Agata Ptaszynska

Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction

BACKGROUND Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. METHODS We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. RESULTS During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. CONCLUSIONS Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)

Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial

Background— The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF. Methods and Results— All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan. Conclusions— Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Heart failure with preserved ejection fraction: Clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial

We describe the baseline characteristics of subjects randomised in the largest placebo‐controlled, morbidity‐mortality trial to date in patients with heart failure and preserved ejection fraction — the irbesartan in heart failure with preserved systolic function trial (I‐PRESERVE).

Factors Associated with Outcome in Heart Failure with Preserved Ejection Fraction: Findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE)

Background—The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results—We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions—In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.Background— The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results— We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions— In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration— URL: . Unique identifier: [NCT00095238][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00095238&atom=%2Fcirchf%2F4%2F1%2F27.atom

Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin

BACKGROUND Vulvovaginitis, balanitis, and related genital infections are common in patients with type 2 diabetes. Glucosuria, which is an outcome of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors, is among the possible causes. Dapagliflozin, an SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes, has been studied across a broad spectrum of patients. Analysis of multi-trial safety data may better define the relationship between glucosuria and genital infection. METHODS Safety data were pooled from 12 randomized, placebo-controlled Phase 2b/3 trials to analyze the association of glucosuria with genital infection in patients with suboptimally controlled diabetes (HbA1c >6.5%-12%). Patients were randomized to receive dapagliflozin (2.5mg, 5mg, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and of events suggestive of genital infection was evaluated. RESULTS The pooled safety data included 4545 patients: 3152 who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 4.1%, 5.7%, 4.8%, and 0.9%, respectively. Most infections were mild or moderate and responded to standard antimicrobial treatment. Discontinuation due to these events was rare. No clear dose-response relationship between dapagliflozin and genital infection was demonstrated. CONCLUSIONS Treatment with dapagliflozin 2.5mg, 5mg, or 10mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis, related to the induction of glucosuria. Events were generally mild to moderate, clinically manageable, and rarely led to discontinuation of treatment.

Urinary tract infections in patients with diabetes treated with dapagliflozin

AIMS Urinary tract infection is common in patients with type 2 diabetes. Possible causative factors include glucosuria, which is a result of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin is an investigative SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes. Data from dapagliflozin multi-trial safety data were analyzed to clarify the association between glucosuria and urinary tract infection. METHODS Safety data from 12 randomized, placebo-controlled trials were pooled to evaluate the relationship between glucosuria and urinary tract infection in patients with inadequately controlled diabetes (HbA1c >6.5%-12%). Patients were treated with dapagliflozin (2.5, 5, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and events suggestive of urinary tract infection were quantified. RESULTS This analysis included 3152 patients who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. Urinary glucose levels, but not the incidence of urinary tract infection, increased progressively with dapagliflozin dosage. Most identified infections were those considered typical for patients with diabetes. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient. Most diagnosed infections were mild to moderate and responded to standard antimicrobial treatment. CONCLUSIONS Treatment of type 2 diabetes with once-daily dapagliflozin 5 or 10mg is accompanied by a slightly increased risk of urinary tract infection. Infections were generally mild to moderate and clinically manageable. This analysis did not demonstrate a definitive dose relationship between glucosuria and urinary tract infection.

Factors Associated With Outcome in Heart Failure With Preserved Ejection FractionClinical Perspective

Background—The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results—We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions—In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.Background— The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results— We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions— In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration— URL: . Unique identifier: [NCT00095238][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00095238&atom=%2Fcirchf%2F4%2F1%2F27.atom

Dapagliflozin as Monotherapy in Drug-Naive Asian Patients With Type 2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study

OBJECTIVE Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. METHODS In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% to ≤10.5% (≥53-≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. RESULTS Baseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were -0.29% for placebo versus -1.04% and -1.11% for dapagliflozin 5 and 10 mg, respectively (P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, -25.1, and -31.6 mg/dL (0.14, -1.39, and -1.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, -46.8, and -54.9 mg/dL (0.06, -2.60, and -3.05 mmol/L). Reductions in body weight were -0.27, -1.64, and -2.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. CONCLUSIONS Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.

Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study

BACKGROUND Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension. METHODS In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries across five continents. Patients had uncontrolled type 2 diabetes (HbA1c 7·0%-10·5%; 53-91 mmol/mol) and hypertension (systolic 140-165 mm Hg and diastolic 85-105 mm Hg at both enrolment and randomisation, and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving oral antihyperglycaemic drugs, insulin, or both, plus a renin-angiotensin system blocker and an additional antihypertensive drug. Using an interactive voice-response system, we randomly assigned (1:1) patients to dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set, which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered with ClinicalTrials.gov, number NCT01195662. FINDINGS Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change from baseline -11·90 mm Hg [95% CI -13·97 to -9·82]) compared with those assigned to placebo (-7·62 mm Hg [-9·72 to -5·51]; placebo-adjusted difference for dapagliflozin -4·28 mm Hg [-6·54 to -2·02]; p=0·0002). Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change from baseline -0·63% [95% CI -0·76 to -0·50]) than in those assigned to placebo (-0·02% [-0·15 to 0·12]; placebo-adjusted difference -0·61% [-0·76 to -0·46,]; p<0·0001). In a post-hoc analysis, we found difference in blood pressure versus placebo was greater in patients receiving a β blocker (-5·76 mm Hg [95% CI -10·28 to -1·23]) or a calcium-channel blocker (-5·13 mm Hg, [-9·47 to -0·79]) as their additional antihypertensive drug than in those receiving a thiazide diuretic (-2·38 mm Hg [-6·16 to 1·40]). Adverse events were similar in the dapagliflozin and placebo groups (98 [44%] patients vs 93 [42%], respectively, had at least one adverse event), with few adverse events related to renal function (1% vs <1%) or volume depletion (<1% vs 0%). INTERPRETATION Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens. FUNDING Bristol-Myers Squibb, AstraZeneca.

Effects of Dapagliflozin on Cardiovascular Risk Factors

Abstract People with diabetes are more likely to develop a cardiovascular (CV) disease compared with those without diabetes. Although effective glycemic control has been the focus of the management of type 2 diabetes mellitus (T2DM), it is also important to control other CV risk factors to improve outcomes in these patients. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, lowers glucose levels in patients with T2DM by increasing urinary glucose excretion. Dapagliflozin therapy has been shown to impact a number of CV risk factors. Dapagliflozin improved glycemia with a low intrinsic propensity to cause hypoglycemia. Caloric loss associated with dapagliflozin-induced glucosuria also led to body weight reduction. Small changes from baseline in mean lipid parameters and reductions in serum uric acid levels were observed in patients taking dapagliflozin. Blood pressure reductions were also noted, consistent with modest drug-induced diuresis and weight loss.