Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.

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

Efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease using insulin: A VERTIS CV substudy.

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.

The effects of ertugliflozin on ß-cell function: Pooled analysis from four phase 3 randomized controlled studies.

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

Effect of ertugliflozin on blood pressure in patients with type 2 diabetes mellitus: a post hoc pooled analysis of randomized controlled trials.

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

Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial.

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 <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. CONCLUSIONS: Ertugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non-clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. ClinicalTrials.gov Identifier: NCT02033889.

Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).

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.

Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials.

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.

Efficacy and Safety of Ertugliflozin in Patients with Overweight and Obesity with Type 2 Diabetes Mellitus.

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 < 30, -1.8 kg and -1.9 kg for BMI 30 to < 35, and -2.5 kg and -2.9 kg for BMI ≥ 35. Percent BW changes were similar across BMI subgroups. Incidence of adverse events was 52.5%, 44.6%, and 50.1% with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. CONCLUSIONS: Meaningful reductions in HbA1c, fasting plasma glucose, BW, and SBP were observed with ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. Ertugliflozin improved HbA1c and SBP and reduced BW across BMI subgroups. Ertugliflozin was generally well tolerated.

Efficacy of ertugliflozin in monotherapy or combination therapy in patients with type 2 diabetes: A pooled analysis of placebo-controlled studies.

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 <7.0%, weight loss ⩾5% and systolic blood pressure <130 mmHg versus placebo. Ertugliflozin and placebo safety profiles were similar, including incidences of hypoglycaemia, urinary tract infection and hypovolaemia. Genital mycotic infection and adverse events related to osmotic diuresis were more common with ertugliflozin. CONCLUSION: Ertugliflozin demonstrated efficacy as monotherapy or with other antihyperglycaemic agents in patients with different demographic and disease characteristics and was generally well tolerated.

Impact of the individual components of the metabolic syndrome and their different combinations on the prevalence of atherosclerotic vascular disease in type 2 diabetes: the Diabetes in Germany (DIG) study.

BACKGROUND: One of the major controversies surrounding the metabolic syndrome (MetS) in type 2 diabetes is whether its single components act synergistically as risk factors for atherosclerotic vascular disease (AVD). We aimed to answer this by evaluating the relationship, and its various combinations to AVD in comparison to single traits in a population-based study with type 2 diabetes in Germany. METHODS AND RESULTS: 4020 unselected patients with type 2 diabetes aged 35 - 80 years. MetS was: diabetes plus > or = 2 traits of the MetS by AHA/NHBLI definition.AVD was: history of myocardial infarction and/or coronary revascularization and/or stroke. The occurrence of AVD in relation to overall MetS/single traits/combinations was presented as OR (95% CI). Multiple logistic regression, including established cardiovascular risk factors, modeled their associations. The prevalence of overall MetS was 74.4% and the OR for AVD was 1.41 (1.12-1.78), which however was higher for hypertension as single trait (OR 4.76). Different combinations of MetS presented a wide range of ORs (0.47 to 10.90) and strong sex differences. Some clusters of MetS including hypertension and low HDL-cholesterol presented a higher risk factor than single traits or their sum, whereas the others out of 11 possible carried no increased AVD risk. Multiple logistic regression showed independent association between AVD and overall MetS. CONCLUSION: The overall MetS in type 2 diabetes comprises 11 heterogenous clusters of traits. Overall MetS increases the risk of AVD in type 2 diabetes and individual traits in some clusters with hypertension and low HDL-cholesterol may act synergistically as risk factors particularly in women.