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The article discusses a study that examined the relationship between hypoglycemia and kidney events in individuals with type 2 diabetes and cardiovascular disease. The study found no significant association between hypoglycemia events and adverse kidney outcomes. However, it did find that a previous adverse kidney outcome was linked to a higher risk of subsequent hypoglycemia events. The authors recommend further research using real-world data to explore this association and the safety of glucose-lowering medications. [Extracted from the article]

This article discusses the results of a post-hoc analysis of the VERTIS CV trial, which examined the effects of the medication ertugliflozin on the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease. The study found that ertugliflozin significantly reduced the risk of first HHF in the overall cohort of participants. However, the treatment effect was more pronounced in individuals with a pre-trial ejection fraction (EF) of less than 45% and attenuated in those with an EF greater than 60%. These findings contribute to the understanding of the efficacy of SGLT2 inhibitors in reducing the risk of HHF across different EF ranges. [Extracted from the article]

Context: VERTIS CV evaluated the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). Objective: The aim of these analyses was to assess the insulin requirements of VERTIS CV patients over the trial duration. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Keywords: cardiovascular risk reduction; icosapent ethyl; REDUCE-IT; type 2 diabetes; VERTIS CV EN cardiovascular risk reduction icosapent ethyl REDUCE-IT type 2 diabetes VERTIS CV 1398 1402 5 04/04/23 20230501 NES 230501 BACKGROUND Cardiovascular (CV) disease is the leading cause of morbidity and mortality for people with type 2 diabetes (T2D).[[1]] Accordingly, CV risk reduction is a key component of the standard of care for T2D, with professional society treatment recommendations endorsing a multifactorial approach that simultaneously targets individual atherosclerotic CV disease (ASCVD) risk factors.[[1], [3]] These risk factors include obesity, physical inactivity, smoking, hypertension, hyperglycaemia, insulin resistance/hyperinsulinaemia and dyslipidaemia.[[1], [3]] With regards to lipids, statins are the mainstay for ASCVD risk reduction for people with T2D, but even when low-density lipoprotein cholesterol (LDL-C) levels are controlled, residual ASCVD risk remains.[[5]] Results from the REDUCE-IT trial demonstrated that icosapent ethyl (IPE) decreased the risk of ischaemic events, including CV death, in a population with established ASCVD or with diabetes plus other ASCVD risk factors, whose LDL-C levels on statin treatment were 41-100 mg/dl with elevated fasting triglyceride (TG) levels (135-499 mg/dl).[7] The prevalence of these criteria in populations with T2D and ASCVD is not well documented. These data show that 29.6% of participants in VERTIS CV would be eligible for IPE therapy based on the REDUCE-IT trial inclusion criteria. The REDUCE-IT trial inclusion criteria were met by 29.6% of the overall VERTIS CV population at baseline, with a further 30.3% not meeting the full REDUCE-IT criteria but having baseline TG >135 mg/dl (Figure 1). [Extracted from the article]

Purpose: 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. Methods: 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. Results: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m2; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28–0.96; P = 0.04). Conclusions: 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. Trial registration. ClinicalTrials.gov identifier: NCT01986881. [ABSTRACT FROM AUTHOR]

Aim: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. Materials and Methods: 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). Results: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m2, HSI 44.0 and FIB‐4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB‐4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB‐4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy and safety of ertugliflozin have not been well characterized in Asian populations with type 2 diabetes (T2D) and overweight or obesity as defined by the Chinese Diabetes Society [body mass index (BMI) ≥ 24 kg/m2]. Methods: These post hoc analyses of pooled data from two randomized, double-blind, 26-week studies assessed the efficacy and safety of ertugliflozin (5 mg or 15 mg) compared with placebo in participants from Asia with T2D and baseline BMI ≥ 24 kg/m2, with inadequate glycemic control on metformin. Longitudinal analyses were used to calculate least squares (LS) mean [95% confidence interval (CI)] change from baseline in glycemic indices and body weight. The proportions of participants achieving efficacy targets and experiencing adverse events (AEs) were assessed. Results: The 445 participants had a mean age of 55.5 years, T2D duration 6.6 years, glycated hemoglobin (HbA1c) 8.1%, and BMI 27.6 kg/m2. At week 26, placebo-adjusted LS mean (95% CI) changes from baseline for ertugliflozin 5 mg and 15 mg, respectively, were − 0.78% (− 0.95% to − 0.61%) and − 0.80% (− 0.98% to − 0.63%) for HbA1c, and − 1.74 kg (− 2.29 kg to − 1.19 kg) and − 2.04 kg (− 2.60 kg to − 1.48 kg) for body weight. A greater proportion of participants receiving ertugliflozin 5 mg and 15 mg versus placebo, respectively, achieved HbA1c < 7.0% (42.1% and 46.3% vs. 13.9%), body weight reduction ≥ 5% (35.5% and 38.3% vs. 11.1%), and systolic blood pressure < 130 mmHg (42.4% and 34.5% vs. 21.7%). The proportion of participants with AEs was 52.6% (ertugliflozin 5 mg), 52.3% (ertugliflozin 15 mg), and 55.6% (placebo). Conclusions: In participants from Asia with T2D inadequately controlled by metformin monotherapy, and BMI ≥24 kg/m2, ertugliflozin (5 mg or 15 mg) resulted in greater glycemic and body weight reductions compared with placebo and was generally well tolerated. Trial Registration: Clinicaltrials.gov identifiers NCT02033889, NCT02630706. [ABSTRACT FROM AUTHOR]

Aims: 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. Materials and methods: 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. Results: 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. Conclusions: 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. ClinicalTrials.gov identifier: NCT01986881 [ABSTRACT FROM AUTHOR]

Aim: To assess selected cardiorenal outcomes with ertugliflozin according to use of baseline glucose‐lowering agent. Materials and Methods: 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. Results: 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 Pinteraction > 0.05). Similar results were observed for all secondary outcomes analysed. Conclusion: In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes were consistent across subgroups of patients stratified by baseline glucose‐lowering agent. ClinicalTrials.gov identifier: NCT01986881 [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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). Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Aims: This prespecified exploratory analyses from VERTIS CV (NCT01986881) aimed to assess the effects of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor ertugliflozin on glucosuria‐related (glycated haemoglobin [HbA1c], uric acid, body weight) and natriuresis‐related (blood pressure, haemoglobin, haematocrit, serum albumin) biomarkers according to kidney function risk category. Materials and methods: Patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (1:1:1). Analyses compared placebo (n = 2747) versus ertugliflozin (pooled; n = 5499) on glucosuria‐ and natriuresis‐related biomarkers according to baseline estimated glomerular filtration rate (eGFR) subgroup and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) risk category. Results: Patients were classified according to KDIGO CKD low‐ (49%), moderate‐ (32%) and high‐/very‐high‐risk categories (19%), and eGFR groups 1 (25%), 2 (53%) and 3 (19%). At Week 18, the high‐/very‐high‐risk category had a smaller placebo‐subtracted least squares mean (LSM) change from baseline (95% confidence interval) in HbA1c (−0.34 [−0.43, −0.25]) compared with the low‐ and moderate‐risk categories (−0.54 [−0.60, −0.49] and − 0.47 [−0.54, −0.40], respectively). This pattern was maintained throughout the study (Pinteraction = 0.0001). Similar patterns based on baseline eGFR G stage were observed. Placebo‐subtracted LSM changes from baseline in uric acid were lowest in the high‐/very‐high‐risk category at Weeks 6 and 18, but the pattern was not maintained after Week 156 (Pinteraction = 0.15). Effects of ertugliflozin on body weight and natriuresis‐related biomarkers did not differ across KDIGO CKD categories. Conclusions: In VERTIS CV, ertugliflozin was associated with physiologically favourable changes in glucosuria‐ and natriuresis‐related biomarkers. Glycaemic efficacy of ertugliflozin was attenuated in patients with higher chronic kidney disease (CKD) risk. Effects on other biomarkers were consistent, regardless of CKD risk stage. [ABSTRACT FROM AUTHOR]

Background: A recent meta‐analysis of sodium–glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials. Hypothesis: The apparent heterogeneity of the meta‐analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials. Methods: We performed a meta‐analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE‐TIMI 58 (NCT01730534), and EMPA‐REG OUTCOME (NCT01131676). Results: Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51–0.65]) and with a highly consistent effect across the trials (Q statistic p =.64; I2 = 0.0%). Conclusions: Our meta‐analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: 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). Methods: 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. Results: A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation: 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. Trial registration: ClinicalTrials.gov NCT01986881 [ABSTRACT FROM AUTHOR]

Introduction: VERTIS CV is the cardiovascular outcome trial for the sodium–glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU). Methods: Patients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0–10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%. Results: Of the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] − 0.66% [− 0.89, − 0.43] and − 0.75% [− 0.98, − 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusions: In patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated. Trial Registration: VERTIS CV ClinicalTrials.gov identifier, NCT01986881. [ABSTRACT FROM AUTHOR]

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 < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene. Conclusion: This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors. Trial Registration: Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: This 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.gov NCT01999218 [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. Methods: Post hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks. Results: Overall, mean (SD) baseline eGFR was 88.2 (18.8) ml min−1 (1.73 m)−2 and 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)−2 for 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)−2 for 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 < 0.01) for ertugliflozin 5 mg and −37.6% (−51.8, −19.2; p < 0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA1c (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/interpretation: Ertugliflozin 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 HbA1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria. Trial registration: clinicaltrials.gov NCT01999218 and NCT02033889. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150‐mg subcutaneous dose administered to healthy subjects (n = 156–158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (Cmax) ranged between 11.0 and 11.3 μg/mL, and area under the plasma concentration‐time curve (AUCinf) ranged between 177.6 and 185.0 μg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for Cmax and AUCinf fell within the 80%–125% range for both DS and delivery device comparisons. Comparable low‐density lipoprotein cholesterol profiles were observed, with nadir values of 54.3–56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection‐site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150‐mg subcutaneous injection regardless of site of DS manufacture or delivery device used. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine the safety and cardiovascular (CV) effects of saxagliptin in the predefined elderly (≥65 years) and very elderly (≥75 years) subpopulations of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESEARCH DESIGN AND METHODS Individuals ≥40 years (n = 16,492; elderly, n = 8,561; very elderly, n = 2,330) with HbA1c ≥6.5% (47.5 mmol/mol) and ≤12.0% (107.7 mmol/mol) were randomized (11) to saxagliptin (5 or 2.5 mg daily) or placebo in a double-blind trial for a median follow-up of 2.1 years. RESULTS The hazard ratio (HR) for the comparison of saxagliptin versus placebo for the primary end point (composite of CV mortality, myocardial infarction, or ischemic stroke) was 0.92 for elderly patients vs. 1.15 for patients <65 years (P = 0.06) and 0.95 for very elderly patients. The HR for the secondary composite end points in the entire cohort, elderly cohort, and very elderly cohort were similar. Although saxagliptin increased the risk of hospitalization for heart failure in the overall saxagliptin population, there was no age-based treatment interaction (P = 0.76 for elderly patients vs. those <65 years; P = 0.34 for very elderly patients vs. those <75 years). Among saxagliptin-treated individuals with baseline HbA1c ≥7.6% (59.6 mmol/mol), the mean change from baseline HbA1c at 2 years was -0.69%, -0.64%, -0.66%, and -0.66% for those ≥65, <65, ≥75, and <75 years, respectively. The incidence of overall adverse events (AEs) and serious AEs was similar between saxagliptin and placebo in all cohorts; however, hypoglycemic events were higher for saxagliptin versus placebo regardless of age. CONCLUSIONS The SAVOR-TIMI 53 trial supports the overall CV safety of saxagliptin in a robust number of elderly and very elderly participants, although the risk of heart failure hospitalization was increased irrespective of age category. AEs and serious AEs as well as glycemic efficacy of saxagliptin in elderly patients are similar to those found in younger patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with fewtreatment options.We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DiabetesMellitus (SAVOR)-Thrombolysis inMyocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were strati ed as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m² ; n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m² ; n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m² ; n =336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50mL/min/1.73m² (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m² (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P =0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function. [ABSTRACT FROM AUTHOR]

Background To compare the safety and efficacy of saxagliptin 2.5 mg twice daily (BID) versus placebo add-on therapy to metformin immediate release (IR) in patients with type 2 diabetes and inadequate glycemic control with metformin alone. Methods This multicenter, 12-week, double-blind, parallel-group trial enrolled adult outpatients with type 2 diabetes (glycated hemoglobin [HbA1c] 7.0%-10.0%) on stable metformin IR monotherapy (⩾1500 mg, BID for ⩾8 weeks). Patients were randomized to double-blind saxagliptin 2.5 mg BID or placebo added on to metformin IR following a 2-week, singleblind, placebo add-on therapy lead-in period. The primary end point was the change from baseline to week 12 in HbA1c. Key secondary end points included change from baseline to week 12 in fasting plasma glucose (FPG) and the proportion of patients achieving HbA1c <7.0% or HbA1c ⩽ 6.5% at week 12. Efficacy was analyzed in all patients who received randomized study drug with ⩾1 postbaseline assessment. Safety was assessed in all treated patients. Results In total, 74 patients were randomized to double-blind saxagliptin add-on therapy and 86 to placebo add-on therapy. At week 12, least-squares mean changes (95% CI) from baseline HbA1c (adjusted for baseline HbA1c) were significantly greater (P = 0.006) in the saxagliptin + metformin group -0.56% (-0.74% to -0.38%) versus the placebo + metformin group -0.22% (-0.39% to -0.06%). Adjusted mean changes from baseline in FPG were numerically greater with saxagliptin versus placebo; the difference (95% CI) -9.5 mg/dL (-21.7 to 2.7) was not statistically significant (P = 0.12). A numerically greater proportion of patients in the saxagliptin group than the placebo group achieved HbA1c < 7.0% (37.5% vs 24.2%) or HbA1c ⩽6.5% (24.6% vs 10.7%). There were no unexpected safety findings. Hypoglycemia occurred in 4 patients (5.4%) in the saxagliptin group and 1 patient (1.2%) in the placebo group; confirmed hypoglycemia (symptoms plus fingerstick glucose ⩽50 mg/dL) occurred in 1 patient in the placebo group. Conclusions Addition of saxagliptin 2.5 mg BID to metformin therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy reduced HbA1c compared with placebo added to metformin, with an adverse events profile similar to placebo and no unexpected safety findings. Trial registration ClinicalTrials.gov NCT00885378 [ABSTRACT FROM AUTHOR]

Background It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs. Methods Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigatorreported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method). Results In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12). Conclusions Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk. [ABSTRACT FROM AUTHOR]

Purpose: To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM). Patients and methods: This was a post hoc analysis of pooled data from older patients (⩾65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naïve patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naïve patients. The safety analysis population for the five-study pool included 428 patients ⩾ 65 years of age with baseline glycated hemoglobin (HbA1c) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients ⩾ 65 years of age with baseline HbA1c 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA1c. Results: In the five-study pool, the differences in the adjusted mean change from baseline HbA1c among older patients receiving saxagliptin versus placebo were -0.60% (95% confidence interval [CI], -0.99% to -0.21%) for saxagliptin 2.5 mg and -0.55% (-0.97% to -0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was -1.22% (-2.27% to -0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%-8.0% for comparators) and was confirmed (finger stick glucose # 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%-0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention. Conclusion: Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. Methods: 365 treatment-naïve patients with T2DM (HbA1c 7.0%-10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P. M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c ≥7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. Results: At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). Conclusions: In treatment-naïve patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. Trial registration: ClinicalTrials.gov Identifier: NCT00316082 [ABSTRACT FROM AUTHOR]

To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione monotherapy, 565 patients were randomised to saxagliptin (2.5 mg or 5 mg) or placebo added to thiazolidinedione over 76 weeks (24-week short-term + 52-week long-term extension period) in this phase 3, double-blind, placebo-controlled trial; 360 patients completed the study. At 76 weeks, adjusted mean changes from baseline HbA1C (repeated measures model; 95% CI) for saxagliptin 2.5 mg, 5 mg, and placebo were -0.59% (-0.75, -0.43), -1.09% (-1.26, -0.93), and -0.20% (-0.39, -0.01), respectively (post hoc and nominal p=0.0019 and p<0.0001 for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively). Adverse event frequency was similar between groups. Confirmed hypoglycaemic events were 1.0% and 0% vs. 0.5% for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively. Results should be interpreted with caution given the proportion of patients who discontinued or required glycaemic rescue therapy during the 76-week course of study. Saxagliptin added to thiazolidinedione provided sustained incremental efficacy vs. placebo with little hypoglycaemia for up to 76 weeks and was generally well tolerated. [ABSTRACT FROM PUBLISHER]

Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that chronic intestinal inflammation with increased proinflammatory cytokines elevates serum leptin concentration, thereby contributing to anorexia. This hypothesis was studied in interleukin-2-deficient (IL-2(-/-)) mice, a model of IBD with elevated proinflammatory cytokine production. IL-2(-/-), wild-type pair-fed and wild-type control male mice (8 wk old) were fed regular laboratory mouse food for 2 wk. The IL-2(-/-) and pair-fed groups consumed less food and lost weight. Serum leptin concentrations in the IL-2(-/-) mice in the fed state were lower than controls, but not different from pair-fed mice, and paradoxically increased in the starved state to levels significantly higher than both starved control and pair-fed groups. This result did not change when serum leptin was adjusted for amount of body fat. These data show abnormal leptin responses in IL-2(-/-) mice with increased leptin concentrations disproportionate to fat mass and prevention of the normal decline in leptin with food restriction. [ABSTRACT FROM AUTHOR]

Background: Current perception is that participants of a structured weight-loss program regain all of their weight loss within 5 y. Objective: The objective was to examine the long-term weight-loss maintenance of individuals completing a structured weight-loss program. Design: Studies were required to 1) have been conducted in the United States, 2) have included participants in a structured weight-loss program, 3) have provided follow-up data with variance estimates for ≥2 y. Primary outcome variables were weight-loss maintenance in kilograms, weight-loss maintenance as a percentage of initial weight loss, and weight loss as a percentage of initial body weight (reduced weight). Results: Twenty-nine studies met the inclusion criteria. Successful very-low-energy diets (VLEDs) were associated with significantly greater weight-loss maintenance than were successful hypoenergetic balanced diets (HBDs) at all years of follow-up. The percentage of individuals at 4 or 5 y of follow-up for VLEDs and HBDs were 55.4% and 79.7%, respectively. The results for VLEDs and HBDs, respectively, were as follows: weight-loss maintenance, 7.1 kg (95% CI: 6.1, 8.1 kg) and 2.0 (1.5, 2.5) kg; percentage weight-loss maintenance, 29% (25%, 33%) and 17% (13%, 22%); and reduced weight, 6.6% (5.7%, 7.5%) and 2.1% (1.6%, 2.7%). Weight-loss maintenance did not differ significantly between women and men. Six studies reported that groups who exercised more had significantly greater weight-loss maintenance than did those who exercised less. Conclusions: Five years after completing structured weight-loss programs, the average individual maintained a weight loss of >3 kg and a reduced weight of > 3% of initial body weight. After VLEDs or weight loss of ≥20 kg, individuals maintained significantly more weight loss than after HBDs or weight losses of <10 kg. [ABSTRACT FROM AUTHOR]

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA. Disclosure: D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. [ABSTRACT FROM AUTHOR]

VERTIS CV was a cardiovascular (CV) outcome trial that evaluated the CV safety of ERTU in patients with T2D and atherosclerotic CV disease (ASCVD). This analysis assessed the glycemic efficacy and safety of ERTU in VERTIS CV patients with CKD 3. Among 8246 patients in VERTIS CV, 1776 patients with CKD 3 at baseline (BL) were identified based on an eGFR of 30-<60 mL/min/1.73 m2 (1319 patients with CKD 3A [eGFR 45-<60 mL/min/1.73 m2]), calculated via the MDRD equation. Efficacy endpoints were changes from BL in HbA1c, body weight (BW) and systolic blood pressure (SBP) to Week 18, when doses of background antihyperglycemics were to be held constant. Safety assessments included adverse event (AE) reports. BL characteristics did not differ across randomized groups in patients with CKD 3. At Week 18, significant HbA1c reductions from BL for ERTU 5 mg and 15 mg vs. placebo were observed in patients with CKD 3 and in the CKD 3A subgroup (Table). Significant placebo-subtracted reductions in BW (5 mg: −1.4 kg; 15 mg: −1.5 kg) and SBP (5 mg: −2.9 mm Hg; 15 mg: −3.2 mm Hg) occurred in the CKD 3 patients receiving ERTU. The incidence of overall AEs, symptomatic hypoglycemia, hypovolemia and kidney-related AEs did not differ between ERTU and placebo across CKD 3 subgroups. In patients with T2D, ASCVD and CKD 3, ERTU improved glycemic control, BW and SBP, and was generally well tolerated. Disclosure: S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. A. Raji: Employee; Self; Merck & Co., Inc. I. Gantz: Employee; Self; Merck & Co., Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. [ABSTRACT FROM AUTHOR]

VERTIS CV was a cardiovascular (CV) outcome trial that evaluated the CV safety of ERTU in patients with T2D. In VERTIS CV, 8238 patients received ERTU 5 or 15 mg, or placebo (PBO); doses of background antihyperglycemic medications were to be held constant to Week 18. This analysis assessed the insulin requirements of VERTIS CV patients during the entire study. In 4341 (53%) insulin-naïve patients, insulin was initiated in 12.8% (ERTU 5 mg), 11.6% (ERTU 15 mg) and 17.5% (PBO) of patients after the randomization visit. There was a significantly reduced likelihood of insulin initiation with ERTU 5 and 15 mg vs. PBO (ERTU 5 mg: HR 0.70, 95% CI 0.58-0.84; ERTU 15 mg: HR 0.64, 95% CI 0.53-0.78) and a delay in initiating insulin with ERTU 5 and 15 mg vs. PBO was observed (Figure). In 3897 (47%) patients on insulin at baseline (BL), mean (95% CI) change in insulin dose from BL to Month 60 was −2.47 (−9.65, 4.72) IU/d with ERTU 5 mg, −1.77 (−11.95, 8.42) IU/d with ERTU 15 mg and 9.42 (1.46, 17.39) IU/d with PBO. More patients in the ERTU 15 mg arm (4.1%) had discontinued insulin therapy at end of study than in the ERTU 5 mg (2.4%) or PBO (2.2%) arms. In insulin-naïve patients with T2D, ERTU significantly reduced the likelihood of insulin initiation and delayed new insulin initiations by up to ~1.8 years vs. PBO. In patients already on insulin at BL, ERTU prevented an increase in mean insulin dose. Disclosure: S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. W. J. Shih: None. U. Masiukiewicz: Employee; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. H. Shi: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Bristol-Myers Squibb Company. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. [ABSTRACT FROM AUTHOR]

VERTIS CV was the cardiovascular (CV) outcome trial for the SGLT2 inhibitor ertugliflozin, conducted in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. In the overall population, ertugliflozin was noninferior to placebo for major adverse CV events (MACE). Although superiority for the composite endpoint of CV death or hospitalization for heart failure (HHF) and the renal composite (that included doubling of serum creatinine from BL) were not met, the prespecified secondary objective of HHF showed a 30% risk reduction and a prespecified exploratory renal composite (sustained ≥40% decrease in eGFR from BL, dialysis/transplantation, or renal death) showed improved kidney outcomes. This analysis assessed cardiorenal endpoints of VERTIS CV by BL GLA. Among 8246 patients in VERTIS CV, at BL 6292 (76%) used metformin, 3900 (47%) insulin, 3390 (41%) sulfonylureas (SU), and 911 (11%) dipeptidyl peptidase-4 inhibitors (DPP4i), alone or in combination therapy (67% used >1 GLA at BL). For each of the GLAs, metformin, insulin, SU, and DPP4i, no significant differences were observed for cardiorenal outcomes by BL use (yes, no) of the GLA (FIGURE; all interaction P values >0.05). Cardiorenal outcomes were generally similar across the BL GLA subgroups. In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes in patients with T2D were generally consistent regardless of BL GLA. Disclosure: B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Funding: Merck Sharp & Dohme Corp [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) has the capacity for uncoupled mitochondrial respiration and is proposed to be a key site for regulating energy expenditure in rodents. To better define the role of BAT in energy homeostasis, we previously created a line of transgenic mice with deficiency of BAT (UCP promoter-driven diphtheria toxin A transgenic mice [UCP-DTA]) mice. These mice develop obesity that initially is due to decreased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin. In addition, the obesity of these mice is accompanied by severe insulin-resistant diabetes and hyperlipidemia. To better define the basis for leptin resistance in this model, we treated UCP-DTA mice with leptin (300 microg i.p., b.i.d.) and compared their response with that of leptin-treated ob/ob and FVB control mice (30 microg i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight and food intake and improved their glucose homeostasis. In contrast, tenfold higher dosages of leptin had no effect on body weight, food intake, or circulating insulin or glucose concentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mice in the fed state, and increased progressively in response to food restriction as leptin levels fell. In parallel to the levels of hypothalamic NPY, corticosterone levels were initially suppressed and rose with food restriction. Thus food intake, body weight, and insulin and glucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain under leptin control. Further elucidation of the mechanisms underlying leptin resistance in UCP-DTA mice may provide valuable insights into the basis for leptin resistance in human obesity. [ABSTRACT FROM AUTHOR]

Studies the interactions between melanin-concentrating hormone (MCH) and alpha-melanocyte stimulating hormone (MSH) after intracerebroventricular administration in rats. Analysis of MCH and alpha-MSH; Effects of MCH and alpha-MSH in food intake; Examination of the effects of acute MCH administration in feeding behavior.

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. [ABSTRACT FROM AUTHOR]