Impact of empagliflozin on insulin needs in patients with heart failure and diabetes: An EMPEROR-Pooled analysis.

AIM: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. MATERIALS AND METHODS: We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. RESULTS: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, pinteraction = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88). CONCLUSIONS: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes.

Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes.

BACKGROUND: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated. METHODS: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes. RESULTS: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; Pinteraction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m2 in patients without diabetes; Pinteraction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (Pinteraction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03057951.

Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials.

BACKGROUND: Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD). METHODS: Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models. RESULTS: The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83). CONCLUSIONS: In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

Cardiovascular outcomes trial data from EMPA-REG OUTCOME, CAROLINA and CARMELINA: Assessment of a novel staging system for type 2 diabetes.

AIMS: To apply the diabetes staging system (DSS), a novel disease staging system similar to what is used in oncology but designed to improve diabetes management, to three large type 2 diabetes (T2D) cardiovascular (CV) outcome trials to assess whether increasing DSS stage was associated with higher rates of all-cause mortality (ACM) and/or CV death. MATERIALS AND METHODS: The DSS uses discrete CV events (none to ≥3: Stage 1 to 4), end-stage kidney disease (Stage 5) and microvascular complications (none to 3: A to D) to determine disease stage in individuals with T2D. The DSS stage for patients from the CAROLINA, EMPA-REG OUTCOME and CARMELINA trials was determined. Incidence rates for ACM/CV death were calculated across DSS stages and Cox regression analyses were performed. RESULTS: The risk of ACM or CV death increased with increasing DSS (Stage 1 to 5; P for trend <0.0001) in all trials. In CAROLINA, the risk of ACM and CV death increased with increasing number of microvascular complications (A to D; both P for trend <0.0001), similar in CARMELINA (P for trend = 0.0020 and 0.0005, respectively). In EMPA-REG OUTCOME, having all three microvascular complications (Stage D), versus none, increased the risk of ACM and CV death (P = 0.0015 and 0.0010, respectively). CONCLUSIONS: Applying the DSS across T2D clinical trial populations with different CV risk revealed a significantly increased risk of ACM and CV death with higher DSS stage. The DSS may merit assessment in other T2D populations and evaluation of the impact of additional outcomes, such as heart failure, could also be worthwhile.

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes.

AIMS: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. RESULTS: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups. CONCLUSIONS: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.

SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.

BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.

Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial.

BACKGROUND: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF. METHODS AND RESULTS: We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31-1.17], 0.79 [0.51-1.23], and 0.63 [0.50-0.78], respectively; P interaction = 0.62). CONCLUSIONS: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.

Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial.

AIM: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. MATERIALS AND METHODS: In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. RESULTS: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. CONCLUSIONS: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time.

Impact of polyvascular disease with and without co-existent kidney dysfunction on cardiovascular outcomes in diabetes: A post hoc analysis of EMPA-REG OUTCOME.

AIM: To 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 METHODS: Patients 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. RESULTS: Baseline 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. CONCLUSIONS: Polyvascular 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.

Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial.

BACKGROUND: Glucose 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. METHODS: In 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. RESULTS: HbA1c 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. CONCLUSIONS: HbA1c 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.

Metabolic syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a post hoc analyses of the EMPA-REG OUTCOME trial.

BACKGROUND: Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial. METHODS: A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models. RESULTS: MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01-2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17-4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS. CONCLUSIONS: A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Empagliflozin reduces the risk of mortality and hospitalization for heart failure across Thrombolysis In Myocardial Infarction Risk Score for Heart Failure in Diabetes categories: Post hoc analysis of the EMPA-REG OUTCOME trial.

AIM: To investigate the association of the Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Heart Failure in Diabetes (TRS-HFDM ) with mortality using data from the EMPA-REG OUTCOME trial. MATERIALS AND METHODS: In EMPA-REG OUTCOME, patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease (N = 7020) received the sodium-glucose co-transporter-2 inhibitor, empagliflozin, 10 or 25 mg or placebo. Post hoc, patients were stratified into risk categories (low-intermediate, high, very-high risk scores) using baseline TRS-HFDM . Cox regression analyses evaluated the association of TRS-HFDM categories with all-cause mortality (ACM), CV death, hospitalization for heart failure (HHF) and CV death (excluding fatal stroke) or HHF, and whether empagliflozin reduced the risk of CV outcomes across these risk categories. RESULTS: In placebo patients, increasing risk category was associated with a higher risk of ACM, CV death, and HHF. Empagliflozin reduced the risk of ACM (low-intermediate HR 0.68 [95% CI 0.48, 0.97] and very-high 0.69 [0.52, 0.91]), CV death (0.75 [0.48, 1.18] and 0.56 [0.41, 0.78]), HHF (0.53 [0.28, 1.01] and 0.67 [0.48, 0.96]), and CV death or HHF (0.69 [0.46, 1.03]) and (0.64 [0.49, 0.82]) across all risk categories versus placebo. Higher absolute risk reductions (ARRs) were observed for CV death in the very-high versus low-intermediate category (P = 0.01). CONCLUSIONS: Applied to EMPA-REG OUTCOME, higher TRS-HFDM was associated with increased HHF and mortality risk. Empagliflozin reduced CV outcomes across TRS-HFDM categories. Higher ARRs were associated with higher risk scores.

Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: A subanalysis of EMPA-REG OUTCOME.

In the EMPA-REG OUTCOME trial, we explored the association between pre-randomization uric acid level tertile (<309.30 µmol/L; 309.30 to <387.21 µmol/L; ≥387.21 µmol/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 µmol/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.

Comparison of the associations between non-traditional and traditional indices of adiposity and cardiovascular mortality: an observational study of one million person-years of follow-up.

BACKGROUND/OBJECTIVE: The most widely used adiposity index, body mass index (BMI), is not optimal to evaluate cardiovascular (CV) risk associated with overweight and obesity. We aimed to explore the association between traditional and non-traditional adiposity indices and CV mortality, and compare their discriminative ability for CV death. METHODS: We studied participants (age 19-79 years, BMI ≥18.5 kg/m2) from the population-based Norwegian Nord-Trøndelag Health Study 2 (HUNT 2). Traditional indices explored were BMI, waist circumference (WC) and waist- to-hip ratio, whereas non-traditional were estimated total body fat (eTBF), which is a sex-specific fat%-index, index of central obesity (WC/height) and a body shape index (ABSI) [WC/(BMI2/3 × âˆšheight)]. Associations between the traditional and non-traditional indices and CV death, obtained from the Norwegian Cause of Death Registry, were explored by Cox proportional hazard regression, and the indices' discriminative ability by Harrell's C statistics. RESULTS: Baseline assessments were done from 1995 to 1997 and the population (n = 61,016, 52% women) was observed for 17.7 ± 4.2 years (until 2016), yielding 1,080,473.6 person-years of follow-up. Thirteen thousand one hundred and ninety five (21.6%) subjects died, of whom 4908 (37.2%) died from CV causes. Across genders, eTBF had the strongest association to CV death (unadjusted hazard ratios [HRs] 4th vs. 1st quartile in women and men 13.38 [95% confidence interval (CI): 11.05-16.22] and 9.32 [8.03-10.81], respectively), together with index of central obesity in women and ABSI in men. The other indices showed weaker associations, in particular BMI in men: 1.73 [1.56-1.93]. Age adjustment attenuated the associations, but the pattern remained. In concordance with this, C-statistics was C = 0.725 [0.713-0.737] in women and 0.711 [0.701-0.721] in men for eTBF, and C = 0.622 [0.610-0.634] in women and 0.551 [0.541-0.562] in men for BMI. CONCLUSION: eTBF, a sex-specific total body fat index, was more strongly associated with CV death than other adiposity indices and may be a suitable clinical tool for assessment of obesity-associated CV risk.

Asymptomatic coronary artery disease in a Norwegian cohort with type 2 diabetes: a prospective angiographic study with intravascular ultrasound evaluation.

AIMS: The prevalence of asymptomatic coronary artery disease (CAD) in type 2 diabetes (T2D) is unclear. We investigated the extent and prevalence of asymptomatic CAD in T2D patients by utilizing invasive coronary angiography (ICA) and intravascular ultrasound (IVUS), and whether CAD progression, evaluated by ICA, could be modulated with a multi-intervention to reduce cardiovascular (CV) risk. METHODS: Fifty-six T2D patients with ≥ 1 additional CV risk factor participated in a 2 year randomized controlled study comparing hospital-based multi-intervention (multi, n = 30) versus standard care (stand, n = 26), with a pre-planned follow-up at year seven. They underwent ICA at baseline and both ICA and IVUS at year seven. ICA was described by conventional CAD severity and extent scores. IVUS was described by maximal intimal thickness (MIT), percent and total atheroma volume and compared with individuals without T2D and CAD (heart transplant donors who had IVUS performed 7-11 weeks post-transplant, n = 147). RESULTS: Despite CV risk reduction in multi after 2 years intervention, there was no between-group difference in the progression of CAD at year seven. Overall, the prevalence of CAD defined by MIT ≥ 0.5 mm in the T2DM subjects was 84%, and as compared to the non-T2DM controls there was a significantly higher atheroma burden (mean MIT, PAV and TAV in the T2D population were 0.75 ± 0.27 mm, 33.8 ± 9.8% and 277.0 ± 137.3 mm3 as compared to 0.41 ± 0.19 mm, 17.8 ± 7.3% and 134.9 ± 100.6 mm3 in the reference population). CONCLUSION: We demonstrated that a 2 year multi-intervention, despite improvement in CV risk factors, did not influence angiographic progression of CAD. Further, IVUS revealed that the prevalence of asymptomatic CAD in T2D patients is high, suggesting a need for a broader residual CV risk management using alternative approaches. Trial registration Clinical trials.gov id: NCT00133718 ( https://clinicaltrials.gov/ct2/show/NCT00133718 ).

The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions.

Diabetes and heart failure (HF) are both global epidemics with tremendous costs on society with increased rates of HF hospitalizations and worsened prognosis when co-existing, making it a significant "deadly duo." The evidence for pharmacological treatment of HF in patients with type 2 diabetes mellitus (T2DM) stems typically from either subgroup analyses of patients that were recruited to randomized controlled trials of HF interventions, usually in patients with reduced ejection fraction (EF), or from subgroup analyses of HF patients recruited to cardiovascular (CV) outcome trials (CVOT) of glucose lowering agents involving patients with T2DM. Studies in patients with HF with preserved EF are sparse. This review summarizes the literature on pathophysiology and interventions aiming to reduce the HF burden in T2DM and includes HF trials of ACEi, digoxin, ß-blocker, ARB, If-blocker, MRA, and ARNI involving 38,600 patients, with or without prevalent diabetes, and CV outcome trials in T2DM involving 74,351 patients, with or without prevalent HF. In all HF trials, HF outcomes by prevalent diabetes were reported with an incremental risk of HF and death confessed by prevalent diabetes and a treatment effect similar to those without diabetes. All T2DM CVOTs reported on HF outcomes with heterogeneity between trials with two reporting benefits (empagliflozin and canagliflozin) and two reporting increased risk (saxagliptin, pioglitazone). In vulnerable T2DM patients with concomitant HF, guideline-recommended HF drugs are effective. When choosing glucose-lowering therapy, outcomes from available CVOTs should be considered.

Myocardial dysfunction and cardiovascular disease in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is strongly associated with increased risk of myocardial dysfunction and cardiovascular disease (CVD), two separate conditions which often co-exist and influence each other's course. The prevalence of myocardial dysfunction may be as high as 75% in T2DM populations but is often overlooked due to the initial asymptomatic nature of the disease, complicating co-morbidities such as coronary artery disease (CAD) and obesity, and the lack of consensus on diagnostic criteria. More sensitive echocardiographic applications are furthermore needed to improve detection of early subclinical changes in myocardial function which do not affect conventional echocardiographic parameters. The pathophysiology of the diabetic myocardial dysfunction is not fully elucidated, but involves hyperglycemia and high levels of free fatty acids. It evolves over several years and increases the risk of developing overt HF, and is suggested to at least in part account for the worse outcome seen in T2DM individuals after cardiac events. CAD and stroke are the most frequent CV manifestations among T2DM patients and relate to a large degree to the accelerated atherosclerosis driven by inflammation. Diagnosing CAD is challenging due to the lower sensitivity inherent in the diagnostic tests and there is thus a need for new biomarkers to improve prediction and detection of CAD. It seems that a multi-factorial approach (i.e. targeting several CV risk factors simultaneously) is superior to a strict glucose lowering strategy in reducing risk for macrovascular events, and recent research may even support an effect also on HF outcomes.

Low-dose CT coronary angiography for assessment of coronary artery disease in patients with type 2 diabetes--a cross-sectional study.

BACKGROUND: Silent coronary artery disease (CAD) is prevalent in type 2 diabetes mellitus (T2DM). Although coronary computed tomography angiography (CCTA) over recent years has emerged a useful tool for assessing and diagnosing CAD it's role and applicability for patients with T2DM is still unclarified, in particular in asymptomatic patients. We aimed to assess the role of CCTA in detecting and characterizing CAD in patients with T2DM without cardiac symptoms when compared to gold standard invasive coronary angiography (ICA). METHODS: This was a cross-sectional analysis of patients with T2DM without symptomatic CAD enrolled in the Asker and Baerum Cardiovascular Diabetes Study who, following clinical examination and laboratory assessment, underwent subsequently CCTA and ICA. RESULTS: In total 48 Caucasian patients with T2DM (36 men, age 64.0 ± 7.3 years, diabetes duration 14.6 ± 6.4 years, HbA1c 7.4 ± 1.1 %, BMI 29.6 ± 4.3 kg/m(2)) consented to, and underwent, both procedures (CCTA and ICA). The population was at intermediate cardiovascular risk (mean coronary artery calcium score 269, 75 % treated with antihypertensive therapy). ICA identified a prevalence of silent CAD at 17 % whereas CCTA 35 %. CCTA had a high sensitivity (100 %) and a high negative predictive value (100 %) for detection of patients with CAD when compared to ICA, but the positive predictive value was low (47 %). CONCLUSIONS: Low-dose CCTA is a reliable method for detection and exclusion of significant CAD in T2DM and thus may be a useful tool for the clinicians. However, a low positive predictive value may limit its usefulness as a screening tool for all CAD asymptomatic patients with T2DM. Further studies should assess the applicability for risk assessment beyond the evaluation of the vascular bed.