In the EMPA-REG OUTCOME trial (BI 10773 Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic ...cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.
Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.
Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline ( P>0.05 for randomized group-by-subgroup interactions).
Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.
URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.
As the worldwide prevalence of type 2 diabetes mellitus (T2DM) increases, it is even more important to develop cost-effective methods to predict and diagnose the onset of diabetes, monitor ...progression, and risk stratify patients in terms of subsequent cardiovascular and diabetes complications.
Nonlaboratory clinical risk scores based on risk factors and anthropomorphic data can help identify patients at greatest risk of developing diabetes, but glycemic indices (hemoglobin A
, fasting plasma glucose, and oral glucose tolerance tests) are the cornerstones for diagnosis, and the basis for monitoring therapy. Although family history is a strong predictor of T2DM, only small populations of patients carry clearly identifiable genetic mutations. Better modalities for detection of insulin resistance would improve earlier identification of dysglycemia and guide effective therapy based on therapeutic mechanisms of action, but improved standardization of insulin assays will be required. Although clinical risk models can stratify patients for subsequent cardiovascular risk, the addition of cardiac biomarkers, in particular, high-sensitivity troponin and natriuretic peptide provide, significantly improves model performance and risk stratification.
Much more research, prospectively planned and with clear treatment implications, is needed to define novel biomarkers that better identify the underlying pathogenic etiologies of dysglycemia. When compared with traditional risk features, biomarkers provide greater discrimination of future risk, and the integration of cardiac biomarkers should be considered part of standard risk stratification in patients with T2DM.
Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.
We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and ...followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.
At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio ACR <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m
(BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA
(r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well.
Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.
Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point.
A total of 16 492 patients ...with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups.
In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease.
http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
The accurate assessment of a patient's risk of adverse events remains a mainstay of clinical care. Commonly used risk metrics have been based on logistic regression models that incorporate aspects of ...the medical history, presenting signs and symptoms, and lab values. More sophisticated methods, such as Artificial Neural Networks (ANN), form an attractive platform to build risk metrics because they can easily incorporate disparate pieces of data, yielding classifiers with improved performance. Using two cohorts consisting of patients admitted with a non-ST-segment elevation acute coronary syndrome, we constructed an ANN that identifies patients at high risk of cardiovascular death (CVD). The ANN was trained and tested using patient subsets derived from a cohort containing 4395 patients (Area Under the Curve (AUC) 0.743) and validated on an independent holdout set containing 861 patients (AUC 0.767). The ANN 1-year Hazard Ratio for CVD was 3.72 (95% confidence interval 1.04-14.3) after adjusting for the TIMI Risk Score, left ventricular ejection fraction, and B-type natriuretic peptide. A unique feature of our approach is that it captures small changes in the ST segment over time that cannot be detected by visual inspection. These findings highlight the important role that ANNs can play in risk stratification.
Acute coronary syndrome encompasses a broad and heterogeneous population that challenges the clinician at each step of treatment in terms of: 1) diagnosis; 2) appropriate risk stratification; 3) ...therapeutic decision making; and 4) monitoring response to therapy. Although there are many established tools for diagnosis, prognosis, and clinical decision making, understanding the advantages and limitations of each tool according the clinical scenario is essential. Several emerging tools, such as novel biomarkers (e.g., high-sensitivity troponin and growth differential factor-15), ECG techniques (e.g., heart rate turbulence or T-wave alternans), and imaging modalities (computed tomography angiography and cardiac magnetic resonance) may potentially improve clinical care; however, they must be fully evaluated and validated in different scenarios and patient cohorts before they are incorporated into clinical practice. This review identifies promising new or emerging techniques, as well as established tools, and reviews their current or potential role in clinical practice.
Empagliflozin was shown to reduce risk of cardiovascular death among high-risk patients with type 2 diabetes mellitus (1), which led to the U.S. Food and Drug Administration (FDA) expanding its ...labeling in December 2016 for reducing cardiovascular risk. ...we sought to determine specialty-specific prescriber trends of SGLT2i in a large U.S. tertiary care system over the last 5 years. ...these data from an integrated tertiary care system may not be generalizable to all settings.
To evaluate if previously found associations between low serum bilirubin concentration and kidney function decline is independent of hemoglobin and other key confounders. Clinical trial data from the ...SAVOR-TIMI 53 trial as well as the UK primary care electronic healthcare records, Clinical Practice Research Datalink (CPRD), were used to construct three cohorts of patients at risk of chronic kidney disease (CKD). The randomized clinical trial (RCT) cohort from the subset of SAVOR-TIMI 53 trial consisted of 10,555 type-2 diabetic patients with increased risk of cardiovascular disease. The two observational data cohorts from CPRD consisted of 71,104 newly diagnosed type-2 diabetes (CPRD-DM2) and 82,065 newly diagnosed hypertensive (CPRD-HT) patients without diabetes. Cohorts were stratified according to baseline circulating total bilirubin levels to determine association on the primary end point of a 30% reduction from baseline in estimated glomerular filtration rate (eGFR) and the secondary end point of albuminuria. The confounder adjusted hazard ratios of the subpopulation with lower than median bilirubin levels compared to above median bilirubin levels for the primary end point were 1.18 (1.02-1.37), 1.12 (1.05-1.19) and 1.09 (1.01-1.17), for the secondary end point were 1.26 (1.06-1.52), 1.11 (1.01-1.21) and 1.18 (1.01-1.39) for SAVOR-TIMI 53, CPRD-DM2, CPRD-HT, respectively. Our findings are consistent across all cohorts and endpoints: lower serum bilirubin levels are associated with a greater kidney function decline independent of hemoglobin and other key confounders. This suggests that increased monitoring of kidney health in patients with lower bilirubin levels may be considered, especially for diabetic patients.
Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart ...failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control.
We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models.
We included data from 14 trials, with mean duration 4·3 (2·3) years, comprising 95 502 patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0·50% (SD 0·33) reduction in HbA1c and a 1·7 kg (2·8) weight gain. Overall, glucose-lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1·14, 95% CI 1·01-1·30; p=0·041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction=0·00021). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1·42, 95% CI 1·15-1·76; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1·25, 1·08-1·45; two trials), and neutral with insulin glargine (0·90, 0·77-1·05; one trial). Target-based intensive glycaemic control strategies (RR 1·00, 95% CI 0·88-1·13; four trials) and intensive weight loss (0·80, 95% CI 0·62-1·04; one trial) were also not associated with development of heart failure. Meta-regression analysis showed that for every 1·0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7·1% (95% CI 1·0-13·6) relative increase in the risk of heart failure compared with standard care (p=0·022).
Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain.
None.
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