Empagliflozin and uric acid metabolism in diabetes: A post hoc analysis of the EMPA-REG OUTCOME trial.
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ABSTRACT: Aim
To evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA-REG OUTCOME trial (NCT01131676).Materials and methods
A total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models.Results
Empagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = -0.37 (95% confidence interval [CI] -0.42, -0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = -0.56 (95% CI -0.68, -0.43) and -0.30 (95% CI -0.37, -0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses.Conclusions
Empagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well-established cardio-renal benefits.
SUBMITTER: Ferreira JP
PROVIDER: S-EPMC9293326 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundType 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676).MethodsOverall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled blood pressure (BP; systolic blood pressure (SBP) ≥140 and/or diastolic blood pressure ≥90 mm Hg) or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on cardiovascular (CV) death, heart failure (HF) hospitalization, 3-point major adverse cardiac events, all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis.Results1,579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 vs. placebo was -4.5 (95% confidence interval, -5.9 to -3.1) mm Hg (P < 0.001) in prHT and -3.7 (-4.5, -2.9) mm Hg (P < 0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mm Hg) with empagliflozin than with placebo. Patients with prHT had 1.5- to 2-fold greater risk of HF hospitalization, incident/worsening nephropathy, and CV death compared with those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P > 0.1 for all outcomes).ConclusionsEmpagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D.
| S-EPMC7814223 | biostudies-literature
Project description:Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.
| S-EPMC8174365 | biostudies-literature
Project description:In the EMPA-REG OUTCOME trial, we explored the association between pre-randomization uric acid level tertile (<309.30??mol/L; 309.30 to <387.21??mol/L; ?387.21??mol/L) and cardiovascular (CV) death, hospitalization for heart failure (HHF), HHF or CV death, all-cause mortality, three-point major adverse CV events (MACE), and incident or worsening nephropathy. Patients with type 2 diabetes and CV disease received empagliflozin or placebo. The median baseline plasma uric acid level was 344.98??mol/L, and patients' baseline characteristics were mainly balanced across tertiles. Baseline uric acid levels were associated with cardio-renal outcomes: in the placebo group, for the highest versus lowest tertile, the multivariable hazard ratios for three-point MACE, HHF or CV death, and incident or worsening nephropathy were 1.22 (95% confidence interval [CI] 0.89-1.67; P = 0.2088), 1.51 (95% CI 1.02-2.23; P = 0.0396) and 1.77 (95% CI 1.33-2.34; P?<?0.0001), respectively. When tested as a continuous variable, baseline uric acid was associated with all outcomes in the placebo group. Empagliflozin improved all cardio-renal outcomes across tertiles, with all interaction P values >0.05. Further investigation of these relationships is required.
| S-EPMC7317186 | biostudies-literature
Project description:ObjectiveThe risks of cardio-renal complications of diabetes increase with age. In the EMPA-REG OUTCOME® trial, empagliflozin reduced cardiovascular (CV) mortality by 38% in patients with type 2 diabetes (T2D) and CV disease. Here we compare outcomes with empagliflozin in older patients in EMPA-REG OUTCOME.MethodsPatients with T2D and CV disease were randomised to empagliflozin 10 or 25 mg, or placebo plus standard of care. In post hoc analyses, risks of 3-point major adverse CV events (3P-MACE: composite of CV death, non-fatal myocardial infarction (MI) or non-fatal stroke), CV death, hospitalisation for heart failure, all-cause mortality, all-cause hospitalisation and incident/worsening nephropathy were evaluated for empagliflozin versus placebo by baseline age (<65, 65 to <75, ≥75 years). Adverse events (AEs) were analysed descriptively.ResultsEffect of empagliflozin on all outcomes was consistent across age categories (P ≥ 0.05 for interactions) except 3P-MACE. The 3P-MACE hazard ratios (HRs) were 1.04 (95% confidence interval [CI] 0.84, 1.29), 0.74 (0.58, 0.93) and 0.68 (0.46, 1.00) in patients aged <65, 65 to <75, and ≥75 years, respectively (P = 0.047 for treatment-by-age group interaction). Corresponding CV death HRs were 0.72 (95% CI 0.52, 1.01), 0.54 (0.37, 0.79) and 0.55 (0.32, 0.94), respectively (P = 0.484 for treatment-by-age group interaction). Across age categories, empagliflozin AEs reflected its known safety profile. Rates of bone fractures, renal AEs and diabetic ketoacidosis were similar between empagliflozin and placebo across age categories.ConclusionsIn the EMPA-REG OUTCOME trial, empagliflozin reduced risks of CV mortality, heart failure and renal outcomes, supporting its cardio-renal benefits in older patients.
| S-EPMC7963112 | biostudies-literature
Project description:AimsHypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin.Methods and resultsAbout 7020 patients with T2D (HbA1c 7-10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia [HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia] was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad [hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25-2.93)] and HYPO-strict [1.72 (1.06-2.78)]. HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) [HR 1.56 (1.06-2.29)]. Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05).ConclusionIn this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.
| S-EPMC6945517 | biostudies-literature
Project description:AimTo determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA-REG OUTCOME population, and the relationship of kidney dysfunction co-existent with polyvascular disease on CV/heart failure (HF) outcomes.Materials and methodsPatients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m2 ) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all-cause mortality (ACM) and 3-point major adverse CV events (3P-MACE) were assessed using multivariable Cox regression models.ResultsBaseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P-MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m2 ) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P-MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups.ConclusionsPolyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status.
| S-EPMC8247842 | biostudies-literature
Project description:BACKGROUND:Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. METHODS:Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). RESULTS:Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: -1.46; 95% confidence interval, -1.74 to -1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo -0.02; 95% confidence interval, -0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. CONCLUSIONS:The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
| S-EPMC6218863 | biostudies-literature
Project description:Heart failure (HF) and type 2 diabetes (T2D), common co-morbidities, translate into worse patient prognoses and higher direct costs than for either condition alone. Empagliflozin has been shown to markedly reduce cardiovascular (CV) deaths and HF hospitalizations (HHF) in HF patients with T2D. This study evaluated the lifetime cost-effectiveness of supplementing standard of care (SoC) with empagliflozin, relative to SoC alone, in HF patients with T2D from the UK payer perspective. An existing discrete-event simulation model was adapted for the economic evaluation. Risk equations developed from time-dependent parametric survival analyses using patient-level HF subpopulation data from the EMPA-REG OUTCOME trial were employed to predict CV and renal events. Non-CV death, utility weights, and costs were drawn from UK sources. Quality-adjusted life years (QALYs) and costs were discounted at 3.5% per annum. Relative to SoC, empagliflozin with SoC yielded fewer first HHF, recurrent HHF, CV death, and non-fatal myocardial infarction but more non-fatal stroke events. Empagliflozin with SoC vs. SoC alone was associated with increased average life expectancy (10.80 vs. 9.59 LYs) and quality of life (6.27 vs. 5.62 QALYs), though at higher lifetime cost (£18 197 vs. £16 829) per person, resulting in an incremental cost-effectiveness ratio of £2093 per QALY. The probability of empagliflozin being cost-effective in the HF subpopulation at a £20 000 per QALY willingness-to-pay threshold was 91%. This analysis suggests that adding empagliflozin to SoC in HF patients with T2D constitutes a cost-effective use of UK healthcare resources and may provide long-term health benefits to patients.
| S-EPMC7754962 | biostudies-literature
Project description:Rationale & objectiveKidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2.Study designThis was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2.Setting & participantsAnalysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available.InterventionsPatients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care.OutcomesAnnual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups.ResultsOver the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001).LimitationsThis is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established.ConclusionsPatients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug.FundingThe Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.Trial registrationclinicaltrials.gov ID: NCT01131676.
| S-EPMC10900108 | biostudies-literature
Project description:BackgroundGlucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin's cardiovascular death reductions.MethodsIn total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment.ResultsHbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615.ConclusionsHbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin's reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676.
| S-EPMC7556977 | biostudies-literature