERTU. Results: For SGLT2i, there was a 28.7% (95% CI, 24.5 to 33.1%) greater relative HbA1c efficacy for a 1% absolute increase in baseline HbA1c. Additionally, the HbA1c efficacy was 25.0% (17.0 to 34.0%) greater on a diet background alone relative to a background of metformin (or other oral antidiabetic treatment). For every 10 mL/min/1.73m2 decrease in eGFR, there was a 8.80% (5.90 to 11.6%) decrease in HbA1c efficacy. Conclusion: This MBMA allowed an indirect comparison of SGLT2 inhibitor efficacy across trials (Table). Overall, ERTU doses of 5 and 15 mg were of comparable or numerically greater efficacy to other SGLT2i. Disclosure D. Fediuk: Employee; Self; Pfizer Inc. J. Mandema: Consultant; Self; Merck & Co., Inc., Pfizer Inc., Sanofi. K. Sweeney: Employee; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. V. Sahasrabudhe: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck Sharp & Dohme Corp.

2 RCT evaluating ertugliflozin 5 mg (E5, n=652), 15 mg (E15, n=640) vs. non-ertugliflozin (NE, glimepiride or placebo, n=644) in T2D patients were pooled to evaluate effects on eGFR (MDRD) and albuminuria (UACR, geometric mean of % change from baseline). eGFR and UACR were analyzed by mixed model repeated measures with treatment, time, trial, baseline measures [A1C, SBP, eGFR/UACR] as covariates in overall population and by presence of UACR >30 mg/g. Baseline characteristics in the treatment groups were balanced. Overall, mean baseline eGFR was 88.2 ml/min/1.73m2 and geometric mean baseline UACR was 11.6 mg/g. At week 6, changes in eGFR were: -2.3, -2.7 and -0.7 ml/min/1.73m2, for the E5, E15 and NE groups, respectively. Mean eGFR with ertugliflozin increased over time, while it decreased in the NE group. The week 104 ΔeGFR [95% CI] compared to NE was 1.81 ([0.13, 3.49]; p=0.04) and 2.10 ml/min/1.73m2 ([0.42, 3.78]; p=0.01) for E5 and E15, respectively. In patients with baseline UACR > 30 mg/g (n=415) the ertugliflozin groups had greater UACR reductions. The week 104 ΔUACR [95% CI] compared to NE was -29.0% ([-47.0, -4.5]; p=0.02) for E5 and -32.7% ([-50.4, -8.6]; p=0.01) for E15. Ertugliflozin acutely reduced eGFR in an expected fashion, possibly based of known hemodynamic effects. Over 104 weeks, eGFR values were higher with ertugliflozin than control, suggestive of renal function preservation. Ertugliflozin reduced UACR in subjects with baseline albuminuria. Disclosure D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. R. Frederich: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Z. Xu: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck & Co., Inc.

Background: An ERTU/SITA fixed-dose combination is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). As several SGLT2i + DPP-4i combinations are commercially available, MBMA of the HbA1c-lowering effect of these combinations was undertaken to assess their comparative effectiveness. Methods: MBMA quantified the time course of dose vs. HbA1c response of SGLT2i + DPP-4i combinations and evaluated the impact of covariates including baseline HbA1c, estimated glomerular filtration rate (eGFR) and background diabetes treatment on HbA1c efficacy. Of the 496 randomized controlled trials (RCTs) in the database, 261 RCTs representing >87,000 T2DM patients were with SGLT2 inhibitors and/or DPP-4 inhibitors, including 2 RCTs for ERTU + SITA. Results: For SGLT2i + DPP-4i combinations, the HbA1c efficacy increased with higher baseline HbA1c and decreased with declining renal function. Additionally, the HbA1c efficacy was greater on a diet background alone relative to a background of oral antidiabetic treatment. Conclusion: This MBMA allowed an indirect comparison of SGLT2i + DPP-4i efficacy across trials (Table). Overall, ERTU 5 or 15 mg + SITA 100 mg doses were of comparable or numerically greater efficacy to other SGLT2i + DPP-4i combinations. Disclosure D. Fediuk: Employee; Self; Pfizer Inc. J. Mandema: Consultant; Self; Merck & Co., Inc., Pfizer Inc., Sanofi. K. Sweeney: Employee; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. V. Sahasrabudhe: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck Sharp & Dohme Corp.

Ertugliflozin (ERTU), a SGLT2 inhibitor, improves glycemic control in adults with T2DM. T2DM is prevalent among adults of Hispanic ethnicity in the U.S. Here we report a post hoc analysis of ERTU efficacy and safety in Hispanic/Latino pts in the ERTU Phase 3 program. A1C, body weight (BW), and systolic blood pressure (SBP) were evaluated with ERTU 5 and 15 mg (vs. placebo [PBO] or glimepiride [GLIM]) and ERTU with sitagliptin 100 mg (ERTU 5 or 15 mg/SITA vs. PBO or SITA). Adverse events (AEs) were evaluated. Among 4855 pts, baseline characteristics were generally similar across treatment groups and between the group of pts self-reported as Hispanic/Latino (n=1178, 24.3%) and the non-Hispanic/Latino group. No meaningful differences were observed between these ethnic groups in A1C reductions with ERTU 5 and 15 mg at week 26 in a pooled analysis of PBO-controlled studies, at week 52 in a GLIM-controlled study, or with ERTU 5 mg/SITA and ERTU 15 mg/SITA groups at week 26 in PBO- and SITA-controlled studies (Figure). Similarly, no meaningful differences between ethnic groups were observed in BW and SBP reductions with ERTU 5 and 15 mg across the program. ERTU was generally well tolerated. The incidence of AEs was similar between ethnic groups. ERTU efficacy and safety were similar between Hispanic/Latino and non-Hispanic/Latino groups. NCTs: 01958671, 02033889, 02036515, 01999218, 02226003, 02099110, 01986855. Disclosure J. Liu: Employee; Self; Merck & Co., Inc. L. Tarasenko: Employee; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck & Co., Inc. A. Pong: None. S. Huyck: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

BackgroundThe 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.MethodsThis 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.ResultsOf 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 ConclusionErtugliflozin treatment led to reductions in SBP, DBP, and pulse rate relative to placebo. Reductions in SBP were generally consistent across the subgroups evaluated.Trial registrationNCT01958671; NCT02033889; NCT02036515

IMPORTANCE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain. OBJECTIVE: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes. DATA SOURCES: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020. STUDY SELECTION: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials. DATA EXTRACTION AND SYNTHESIS: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model. MAIN OUTCOMES AND MEASURES: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials. RESULTS: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I(2) = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I(2) = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction). CONCLUSIONS AND RELEVANCE: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

The thiouracil derivative PF-06282999 [2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is an irreversible inactivator of myeloperoxidase and is currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via nonmetabolic routes. To test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays, with the ultimate goal of predicting human pharmacokinetics and elimination mechanisms. Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and humans and was devoid of cytochrome P450 inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all of the species. Pharmacokinetics in preclinical species characterized by low to moderate plasma clearances, good oral bioavailability at 3- to 5-mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single-species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20-200 mg PF-06282999. In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and humans, with renal excretion of the unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies.

Ertugliflozin (ERTU) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor for the treatment of T2DM. Pharmacokinetic analysis indicates ERTU plasma exposure is not affected by race. The efficacy and safety of ERTU by race was assessed in pooled analyses from 3 randomized, double-blind, placebo (PBO)-controlled, Phase 3 trials. Patients received ERTU 5 mg, 15 mg or PBO for 26 weeks. Least-squares (LS) means for change from baseline to Week 26 were calculated for hemoglobin A1C (A1C), body weight (BW) and systolic blood pressure (SBP). General and prespecified adverse events (AEs) were evaluated. The analysis included 1544 patients (white 73%; black 7%; asian 15%; other 5%). Baseline demographics and characteristics were generally similar across treatment groups and racial groups, except lower mean BW and BMI in Asians. No notable differences in A1C, BW and SBP reductions were observed across racial groups (Table 1), except for a greater SBP reduction observed in Blacks. Across racial groups there were no notable differences in general AEs with ERTU vs. PBO. An increase in genital mycotic infections was seen with ERTU vs. PBO across all racial groups. Precision of between-treatment effects was limited in Blacks, Asians and Others due to small group size. ERTU efficacy and safety was generally similar across racial groups although a greater reduction in SBP was observed in Blacks.Table 1. Least-squares Mean Change (Placebo-corrected) in A1C, Body Weight and SBP from Baseline to Week 26 by Racial Group (Excluding Rescue Approach)RaceErtugliflozin Dose (N)*δA1C (%) LS mean (95% CI)δBody Weight (kg) LS mean (95% CI)δSBP (mmHg) LS mean (95% CI)Overall5 mg (519)-0.8 (-0.9, -0.7)-1.8 (-2.2, -1.4)-3.4 (-4.8, -2.0)15 mg (510)-0.9 (-1.0, -0.8)-1.8 (-2.2, -1.4)-3.5 (-4.9, -2.0)White5 mg (382)-0.8 (-1.0, -0.7)-1.9 (-2.3, -1.4)-3.3 (-4.9, -1.6)15 mg (374)-1.0 (-1.1, -0.8)-1.7 (-2.2, -1.2)-3.5 (-5.1, -1.8)Black5 mg (34)-0.7 (-1.2, -0.2)-1.1 (-2.8, 0.6)-9.5 (-16.0, -2.9)15 mg (37)-0.8 (-1.3, -0.3)-2.2 (-3.9, -0.6)-8.1 (-14.6, -1.7)Asian5 mg ( 77)-0.8 (-1.1, -0.5)-1.9 (-2.6, -1.1)-1.8 (-5.3, 1.8)15 mg (77)-1.0 (-1.3, -0.8)-2.1 (-2.8, -1.4)-1.9 (-5.4, 1.7)Other5 mg (26)-0.3 (-0.9, 0.3)-1.7 (-3.2, -0.2)-3.5 (-11.3, 4.4)15 mg (22)-0.9 (-1.5, -0.3)-1.5 (-3.0, 0.1)-4.4 (-12.8, 3.9)CI, confidence interval; LS, Least Squares *N is the number of randomized patients who took at least one dose of study medication. The LS Means for Change from Baseline to Week 26 were estimated from a constrained longitudinal data analysis model. Disclosure J. Liu: None. L. Tarasenko: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. A. Pong: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..

Ertugliflozin (ERTU) is a highly selective sodium-glucose cotransporter 2 inhibitor in development for treatment of patients with type 2 diabetes mellitus (T2DM). This pooled analysis characterized the efficacy and safety of ERTU when used as add-on therapy to metformin (MET). Pooled data from 2 randomized, double-blind, placebo-controlled Phase 3 studies with similar design and patient population (NCT02033889 [VERTIS MET], NCT02036515 [VERTIS SITA2]) were analyzed. Adult patients with T2DM inadequately controlled on MET (± sitagliptin) with A1C ≥7.0 to ≤10.5% were randomized to placebo (PBO), ERTU 5 mg or 15 mg for 26 weeks. Mean baseline (BL) characteristics of patients (N=1083) were similar across pooled treatment groups (age 57.7 years; T2DM duration 8.6 years; A1C 8.1%; body weight [BW] 85.7 kg; systolic blood pressure [SBP] 130.6 mmHg; estimated glomerular filtration rate 89.4 mL/min/1.73 m2). Changes in A1C, BW and SBP after 26 weeks are shown in the Table. Relative to PBO, more patients receiving ERTU had A1C Addition of ERTU to MET (± sitagliptin) provides reductions in A1C, BW and SBP, resulting in more patients achieving metabolic treatment goals.Table. Changes from baseline in A1C, BW and SBP at Week 26Placebo (n=362)Ertugliflozin 5 mg (n=363)Ertugliflozin 15 mg (n=358)Least squares mean change from baseline in A1C at Week 26 (95% CI), % Placebo-adjusted difference–0.1 (–0.2, 0.0) ––0.8 (–0.8, –0.7) –0.7 (–0.8, –0.6)–0.9 (–1.0, –0.8) –0.8 (–1.0, –0.7)Patients with A1C Disclosure R.A. Calle: Employee; Self; Pfizer Inc.. J. Liu: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. A. Pong: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..

This Phase 3 randomized, double-blind study in adults with T2DM (A1C 7.0-10.5%) on MET monotherapy (≥1500 mg/day ≥8 weeks) included a 26 week placebo (PBO)-controlled period followed by a 78 week extension where non-rescued PBO pts with fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride (GLIM). Efficacy, safety and effect on bone mineral density (BMD) of ertugliflozin (ERTU) 5 mg and 15 mg QD at week 104 are reported. Pts (N=621) had baseline mean ± SD: age 56.6 ± 8.8 y; T2DM duration 8.0 ± 6.0 y; BMI 31.1 ± 4.7 kg/m2; A1C 8.1 ± 0.9%. 41% were post-menopausal women. At week 104, ERTU 5 mg and ERTU 15 mg reduced A1C, FPG, body weight (BW) and blood pressure (BP) compared to baseline, and increased the proportion of pts with A1C Incidence of female genital mycotic infections was higher in ERTU 5 mg (7.3%; p=0.017) and 15 mg (9.8%; p=0.003) vs. PBO/GLIM (0.9%). Symptomatic hypoglycemia was lower in ERTU 5 mg (5.8%; p=0.009) and 15 mg (5.9%; p=0.009) vs. PBO/GLIM (13.4%). ERTU had no impact on BMD vs. PBO/GLIM, except total hip where BMD reduction was greater for ERTU 15 mg (Table). Fractures occurred in 3, 2 and 7 pts in ERTU 5 mg, 15 mg and PBO/GLIM, respectively. ERTU added to MET in pts with inadequately controlled T2DM improved glycemic control, BW and BP over 104 weeks. ERTU was well tolerated with no clinically meaningful impact on BMD. Table: Change in efficacy (vs baseline) and bone mineral density (vs PBO/GLIM) endpointsERTU 5 mgERTU 15 mg Efficacy endpointsa (change vs baseline)Change from baseline at Wk 104: LS mean (95% CI)bA1C (%)-0.5 (-0.6, -0.4)-0.8 (-0.9, -0.6)FPG (mg/dL)-17.0 (-22.7, -11.3)-26.7 (-32.5, -21.0)Body weight (kg)-3.6 (-4.2, -3.0)-3.5 (-4.1, -2.9)SBP (mmHg)-3.9 (-5.8, -2.0)-2.8 (-4.8, -0.9)DBP (mmHg)-2.3 (-3.6, -1.1)-1.2 (-2.5, 0.0)Proportion of subjects with A1C Disclosure S. Gallo: Employee; Self; Pfizer Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi, Takeda Development Centre Europe Ltd. A. Goldman: Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. H. Shi: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck & Co., Inc. A. Darekar: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc. S. Terra: Employee; Self; Pfizer Inc..

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 HbA1c7.0% (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 HbA1c7.0% 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.

Aim 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. Methods In this study (http://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. Results 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

Aim 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. Materials and methods 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. Results 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

Aims To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. Materials and Methods 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 m2) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. Results A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were −0.7% (−7.5 mmol/mol) and −0.8% (−8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P

Ertugliflozin, a selective sodium-glucose cotransporter-2 inhibitor, is being developed for the treatment of type 2 diabetes mellitus. This randomized, 6-sequence, 3-period crossover study assessed the effect of ertugliflozin (100 mg; supratherapeutic dose) vs placebo and moxifloxacin (400 mg; positive control) on the QT interval corrected for heart rate (QTc) in 42 male or female healthy subjects. Triplicate electrocardiograms were performed predose and serially over 48 hours postdose in each treatment period. The maximum observed least-squares mean (90% CI) difference in QTc using the Fridericia correction (QTcF) between ertugliflozin and placebo was 2.99 (1.68, 4.30) milliseconds, 24 hours postdose, below the 5-millisecond threshold of potential clinical concern. The upper limits of the 2-sided 90% CI were less than 10 milliseconds at all postdose time points. The lower 90% CIs for the least-squares mean QTcF difference between moxifloxacin and placebo were greater than 5 milliseconds at the preselected time points of 2, 3, and 4 hours postdose, establishing study sensitivity. The majority of adverse events were mild in severity. In healthy volunteers, at a supratherapeutic dose of 100 mg, ertugliflozin was not associated with QTc interval prolongation.

1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP-778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4. Inhibition of organic anion transporting polypeptide 1B1 by CP-778875 (IC50 = 2.14 ± 0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF-734200, a potent DPP-IV inhibitor in subjects with normal renal function, have been published or presented. WHAT THIS STUDY ADDS • This study provides better data on the PK of PF-734200 in subjects with varying degrees of renal insufficiency and in subjects with end-stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF-734200, this study provides evidence for potential dose adjustment of PF-734200 in patients with certain categories of renal impairment. AIMS PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20 mg PF-734200 in subjects with varying degrees of renal insufficiency or with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF-734200 in ESRD. METHODS Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20-mg dose was given to subjects with ESRD and serum samples were collected. After a 7-day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC-based method. RESULTS Systemic exposures of PF-734200 increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half-life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4 h HD. CONCLUSIONS Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest.

Diabet. Med. 28, 464–469 (2011) Abstract Aims PF-734200 is a potent and selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor. This study assessed the efficacy and safety of PF-734200 at dose rates of 20 and 30 mg/day in subjects with Type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Methods This was a placebo-controlled, double-blind, randomized, multicentre, 12 week study. Subjects with Type 2 diabetes mellitus were eligible if screening glycosylated haemoglobin (HbA1c) was 7–11% (53.0–96.7 mmol/mol) and they had been receiving metformin monotherapy for ≥2 months. Subjects receiving metformin and an insulin secretagogue or metformin and thiazolidinedione needed to have a screening HbA1c of 6.5–9.5% (47.5–80.3 mmol/mol), measured prior to discontinuing the insulin secretagogue or thiazolidinedione. The primary end-point of the study was a change from baseline to week 12 in HbA1c levels. Results Baseline characteristics for 289 subjects randomized to PF-734200 or placebo groups were similar (mean age 56.5 years, mean body mass index 32.2 kg/m2 and mean HbA1c 8.2%, 66.1 mmol/mol). In the predefined per protocol data set, least-squares mean HbA1c at week 12 was reduced by 0.79 (8.6 mmol/mol 95% confidence interval –1.10 to –0.49, −12.0 to −5.4 mmol/mol) and 0.92% (10.1 mmol/mol; –1.23 to –0.61, −13.4 to −6.7 mmol/mol) in the 20 and 30 mg groups, respectively, compared with placebo. Differences from placebo were statistically significant (P