Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.

Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 10 mg (n = 302) or placebo (n = 311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p < 0.0001), mean seated SBP (-10.4 vs -7.3 mmHg, p = 0.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.7 mmHg, p = 0.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.3 kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension.

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.

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.)

Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan in heart failure with preserved ejection fraction trial.

BACKGROUND: N-terminal B type natriuretic peptide (NT-proBNP) is usually elevated in heart failure (HF) patients with reduced ejection fraction (EF). Less is known about NT-proBNP in HF with preserved EF (HF-PEF). We measured baseline NT-proBNP in 3562 HF-PEF enrolled patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial. METHODS AND RESULTS: Patients with EF >or=45%, age >or=60 years, and either New York Heart Association (NYHA) II-IV symptoms with HF hospitalization (HFH) within 6 months or NYHA III-IV symptoms with corroborative evidence of HF or structural changes associated with HF-PEF. NT-proBNP (pg/mL) measured centrally using the Elecsys proBNP assay (Roche). Mean age 72 +/- 7 years, 60% were women, the investigator indicated HF etiology was hypertension in 64%; the majority were in NYHA III. Medications included diuretics in 82%, angiotensin-converting enzyme inhibitor in 26%, beta-blocker in 59%, and spironolactone in 15%. Median NT-proBNP was 341 pg/mL (interquartile range 135 to 974 pg/mL) and geometric mean was 354 pg/mL. In multivariate analysis, the baseline characteristics most strongly associated with higher NT-proBNP levels were atrial fibrillation (ratio of geometric mean 2.59, P < .001), NYHA IV symptoms (1.52, P < .001), lower estimated glomerular filtration rate (1.44, P < .001), and HFH hospitalization within 6 months (1.37, P < .001). CONCLUSIONS: Most HF-PEF patients have elevated NT-proBNP levels. The NT-proBNP concentrations were related to baseline characteristics generally associated with worse outcomes for HF patients.

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

BACKGROUND: 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). METHODS AND RESULTS: 4133 patients with a mean age of 72 years (a third were 75 years or older) were randomised and 60% were women. The mean (SD) LVEF was 59 (9)% and almost 80% of patients were in NYHA Class III or IV. Approximately 80% of patients were also overweight or obese. Heart failure was reported by investigators to have a hypertensive aetiology in 64% of patients. Prior myocardial infarction was relatively uncommon (24%), as was coronary revascularisation (13%). Atrial fibrillation and diabetes each occurred in between a quarter and a third of patients. The following treatments were used at baseline: diuretic 83%, beta-blocker 59%, calcium channel blocker 40%, ACE inhibitor 25%, spironolactone 15% and digoxin 14%. CONCLUSIONS: Patients in I-PRESERVE are broadly representative of those seen in epidemiological studies and, because of this, the results of this trial should be generally applicable to "real world" patients with heart failure and preserved ejection fraction.

Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: A randomized controlled trial.

BACKGROUND: This 24-week Phase 3 double-blind placebo-controlled study assessed the safety and efficacy of dapagliflozin as add-on to insulin, with or without oral antihyperglycemic drugs (OADs), in Asian patients with inadequately controlled type 2 diabetes mellitus. METHODS: Adult patients with HbA1c between ≥7.5% and ≤10.5%, body mass index ≤45 kg/m2 , and on insulin doses ≥20 IU daily were randomized to dapagliflozin 10 mg (n = 139) or placebo (n = 133) to assess 24-week changes in HbA1c (primary outcome), fasting plasma glucose (FPG), body weight, total daily dose of insulin (TDDI), and seated systolic blood pressure (SeSBP; exploratory outcome). RESULTS: Baseline characteristics were similar in both groups. At Week 24, compared with placebo, dapagliflozin significantly improved HbA1c (mean [95% confidence interval] 0.03% [-0.11, 0.17] for placebo vs -0.87% [-1.00, -0.74] for dapagliflozin; between-group difference - 0.90% [-1.09, -0.71], P < 0.0001]), FPG, body weight, TDDI, and SeSBP. The incidence of adverse events (AEs) in the dapagliflozin and placebo groups was 80.5% and 71.2%, respectively, with few patients discontinuing due to AEs (dapagliflozin, 2.2%; placebo, 4.2%). The occurrence of hypoglycemia was similar in the dapagliflozin and placebo groups (23.7% and 22.6%, respectively; no major events). The frequency of urinary tract and genital infections was low; no deaths were reported. CONCLUSIONS: Dapagliflozin as add-on to insulin, with or without OADs, significantly improved glycemic control and reduced body weight and blood pressure in Asian patients. Dapagliflozin was well tolerated, with a similar frequency of hypoglycemia in both groups. These results support the use of dapagliflozin as add-on to insulin, with or without OADs, in this population.

Efficacy and safety of irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension.

Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] > or =110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P=.0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P<.0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg (P<.0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects.

Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

OBJECTIVE: To evaluate the 104-week safety of dapagliflozin in older patients with type 2 diabetes mellitus. METHODS: Pooled analysis assessing general safety (nine phase III studies ≤104 weeks) and cardiovascular safety (21 phase IIb/III studies ≤208 weeks) by age (<65; ≥65; ≥75 years). Patients with type 2 diabetes mellitus (±background glucose-lowering therapy) received: dapagliflozin 10 mg (n = 2026) vs. placebo (n = 1956) (nine-study pool); or dapagliflozin (2.5-50 mg; n = 5936) vs. control (placebo/comparator) (n = 3403) (21-study pool). RESULTS: Adverse events (AEs) and discontinuations owing to AEs were more common in older vs. younger patients, and were more frequent with dapagliflozin than placebo (AEs: <65 years: 73.1 vs. 70.7 %; ≥65 years: 77.4 vs. 73.1 %; ≥75 years: 80.4 vs. 75.3 %, respectively; discontinuations: <65 years: 5.9 vs. 5.0 %; ≥65 years: 14.4 vs. 12.2 %; ≥75 years: 26.8 vs. 22.1 %, respectively); serious AE (SAE) frequency was similar (<65 years: 11.0 vs. 11.8 %; ≥65 years: 20.0 vs. 20.2 %; ≥75 years: 19.6 vs. 18.2 %, respectively). Hypoglycaemia frequency was similar across age groups and was higher with dapagliflozin than placebo (<65 years: 18.0 vs. 13.4 %; ≥65 years: 20.2 vs. 17.7 %; ≥75 years: 17.5 vs. 16.9 %, respectively); major episodes were rare. Urinary tract infection frequency was similar between treatment groups in older patients, with no increase vs. younger patients (<65 years: 8.8 vs. 5.5 %; ≥65 years: 8.1 vs. 7.6 %; ≥75 years: 8.2 vs. 9.1 %, respectively); urinary tract infection SAEs were rare. Genital infection AEs were more common with dapagliflozin, with no increase in older patients (<65 years: 8.2 vs. 1.0 %; ≥65 years: 6.6 vs. 0.9 %; ≥75 years: 7.2 vs. 0.0 %, respectively) and no SAEs. Volume reduction AEs were uncommon, with a higher frequency with dapagliflozin vs. placebo and in patients ≥75 years (<65 years: 1.7 vs. 1.2 %; ≥65 years: 2.3 vs. 1.7 %; ≥75 years: 3.1 vs. 2.6 %, respectively). Dapagliflozin did not increase the risk of fractures (<65 years: 1.1 vs. 1.1 %; ≥65 years: 1.1 vs. 2.7 %; ≥75 years: 1.0 vs. 2.6 %, respectively) or falls (<65 years: 0.7 vs. 0.7 %; ≥65 years: 0.6 vs. 2.1 %; ≥75 years: 0.0 vs. 1.3 %, respectively), regardless of age. AEs of renal function were more common with dapagliflozin than placebo and increased with age (<65 years: 3.5 vs. 2.3 %; ≥65 years: 14.0 vs. 7.9 %; ≥75 years: 29.9 vs. 20.8 %, respectively). Most were non-serious small transient increases in serum creatinine. Dapagliflozin did not increase cardiovascular risk regardless of age [hazard ratio (95 % confidence interval) vs. CONTROL: <65 years: 0.726 (0.473, 1.114); ≥65 years: 0.879 (0.565, 1.366); ≥75 years: 0.950 (0.345, 2.617), respectively]. CONCLUSION: Dapagliflozin treatment up to 104 weeks was well tolerated in older patients. Older dapagliflozin-treated patients had more renal AEs than placebo-treated patients; the majority of which were non-serious small transient changes in serum creatinine.

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 ß 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 ß 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.

Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials.

OBJECTIVE: Dapagliflozin reduces hyperglycemia in type 2 diabetes mellitus (T2DM) and lowers blood pressure, at least in part, secondary to mild diuresis consequent to dapagliflozin-induced glucosuria. While blood-pressure lowering may contribute to cardiovascular risk reduction, dapagliflozin-induced diuresis may potentially contribute to adverse events (AEs) of volume reduction. The present analysis compared the frequency of AEs of volume reduction between dapagliflozin and placebo. METHODS: Pooled data were assessed from 13 placebo-controlled dapagliflozin clinical trials ≤24 weeks in patients with T2DM, overall, and in those at risk (aged ≥65y, estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2), or on antihypertensive therapy). Longer-term (≤104 weeks) data were available for 9 of these trials. RESULTS: The frequency of patients experiencing ≥1 AE of volume reduction over 24 weeks was low overall; 27/2360 (1.1%) with dapagliflozin 10 mg and 17/2295 (0.7%) with placebo; and slightly more frequent in patients ≥65 years (11/665 [1.7%] and 6/711 [0.8%], respectively) and in patients receiving loop diuretics (6/236 [2.5%] and 4/267 [1.5%], respectively). Over 104 weeks, AEs of volume reduction occurred in 38/2026 (1.9%) with dapagliflozin 10 mg and in 27/1956 (1.4%) with placebo; serious AEs of volume reduction in 4/2026 (0.2%) and 6/1956 (0.3%), respectively; and 2 patients in each group discontinued therapy due to these AEs. Dapagliflozin versus placebo incidence rate ratios did not suggest any meaningful increase in frequency of these AEs with dapagliflozin 10 mg, either overall or in those at risk. Although mean eGFR declined by 4.2 ml/min/1.73 m(2) within the first week of dapagliflozin therapy, thereafter eGFR gradually recovered to baseline levels by 104 weeks (mean change from baseline +0.02 mL/min/1.73 m(2); 95%CI: -0.9, 1.0). CONCLUSION: No meaningful increase in frequency of AEs of volume reduction occurred with dapagliflozin 10 mg in patients with T2DM, either overall, or in those at increased risk of these events. However, caution should nevertheless be exercised when prescribing dapagliflozin to elderly patients, those with reduced eGFR, and those receiving antihypertensive medication.

The effect of dapagliflozin on renal function in patients with type 2 diabetes.

BACKGROUND: Dapagliflozin's antihyperglycemic effects are mediated by inhibition of renal sodium-glucose cotransporter-2; therefore, renal safety of dapagliflozin was assessed. METHODS: Twelve double-blind, placebo-controlled, randomized clinical trials were analyzed up to 24 weeks (N = 4545). Six of the 12 studies included long-term data for up to 102 weeks (N = 3036). Patients with type 2 diabetes with normal or mildly impaired renal function [estimated glomerular filtration rate (eGFR) 60 to <90 mL/min/1.73 m(2)] were treated with dapagliflozin (2.5, 5, or 10 mg/day) or placebo. Renal adverse events (AEs) were assessed. RESULTS: Mean eGFR showed small transient reductions with dapagliflozin at week 1, but returned to near baseline values by week 24 and remained stable to week 102. Mean eGFR changes were not very different for dapagliflozin 2.5, 5 and 10 mg versus placebo at 102 weeks: -0.74, 2.52 and 1.38 versus 1.31 mL/min/1.73 m(2), respectively. Renal AEs were similar in frequency to placebo through 24 weeks (1.4, 1.3, 0.9, and 0.9 %, respectively) and 102 weeks (2.4, 1.8, 1.9 and 1.7 %, respectively). Few were serious (0.2, 0.1, 0 and 0.3 %, respectively, over 102 weeks). The most common renal event was serum creatinine increase. In sub-group analyses in patients ≥65 years of age or those with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m(2)), renal AEs occurred more frequently with dapagliflozin than placebo. No events of acute tubular necrosis were reported. CONCLUSION: In patients with normal or mildly impaired renal function, dapagliflozin is not associated with increased risk of acute renal toxicity or deterioration of renal function. All trials included in this analysis are registered at ClinicalTrials.gov: NCT00263276, NCT00972244, NCT00528372, NCT00736879, NCT00528879, NCT00855166, NCT00357370, NCT00680745, NCT00683878, NCT00673231, NCT00643851, NCT00859898.

Effect of the SGLT2 Inhibitor Dapagliflozin on Potassium Levels in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

INTRODUCTION: Hyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM). METHODS: Fourteen randomized, placebo-controlled, double-blind T2DM studies were analyzed: pooled data from 13 studies of ≤24 weeks' duration (dapagliflozin 10 mg, N = 2360; placebo, N = 2295); and one 52-week moderate renal impairment study in patients with baseline eGFR ≥30 to <60 mL/min/1.73 m(2) (dapagliflozin 10 mg, N = 85; placebo, N = 84). Central laboratory serum potassium levels were determined at each study visit. RESULTS: No clinically relevant mean changes from baseline in serum potassium ≤24 weeks were reported for dapagliflozin 10 mg [-0.05 mmol/L; 95% confidence interval (CI) -0.07, -0.03] versus placebo (-0.02 mmol/L; 95% CI -0.04, 0.00) in the pooled population or in the renal impairment study (-0.03 mmol/L; 95% CI -0.14, 0.08 vs. -0.02 mmol/L; 95% CI -0.13, 0.09, respectively). The incidence rate ratio for serum potassium ≥5.5 mmol/L over 24 weeks for dapagliflozin 10 mg versus placebo was 0.90 (95% CI 0.74, 1.10) in the pooled population; with no increased risk in patients receiving ARBs/ACE inhibitors, or potassium-sparing diuretics, or in those with moderate renal impairment. Slightly more patients receiving dapagliflozin 10 mg had serum potassium ≤3.5 mmol/L versus placebo (5.2% vs. 3.6%); however, no instances of serum potassium ≤2.5 mmol/L were reported. CONCLUSION: Dapagliflozin is not associated with an increased risk of hyperkalemia or severe hypokalemia in patients with T2DM. FUNDING: Bristol-Myers Squibb and AstraZeneca.

Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial.

BACKGROUND: Dapagliflozin, a highly selective sodium-glucose cotransporter 2 inhibitor, reduces hyperglycemia, body weight, and blood pressure in patients with type 2 diabetes (T2D). METHODS: This randomized double-blind placebo-controlled parallel-group 24-week study assessed the efficacy, safety, and tolerability of dapagliflozin added to metformin in Asian patients with inadequately controlled T2D (HbA1c 7.5%-10.5%). Patients were randomized to receive placebo (n = 145) or dapagliflozin 5 (n = 147) or 10 mg (n = 152). RESULTS: Most participants were Chinese (86.0%), with a mean age of 53.8 years and mean T2D duration of 4.9 years; 92.1% completed the study. Adjusted mean HbA1c changes from baseline at Week 24 (primary endpoint) were -0.23%, -0.82%, and -0.85% in the placebo, dapagliflozin 5 and 10 mg groups, respectively, resulting in dapagliflozin 5 and 10 mg versus placebo differences of -0.59% and -0.62%, respectively (both P < 0.0001). Dapagliflozin 5 and 10 mg differences versus placebo were, respectively: -1.2 and -1.5 mmol/L for fasting plasma glucose; -1.1 and -1.8 kg for weight; and -2.3 and -2.7 mmol/L for 2-h postprandial glucose (all P <0.0001). In the placebo, dapagliflozin 5 and 10 mg groups, respectively: adverse events (AEs) occurred in 52.4%, 52.4%, and 55.3% of patients; serious AEs occurred in 4.1%, 2.0%, and 2.0%; urinary tract infections occurred in 4.8%, 4.1%, and 6.6%; and genital infections occurred in 0%, 2.0%, and 1.3%. No AEs of pyelonephritis or renal failure occurred. CONCLUSIONS: Dapagliflozin 5 or 10 mg as add-on to metformin was well tolerated in Asian patients with T2D and significantly improved glycemic control with the additional benefit of weight reduction.

Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes.

The effect of dapagliflozin on blood pressure was evaluated in non-hypertensive (<140 mm Hg) and hypertensive (⩾140 mm Hg) patients with type 2 diabetes mellitus. Data were pooled from 13 placebo-controlled studies. Patients received dapagliflozin 10 mg/day (n = 2360) or placebo (n = 2295) for up to 24 weeks. Dapagliflozin was associated with placebo-subtracted changes from baseline in systolic and diastolic blood pressures of -3.6 and -1.2 mm Hg, respectively, in hypertensive patients and -2.6 and -1.2 mm Hg, respectively, in non-hypertensive patients. At 24 weeks, a similar proportion of patients experienced measured orthostatic reactions with dapagliflozin versus placebo in hypertensive (6.1% and 6.6%, respectively) and non-hypertensive (4.0% and 4.2%) patients. No clinically relevant difference was observed between dapagliflozin and placebo in heart rate. In conclusion, dapagliflozin 10 mg induces a modest reduction in blood pressure compared with placebo in patients with diabetes with a low risk of orthostatic reactions, regardless of baseline blood pressure.

Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a 'Case Study'.

INTRODUCTION: Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, decreases plasma glucose levels by suppressing renal glucose reabsorption and increasing urinary glucose excretion. Previously published pre-clinical data suggest that dapagliflozin lacks carcinogenic potential. This article reviews data on bladder cancer with dapagliflozin to illustrate the challenges in assessing bladder cancer in drug development programs in patients with type 2 diabetes mellitus (T2DM). METHODS: Clinical cases of bladder cancer were analyzed in a pooled population of >9000 patients in 21 phase 2b/3 dapagliflozin clinical trials of up to 208 weeks' duration. RESULTS: In the 21-study pool, demographic and baseline characteristics were generally consistent between dapagliflozin and comparator groups. The overall incidence of malignancies was also balanced between the treatment groups, with an incidence rate ratio (IRR) of 1.035 [95% confidence interval (CI): 0.724, 1.481]. Nine of 5936 dapagliflozin-treated patients and 1 of 3403 comparator-treated patients reported bladder cancer, with an IRR of 5.168 (95% CI: 0.677, 233.55). All of these patients had clinical attributes typical of bladder cancer in the general population (≥60-year-old males; 8 of the 10 patients were current/former smokers). All cases of bladder cancer were reported within 2 years of starting study treatment. There was an absence of detailed workup of hematuria prior to randomization, and no hematuria workup data were collected proactively in the dapagliflozin trials, which is typical of clinical practice. Failure to exclude bladder cancer prior to randomization increases the chance of recruiting patients with pre-existing bladder cancer in clinical trials and may delay the final diagnosis. Of the nine dapagliflozin-treated patients with bladder cancer, eight had microscopic hematuria prior to start of treatment or within 6 months of initiating study treatment. CONCLUSION: The assessment of bladder cancer data illustrates the challenges of characterizing cancer risk in T2DM drug development programs. The totality of evidence to date does not suggest a causal relationship between dapagliflozin and bladder cancer. FUNDING: AstraZeneca.

Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events.

BACKGROUND: Dapagliflozin reduces hyperglycaemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. OBJECTIVES: This study determined the overall safety profile of dapagliflozin in T2DM. METHODS: Safety of dapagliflozin in pooled analyses of phase IIb/III studies was evaluated. Patients received comparator or dapagliflozin as monotherapy, add-on to antidiabetic therapy, or as initial combination with metformin. Proportions of patients with adverse events (AEs) and prespecified parameters related to previous clinical observations and dapagliflozin's action were assessed. The principal analysis used data from 12 placebo-controlled studies. Rare events were assessed across phase IIb/III studies, including special populations, comparator-controlled trials and ongoing long-term extensions. RESULTS: In placebo-controlled studies, hypoglycaemia was more common with dapagliflozin (11.8 %) than placebo (7.0 %), with imbalance driven by add-on of dapagliflozin to sulfonylurea or insulin. Urinary tract infections (4.8 vs 3.7 %), vulvovaginitis/balanitis and related infections (5.1 vs 0.9 %), and non-serious volume-related events (0.8 vs 0.4 %) occurred more often with dapagliflozin than placebo. No substantial AEs were seen on electrolytes or renal function. Pyelonephritis was rare and balanced among treatments; there were no imbalances in fractures or liver test elevations. Overall incidence of malignancies was balanced between groups. The incidence rate ratios of malignancy in certain organ systems were slightly lower for dapagliflozin (renal tract, female reproductive) and in others were slightly lower for control (breast, prostate, bladder). Most AEs associated with dapagliflozin were mild/moderate and related to the mechanism of action. CONCLUSION: Dapagliflozin has a favourable and predictable tolerability profile, with reported events related to its mechanism of action.

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.

Effects of dapagliflozin on cardiovascular risk factors.

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. Furthermore, a lower rate of cardiac events was seen in patients taking dapagliflozin compared with those taking comparators in a meta-analysis of clinical trials on dapagliflozin. Overall, dapagliflozin has shown beneficial effects on CV risk factors in patients with T2DM. Further studies are underway to evaluate the effect of dapagliflozin on CV outcomes.

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.