5 research outputs found
Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial
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 NCT0198688
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes
BACKGROUND
The cardiovascular effects of adding once-weekly treatment with exenatide to usual
care in patients with type 2 diabetes are unknown.
METHODS
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide
at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to
safety and superior to placebo with respect to efficacy.
RESULTS
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular
disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4).
A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7
events per 100 person-years) in the exenatide group and in 905 of 7396 patients
(12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91;
95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis
indicating that exenatide, administered once weekly, was noninferior to placebo with
respect to safety (P<0.001 for noninferiority) but was not superior to placebo
with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke,
hospitalization for heart failure, and hospitalization for acute coronary syndrome,
and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid
carcinoma, and serious adverse events did not differ significantly between the two
groups.
CONCLUSIONS
Among patients with type 2 diabetes with or without previous cardiovascular
disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number,
NCT01144338.
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.)
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
BACKGROUND
Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent
ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data
are needed to determine its effects on ischemic events.
METHODS
We performed a multicenter, randomized, double-blind, placebo-controlled trial involving
patients with established cardiovascular disease or with diabetes and other risk factors, who
had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg
per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of
41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned
to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary
end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, or unstable angina. The key secondary end point was a
composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
RESULTS
A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular
events) and were followed for a median of 4.9 years. A primary end-point event occurred in
17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients
in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001);
the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio,
0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed
according to a prespecified hierarchical schema, were significantly lower in the icosapent
ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs.
5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in
the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation
or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients
in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).
CONCLUSIONS
Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded
by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361
Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes
BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo