8 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
Ertugliflozin and Slope of Chronic eGFR: Prespecified Analyses from the Randomized VERTIS CV Trial
Background and objectives A 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, & measurements Patients 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, n55499) versus placebo (n52747) 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.
Results In 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 20.07 (20.16 to 0.03) and 20.54 (20.61 to 20.48) for the placebo and
ertugliflozin groups, respectively; the difference was 20.47 (20.59 to 20.36). During weeks 6–52, least squares
mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were 20.12 (20.70 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 21.51 (21.70 to 21.32) and 20.32 (20.45 to 20.19)
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.
Conclusions Ertugliflozin 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 number: US National Library of Medicine, ClinicalTrials.gov
NCT01986881. Date of trial registration: November 13, 2013
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.)
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. (Am Heart J 2018;206:11-23.
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 the lercanidipine - Enalapril combination vs. The corresponding monotherapies on home blood pressure in hypertension: Evidence from a large database
103siObjective: To compare a combination of a dihydropyridine
calcium-channel blocker with an angiotensin converting
enzyme inhibitor vs. monotherapy with one or the other
drug and placebo for their effects on home blood pressure
(HBP).
Methods: After a 2-week placebo wash-out, patients with
an elevated office blood pressure (BP) (diastolic 100–109
and systolic <180 mmHg) and HBP (diastolic 85 mmHg)
were randomized double-blind to a 10-week treatment
with placebo, lercanidipine, 10 or 20mg daily, enalapril,
10 or 20mg daily, or the four possible combinations. In
addition to office BP, HBP was self-measured via a
validated semiautomatic device twice in the morning and
twice in the evening during the 7 days before
randomization and at the end of treatment. Baseline and
treatment HBP values were separately averaged for each
day, morning, evening or the whole monitoring period,
excluding the first day. Day-by-day HBP variability was
defined as the SD or the variation coefficient of the daily
BP averages.
Results: Eight hundred and fifty-four patients with valid
HBP recordings at baseline and at the end of treatment
were analyzed (intention-to-treat population). From the
baseline value (147.011.6 mmHg) systolic/diastolic HBP
showed a small reduction (average baseline-adjusted
change: –1.8/–1.6 mmHg) with placebo, a more marked
significant fall with monotherapies (8.8/5.9 mmHg,
P<0.001/<0.001 vs. placebo) and even more with
combination treatment (11.6/7.6 mmHg, P<0.001/
<0.001 vs. placebo and P<0.01/<0.05 vs.
monotherapy). A similar pattern was observed for each of
the days of the BP self-monitoring period as well as for
either morning or evening values, although the difference
between mono and combination treatment appeared to be
consistently significant for the morning values only. Dayby-
day systolic BP-SD was unaffected by placebo and
slightly reduced by drug treatments, with no, however,
significant changes in SBP-variation coefficient. Baseline
and end of treatment HBP values showed a limited
correlation with office BP values, this being particularly the
case for treatment-induced changes (correlation
coefficients: 0.37 for systolic and 0.45 for diastolic BP).
Conclusion: This large HBP database shows that the
lercanidipine–enalapril combination lowers HBP more
effectively than the corresponding monotherapies and
placebo, and that this greater effect is consistent between
days.reservedmixedMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek-Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza-Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka-Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk-Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, ValeriiMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, Valeri
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