Efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease using insulin: A VERTIS CV substudy.
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ABSTRACT: Aim
To assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled by insulin.Materials and methods
VERTIS CV was the cardiovascular outcome study for ertugliflozin. Patients were randomly assigned to placebo, or ertugliflozin 5 mg or 15 mg once daily. We report the results of a substudy in patients on a stable dose of insulin ≥20 units/d. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to 18 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), body weight (BW), the proportion of patients with HbA1c <53 mmol/mol (<7%), systolic blood pressure (SBP), diastolic blood pressure and insulin dose.Results
Of 8246 patients randomized in VERTIS CV, 1065 were included in the substudy (68.2% men, mean [SD] age 64.8 [7.8] years, T2DM duration 16.7 [9.0] years, HbA1c 8.4 [1.0]%). At week 18, the least squares (LS) mean change from baseline in HbA1c was significantly greater with ertugliflozin 5 mg and 15 mg versus placebo (placebo-adjusted LS mean change -0.58%, 95% confidence interval [CI] -0.71, -0.44 and -0.65%, 95% CI -0.78, -0.51, respectively; P < 0.001 for both). Ertugliflozin significantly reduced FPG, BW and SBP. In women, the incidence of genital mycotic infections was higher with ertugliflozin (3.5%) versus placebo (0.0%). The incidence of symptomatic hypoglycaemia was similar across treatment groups.Conclusions
Ertugliflozin added to insulin improved glycaemic control, BW and SBP versus placebo at 18 weeks in patients with T2DM and ASCVD.
SUBMITTER: Lingvay I
PROVIDER: S-EPMC8252001 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionSulfonylureas (SU) are commonly used antihyperglycemic agents. VERTIS CV was the cardiovascular outcome study for the sodium-glucose cotransporter 2 inhibitor ertugliflozin. Enrollment of patients in VERTIS CV occurred in two sequential cohorts (Cohort 1 and Cohort 2).MethodsThis substudy assessed the efficacy and safety of adding ertugliflozin to SU monotherapy. The primary endpoint was the change in HbA1c from baseline at 18 weeks.ResultsAmong the 8246 patients who were randomized in VERTIS CV, 157 patients in Cohort 1 and 135 patients in Cohort 2 were on SU monotherapy at baseline. In the prespecified analysis (Cohort 1 only), the least squares (LS) mean HbA1c change from baseline for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was - 0.56%, - 0.91%, and - 0.78%, respectively (placebo-adjusted LS mean [95% CI] change: - 0.35% [- 0.72%, 0.02%]; - 0.22% [- 0.60%, 0.16%] for ertugliflozin 5 and 15 mg, respectively; p > 0.05 for both). In a post-hoc analysis that included Cohorts 1 and 2 (N = 292), the LS mean HbA1c change from baseline at week 18 for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was - 0.31%, - 0.77%, and - 0.68%, respectively (placebo-adjusted change: - 0.46% [- 0.73%, - 0.18%]; - 0.37% [- 0.66%, - 0.09%]; p = 0.001 and 0.01 for ertugliflozin 5 and 15 mg, respectively). In Cohort 1, adverse events were reported in 45.8%, 47.3%, and 25.9% of patients with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg. The incidence rates of symptomatic hypoglycemia were 0.0%, 5.5%, and 3.7%, respectively, with no cases of severe hypoglycemia. The safety profile was similar for Cohorts 1 and 2 combined.ConclusionThe addition of ertugliflozin to SU monotherapy reduced HbA1c but did not result in significant placebo-adjusted reductions from baseline according to the prespecified primary analysis (n = 157); however, in a post-hoc analysis with a larger patient population (n = 292), significant and clinically relevant HbA1c reductions were observed. Ertugliflozin was generally well tolerated.Trial registrationClinicalTrials.gov identifier: NCT01986881.
| S-EPMC7994479 | biostudies-literature
Project description: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 <60 mL·min-1·1.73 m-2, albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96]).Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.
| S-EPMC7717477 | biostudies-literature
Project description:IntroductionIn the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881), patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) were randomized (1:1:1) to placebo, ertugliflozin 5 mg or 15 mg (doses pooled for analyses as prospectively planned). In this post hoc analysis, the effects of ertugliflozin on kidney outcomes were assessed in analyses stratified by baseline heart failure (HF).MethodsBaseline HF was defined as a history of HF or prerandomization left ventricular ejection fraction ≤45%. Outcomes included estimated glomerular filtration rate (eGFR) over time, total 5-year eGFR slopes and time to first event of a prespecified exploratory kidney composite outcome of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death. All analyses were stratified by baseline HF status.ResultsCompared with no-HF at baseline (n = 5807; 70.4%), patients with HF (n = 2439; 29.6%) had a notably faster rate of eGFR decline, which is unlikely to be explained by the slightly lower baseline eGFR in that group. Ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slopes (ml/min per 1.73 m2 per year [95% confidence intervals; CI]) were 0.96 (0.67-1.24) and 0.95 (0.76-1.14) for HF and no-HF subgroups, respectively. The placebo HF (vs. placebo no-HF) subgroup had a higher incidence of the composite kidney outcome (35/834 [4.20%] vs. 50/1913 [2.61%]). Hazard ratios (95% CI) for the effect of ertugliflozin on the composite kidney outcome did not differ significantly between HF and no-HF subgroups: 0.53 (0.33-0.84) and 0.76 (0.53-1.08), respectively (P interaction = 0.22).ConclusionAlthough patients with HF at baseline had a faster rate of eGFR decline in VERTIS CV, the beneficial effects of ertugliflozin on kidney outcomes did not differ when stratified by baseline HF.
| S-EPMC10105061 | biostudies-literature
Project description:AimPhase 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 methodsA 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c <7.0%. Hypotheses for the primary endpoint and FPG and BW secondary endpoints were tested in the China subpopulation.ResultsAt week 26, least squares mean (95% CI) change from baseline HbA1c was significantly greater with ertugliflozin 5- and 15 mg versus placebo: -1.0% (-1.1, -0.9), -0.9% (-1.0, -0.8), -0.2% (-0.3, -0.1), respectively. Ertugliflozin significantly reduced FPG, BW and SBP. Reductions in DBP with ertugliflozin were not significant. At week 26, 16.2%, 38.2% and 40.8% of patients had HbA1c <7.0% with placebo, ertugliflozin 5- and 15 mg, respectively. 59.3%, 56.5% and 53.3% of patients experienced adverse events with placebo, ertugliflozin 5- and 15 mg, respectively. Incidence of symptomatic hypoglycaemia was higher for ertugliflozin 15 mg vs placebo. Results in the China subpopulation were consistent.ConclusionsErtugliflozin significantly improved glycaemic control and reduced BW and SBP in Asian patients with T2DM. Ertugliflozin was generally well-tolerated. Results in the China subpopulation were consistent with the overall population. ClinicalTrials.gov: NCT02630706.
| S-EPMC7379575 | biostudies-literature
Project description:IntroductionVERTIS 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).MethodsPatients 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%.ResultsOf 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).ConclusionsIn patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated.Trial registrationVERTIS CV ClinicalTrials.gov identifier, NCT01986881.
| S-EPMC8099972 | biostudies-literature
Project description:Background and objectivesA reduction in the rate of eGFR decline, with preservation of ≥0.75 ml/min per 1.73 m2 per year, has been proposed as a surrogate for kidney disease progression. We report results from prespecified analyses assessing effects of ertugliflozin versus placebo on eGFR slope from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881).Design, setting, participants, & measurementsPatients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg (1:1:1). The analyses compared the effect of ertugliflozin (pooled doses, n=5499) versus placebo (n=2747) on eGFR slope per week and per year by random coefficient models. Study periods (weeks 0-6 and weeks 6-52) and total and chronic slopes (week 0 or week 6 to weeks 104, 156, 208, and 260) were modeled separately and by baseline kidney status.ResultsIn the overall population, for weeks 0-6, the least squares mean eGFR slopes (ml/min per 1.73 m2 per week [95% confidence interval (95% CI)]) were -0.07 (-0.16 to 0.03) and -0.54 (-0.61 to -0.48) for the placebo and ertugliflozin groups, respectively; the difference was -0.47 (-0.59 to -0.36). During weeks 6-52, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were -0.12 (-0.70 to 0.46) and 1.62 (1.21 to 2.02) for the placebo and ertugliflozin groups, respectively; the difference was 1.74 (1.03 to 2.45). For weeks 6-156, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were -1.51 (-1.70 to -1.32) and -0.32 (-0.45 to -0.19) for the placebo and ertugliflozin groups, respectively; the difference was 1.19 (0.95 to 1.42). During weeks 0-156, the placebo-adjusted difference in least squares mean slope was 1.06 (0.85 to 1.27). These findings were consistent by baseline kidney status.ConclusionsErtugliflozin has a favorable placebo-adjusted eGFR slope >0.75 ml/min per 1.73 m2 per year, documenting the kidney function preservation underlying the clinical benefits of ertugliflozin on kidney disease progression in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.Clinical trial registry name and registration numberUS National Library of Medicine, ClinicalTrials.gov NCT01986881. Date of trial registration: November 13, 2013.
| S-EPMC8729577 | biostudies-literature
Project description:AimTo evaluate the long-term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin.Materials and methodsA 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.ResultsMean (standard error) change in HbA1c from baseline was -0.7% (0.07) and -1.0% (0.07) at week 52; -0.6% (0.08) and -0.9% (0.08) at week 104 for ertugliflozin 5 and 15 mg. At week 52, 34.8% and 36.6% participants had HbA1c <7.0%, and 24.6% and 33.7% at week 104, for ertugliflozin 5 and 15 mg. Ertugliflozin reduced fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP) from baseline through week 104. The incidence of female genital mycotic infections (GMIs) was higher with ertugliflozin, and symptomatic hypoglycaemia was lower for ertugliflozin versus placebo/glimepiride. Minimal bone mineral density (BMD) changes were observed, similar to placebo/glimepiride, except at total hip where reduction in BMD was greater with ertugliflozin 15 mg versus placebo/glimepiride: difference in least squares means (95% CI) -0.50% (-0.95, -0.04) at week 52 and -0.84% (-1.44, -0.24) at week 104.ConclusionsErtugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non-clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. ClinicalTrials.gov Identifier: NCT02033889.
| S-EPMC6593724 | biostudies-literature
Project description:AimTo assess selected cardiorenal outcomes with ertugliflozin according to use of baseline glucose-lowering agent.Materials and methodsVERTIS 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.ResultsOf 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.ConclusionIn VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes were consistent across subgroups of patients stratified by baseline glucose-lowering agent.Clinicaltrialsgov identifier: NCT01986881.
| S-EPMC9314942 | biostudies-literature
Project description:IntroductionUsing 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.MethodsPatients 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).ResultsIn 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.ConclusionWith 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.
| S-EPMC9501765 | biostudies-literature
Project description:Aims/hypothesisIn 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).MethodsIndividuals 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.ResultsA 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/interpretationAmong 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 registrationClinicalTrials.gov NCT01986881.
| S-EPMC8099851 | biostudies-literature