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Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Aim: To examine the generalizability of results from glucagon-like peptide-1 receptor agonist (GLP-1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population., Materials and Methods: Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN-6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria., Results: No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN-6, and 12.9% in LEADER., Conclusions: Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP-1 RA CVOTs., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure., Methods: UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study--ie, death from cardiovascular causes or admission to hospital with worsening heart failure--and death from any cause were assessed., Findings: 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1.43 (95% CI 1.21-1.69; p<0.0001) and for macroalbuminuria versus normoalbuminuria was 1.75 (1.39-2.20; p<0.0001). The adjusted values for death were 1.62 (1.32-1.99; p<0.0001) for microalbuminuria versus normoalbuminuria, and 1.76 (1.32-2.35; p=0.0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin., Interpretation: Increased UACR is a powerful and independent predictor of prognosis in heart failure., Funding: AstraZeneca.

Diabetes is a risk factor for cardiovascular disease. However, even elevated glucose levels below the diabetic range increase cardiovascular risk. There are several possible explanations for this relationship. First, glucose and its metabolites have direct toxic effects on vascular endothelium. Second, abnormal glucose is evidence of absolute or relative insulin deficiency, which can predispose patients to cardiovascular disease via endothelial dysfunction, lipid abnormalities, and inflammation. Third, antecedent factors, such as toxins, abnormal energy storage, and hypertension, may contribute to the development of both diabetes and cardiovascular disease. Whether glucose lowering can reduce the risk of cardiovascular disease is currently being studied in a number of large trials.

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: the ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Objective: Identifying individuals who have elevated glucose concentrations is important for clinicians so that preventive strategies can be invoked, and it is useful for researchers who study associations between elevated glucose and adverse health outcomes. These methods should be applicable worldwide across different ethnic groups. Therefore, the objective of our analysis was to determine whether using the fasting glucose and HbA(1c) together could improve the classification of individuals with impaired glucose tolerance and diabetes in a multiethnic cohort randomly assembled in Canada., Research Design and Methods: We determined the optimum diagnostic criteria to identify people with abnormal glucose tolerance using fasting plasma glucose, 2-h post-glucose load plasma glucose, and HbA(1c) in 936 Canadians of South Asian, Chinese, and European descent., Results: The sensitivity of the American Diabetes Association (ADA) criteria to diagnose diabetes compared with the World Health Organization definitions was poor at 48.3% (95% confidence interval [CI] 35.7-61.0). Using a receiver operator characteristic curve, the optimum combined cut-point using fasting glucose and HbA(1c) to diagnose diabetes was a fasting glucose > or =5.7 mmol/l and an HbA(1c) > or =5.9%. These cut-points were associated with a sensitivity and specificity of 71.7% (60.3-83.1) and 95.0% (93.5-96.4), respectively, a positive likelihood ratio (LR) of 14.3 (9.6-19.0), and a negative LR of 0.3 (0.2-0.4). Significant ethnic variation in the sensitivity and specificity of this approach was observed: 47.4% (24.9-69.8) and 97.6% (95.9-99.4) among Europeans, 78.6% (57.1-100) and 95.9% (93.6-98.2) among Chinese, and 85.2% (71.8-98.6) and 91.3% (88.1-94.6) among South Asians, respectively. Participants with impaired glucose tolerance could not be identified reliably using the fasting glucose or HbA(1c) alone or in combination., Conclusions: The sensitivity of the ADA criteria to diagnose diabetes is low, and there is substantial variation between ethnic groups. Fasting glucose and HbA(1c) may be used together to improve the identification of individuals who have diabetes, allowing clinicians to streamline the use of the oral glucose tolerance test.