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ObjectiveTo evaluate the associations between long-term change and variability in glycemia with risk of heart failure (HF) among patients with type 2 diabetes mellitus (T2DM).Research design and methodsAmong participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, variability in HbA1c was assessed from stabilization of HbA1c following enrollment (8 months) to 3 years of follow-up as follows: average successive variability (ASV) (average absolute difference between successive values), coefficient of variation (SD/mean), and SD. Participants with HF at baseline or within 3 years of enrollment were excluded. Adjusted Cox models were used to evaluate the association of percent change (from baseline to 3 years of follow-up) and variability in HbA1c over the first 3 years of enrollment and subsequent risk of HF.ResultsThe study included 8,576 patients. Over a median follow-up of 6.4 years from the end of variability measurements at year 3, 388 patients had an incident HF hospitalization. Substantial changes in HbA1c were significantly associated with higher risk of HF (hazard ratio [HR] for ≥10% decrease 1.32 [95% CI 1.08-1.75] and for ≥10% increase 1.55 [1.19-2.04]; reference

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

ObjectiveTo develop and validate a novel, machine learning-derived model to predict the risk of heart failure (HF) among patients with type 2 diabetes mellitus (T2DM).Research design and methodsUsing data from 8,756 patients free at baseline of HF, with

BackgroundAlthough practice guidelines stress individualization of glucose management in patients with type 2 diabetes (T2D), the extent to which providers take patient factors into account when selecting medications is not well known.MethodsDiabetes Collaborative Registry (DCR) is an outpatient diabetes registry including primary care, cardiology, and endocrinology practices. T2D medications were grouped as those which may be suboptimal for key patient subgroups, and we examined patient factors associated with use of these agents using hierarchical, multivariable Poisson models.ResultsIn DCR, 157,551 patients from 374 US practices were prescribed a glucose-lowering medication. Patients with morbid obesity were more likely treated with medications prone to cause weight gain (relative rate [RR] 1.09, 95% CI 1.07-1.11). Older patients were more likely to be treated with medications with increased risk of hypoglycemia (RR 1.04 per 5 years, 95% CI 1.04-1.05). Patients with CKD 4/5 were less likely to be treated with agents with known risk in patients with advanced CKD (RR 0.74, 95% CI 0.71-0.77). Patients with coronary artery disease were no more or less likely to be treated with medications with potential cardiovascular safety issues (RR 0.99, 95% CI 0.96-1.01).ConclusionsWe observed some targeted use of glucose-lowering therapies in certain subgroups but also identified potential opportunities for better personalization of treatment. Data sources such as the DCR can highlight potential areas for improving targeted approaches to pharmacologic therapy in order to optimize selection of patients most likely to benefit (and least likely to be harmed) from treatments.

Although guidelines and performance measures exist for patients with diabetes mellitus, achievement of these metrics is not well known. The Diabetes Collaborative Registry® (DCR) was formed to understand the quality of diabetes mellitus care across the primary and specialty care continuum in the United States. We assessed the frequency of achievement of 7 diabetes mellitus-related quality metrics and variability across the Diabetes Collaborative Registry® sites. Among 574 972 patients with diabetes mellitus from 259 US practices, median (interquartile range) achievement of the quality metrics across the practices was the following: (1) glycemic control: 19% (5-47); (2) blood pressure control: 80% (67-88); (3) angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in patients with coronary artery disease: 62% (51-69); (4) nephropathy screening: 62% (53-71); (5) eye examination: 0.7% (0.0-79); (6) foot examination: 0.0% (0.0-2.3); and (7) tobacco screening/cessation counseling: 86% (80-94). In hierarchical, modified Poisson regression models, there was substantial variability in meeting these metrics across sites, particularly with documentation of glycemic control and eye and foot examinations. There was also notable variation across specialties, with endocrinology practices performing better on glycemic control and diabetes mellitus foot examinations and cardiology practices succeeding more in blood pressure control and use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. The Diabetes Collaborative Registry® was established to document and improve the quality of outpatient diabetes mellitus care. While target achievement of some metrics of cardiovascular risk modification was high, achievement of others was suboptimal and highly variable. This may be attributable to fragmentation of care, lack of ownership among various specialists concerning certain domains of care, incomplete documentation, true gaps in care, or a combination of these factors.

Aims To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). Methods and results Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning-[WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P =0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (<13) vs. high (=13)WATCH-DM(i) scores [0.71 (95% confidence interval 0.68-0.74) vs. 0.64 (95% confidence interval 0.61-0.66)]. When NP levels were combined with the WATCH-DM(i) score, HF risk discrimination improvement and NRI varied across the spectrum of risk with greater improvement observed at low/intermediate risk [WATCH-DM(i)<13] vs. high risk [WATCH-DM(i) =13] (C-index = 0.73 vs. 0.71; NRI = 0.45 vs. 0.17). Conclusion TheWATCH-DM risk score can accurately predict incident HF risk in community-based individuals with dysglycaemia. The addition of NP levels is associated with greater improvement in the HF risk prediction performance among individuals with low/intermediate risk than those with high risk. [ABSTRACT FROM AUTHOR]

In patients with acute myocardial infarction (MI), therapies that could further reduce the risk of adverse cardiovascular and metabolic outcomes are needed. In this international registry-based, randomized, double-blind trial, patients without prior diabetes or chronic heart failure, presenting with acute MI and impaired left ventricular systolic function, were randomly assigned 10 mg of dapagliflozin or placebo, given once daily. The primary outcome was the hierarchical composite of death, hospitalization for heart failure, nonfatal MI, atrial fibrillation/flutter, type 2 diabetes mellitus, New York Heart Association Functional Classification at the last visit, and body weight decrease of 5% or greater at the last visit using the win ratio analysis method. The key secondary outcome was the same hierarchical composite excluding the body weight component. We enrolled 4017 patients of whom 2019 were assigned to dapagliflozin and 1998 to placebo. The analysis of the primary hierarchical composite outcome resulted in significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval [CI], 1.20 to 1.50; P<0.001). The win ratio outcome, which was adopted in a change of analysis during trial performance because of low event accrual, was mainly driven by the added cardiometabolic outcomes. The composite of time to cardiovascular death/hospitalization for heart failure occurred in 50/2019 (2.5%) patients assigned to dapagliflozin and 52/1998 (2.6%) patients assigned to placebo (hazard ratio, 0.95; 95% CI, 0.64 to 1.40). The rates of other cardiovascular events were low, with differences between the groups not reaching nominal statistical significance. No safety concerns were identified. In patients with acute MI as noted above, after approximately 1 year of treatment with dapagliflozin there were significant benefits with regard to improvement in cardiometabolic outcomes but no impact on the composite of cardiovascular death or hospitalization for heart failure compared with placebo. (Funded by AstraZeneca; ClinicalTrial.gov number, NCT04564742.) [ABSTRACT FROM AUTHOR]

In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe. [ABSTRACT FROM AUTHOR]

Byline: Klas Malmberg, Darren K. McGuire Author Affiliation: Stockholm, Sweden, and Durham, NC From the Department of Cardiology, Karolinska Hospital; and Duke Clinical Research Institute, Duke University Medical Center Article Note: (footnote) [star] Reprint requests: Klas Malmberg, MD, PhD, Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden., [star][star] Am Heart J 1999;138:S381-S386. , a 0002-8703/99/$8.00 + 0 4/0/101023

Byline: Darren K. McGuire, Christopher B. Granger Author Affiliation: Duke Clinical Research Institute and the Division of Cardiology, Department of Medicine, Duke University Medical Center. Durham, NC Article Note: (footnote) [star] Reprint requests: Christopher B. Granger, MD, FACC, Division of Cardiology, Department of Medicine, Duke University Medical Center, PO Box 3409, Durham, NC 27710., [star][star] Am Heart J 1999;138:S366-S375. , a 0002-8703/99/$8.00 + 0 4/0/101020

Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo‐controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant‐years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71‐0.89, adjusted HR 0.64, 95% CI 0.55‐0.74; P < .0001). Women also had a significantly lower risk of secondary CV outcomes and all‐cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk for cardiovascular (CV) events. Hyperglycaemia itself contributes to the pathogenesis of atherosclerosis and heart failure (HF) in these patients, but glucose-lowering strategies studied to date have had little to no impact on reducing CV risk, especially in patients with a long duration of T2D and prevalent CV disease (CVD). Sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic medications that increase urinary glucose excretion, thus improving glycaemic control independent of insulin. The recently published CV outcome trial, EMPA-REG OUTCOME, demonstrated in 7020 patients with T2D and prevalent CVD that the SGLT2-inhibitor empagliflozin significantly reduced the combined CV endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD. In addition and quite unexpectedly, empagliflozin significantly and robustly reduced the individual endpoints of CV death, overall mortality, and hospitalization for HF in this high-risk population. Various factors beyond glucose control such as weight loss, blood pressure lowering and sodium depletion, renal haemodynamic effects, effects on myocardial energetics, and/or neurohormonal effects, among others may contribute to these beneficial effects of SGLT2-inhibition. The present review summarizes known and postulated effects of SGLT2-inhibition on the CV system and discusses the role of SGLT2-inhibition for the treatment of high-risk patients with T2D and CVD. [ABSTRACT FROM AUTHOR]

Background: Although patients with diabetes mellitus experience high rates of adverse events after acute myocardial infarction (AMI), including death and recurrent ischemia, some diabetic patients are likely at low risk, whereas others are at high risk. We sought to develop prediction models to stratify risk after AMI in patients with diabetes mellitus.Methods and Results: We developed prediction models for long-term mortality and angina among 1613 patients with diabetes mellitus discharged alive after AMI from 24 US hospitals and then validated the models in a separate, multicenter registry of 786 patients with diabetes mellitus. Event rates in the derivation cohort were 27% for 5-year mortality and 27% for 1-year angina. Parsimonious prediction models demonstrated good discrimination (c-indices=0.78 and 0.69, respectively) and excellent calibration. Within the context of the predictors we estimated, the strongest predictors for mortality were higher creatinine, not working at the time of the AMI, older age, lower hemoglobin, left ventricular dysfunction, and chronic heart failure. The strongest predictors for angina were angina burden in the 4 weeks before the AMI, younger age, history of prior coronary bypass graft surgery, and non-white race. The lowest and highest deciles of predicted risk ranged from 4% to 80% for mortality and 12% to 59% for angina. The models also performed well in external validation (c-indices=0.78 and 0.73, respectively).Conclusions: We found a wide range of risk for adverse outcomes after AMI in diabetic patients. Predictive models can identify patients with diabetes mellitus for whom closer follow-up and aggressive secondary prevention strategies should be considered. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend surgical revascularization (coronary artery bypass graft [CABG]) over percutaneous coronary intervention (PCI) in patients with diabetes mellitus and multivessel coronary artery disease. Few data are available describing revascularization patterns among these patients in the setting of non-ST-segment-elevation myocardial infarction.Methods and Results: Using Acute Coronary Treatment and Intervention Outcomes Network Registry-Get with the Guidelines (ACTION Registry-GWTG), we compared the in-hospital use of different revascularization strategies (PCI versus CABG versus no revascularization) in diabetes mellitus patients with non-ST-segment-elevation myocardial infarction who had angiography, demonstrating multivessel coronary artery disease between July 2008 and December 2014. Factors associated with use of CABG versus PCI were identified using logistic multivariable regression analyses. A total of 29 769 patients from 539 hospitals were included in the study, of which 10 852 (36.4%) were treated with CABG, 13 760 (46.2%) were treated with PCI, and 5157 (17.3%) were treated without revascularization. The overall use of revascularization increased over the study period with an increase in the proportion undergoing PCI (45% to 48.9%; Ptrend=0.0002) and no change in the proportion undergoing CABG (36.1% to 34.7%; ptrend=0.88). There was significant variability between participating hospitals in the use of PCI and CABG (range: 22%-100%; 0%-78%, respectively; P value <0.0001 for both). Patient-level, but not hospital-level, characteristics were statistically associated with the use of PCI versus CABG, including anatomic severity of the disease, early treatment of adenosine diphosphate receptor antagonists at presentation, older age, female sex, and history of heart failure.Conclusions: Among patients with diabetes mellitus and multivessel coronary artery disease presenting with non-ST-segment-elevation myocardial infarction, only one third undergo CABG during the index admission. Furthermore, the use of PCI, but not CABG, increased modestly over the past 6 years. [ABSTRACT FROM AUTHOR]

More than 1 in 10 US adolescents have prediabetes or diabetes, and elevated glycosylated haemoglobin (HbA1C) in youth is associated with increased risk of death before the age of 55 years. We conducted a prospective, cross-sectional study of 31,546 consecutive volunteer blood donors, 16–19 years of age, who donated blood during school blood drives between 1 September 2011 and 21 December 2012 in Texas. In the overall cohort, the prevalence of elevated HbA1C was 11.5%, including 11.0% in the prediabetes range (HbA1C 5.7%–6.4%) and 0.5% in the diabetes range (HbA1C ⩾ 6.5%). The prevalence of elevated HbA1C was higher in boys compared with girls (15.7% vs 7.9%, p < 0.001) and was especially high in racial/ethnic minorities (Blacks 32.7%, Asians 19.7%, Hispanics 13.1%) compared with Whites (8.0%, p < 0.001). There was a significant increase in total cholesterol and blood pressure across categories of increasing HbA1C in the overall cohort and stratified by sex and race/ethnicity. Blood donation programmes can serve as unique portals for health screening with potential for intervention in adolescents. [ABSTRACT FROM AUTHOR]

OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with fewtreatment options.We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DiabetesMellitus (SAVOR)-Thrombolysis inMyocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were strati ed as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m² ; n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m² ; n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m² ; n =336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50mL/min/1.73m² (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m² (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P =0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function. [ABSTRACT FROM AUTHOR]

The article discusses research on the association of type 1 diabetes with cardiovascular disease. Topics covered include the risk of diabetic patients for having cardiovascular conditions as well as information on the different approaches to manage type 2 disease. Also mentioned is the need for the intensive management of diabetes to avoid experiencing cardiovascular problems.

The article presents a study on recent trends in hospital mortality for patients with myocardial infarction (MI) according to diabetes mellitus (DM) status from 1994-2006. It analyzed data from the U.S. National Registry of Myocardial Infarction, representing a fourth of all U.S. acute care hospitals. It finds that the hospital mortality gap between MI patients with and without DM narrowed significantly within the period, with the greatest improvement seen in women with DM.

The article discusses the long term outcome of bariatric surgery. It reports that sustained weight loss, lower incidences of cardiovascular diseases, diabetes and cancer are some of the benefits from bariatric surgery. The study was conducted in obese controlled Swedish subjects. During a follow up of 20 years following the bariatric procedure, the surgery patients used a 54 mean cumulative hospital days against the 40 days of the control group at a confidence interval (C.I.) of 95 percent. However, the study highlights that the drug costs from the seventh year were lower for patients who underwent the surgery than control patients.

Background: Metabolic syndrome (MetSyn) is associated with increased cardiovascular risk in the general population. Its prognostic implications are less well defined in patients with coronary artery disease. Methods and Results: We analyzed patients in the Duke Database for Cardiovascular Disease with a diagnosis of incident obstructive coronary artery disease. Diabetes mellitus (DM) was classified as a clinical history of DM, use of hypoglycemic drugs, or fasting glucose of >or=126 mg/dL. MetSyn was defined as having 3 of 5 characteristics: fasting glucose >or=100 and <126 mg/dL, low high-density lipoprotein cholesterol (men, <40 mg/dL; women, <50 mg/dL), triglycerides >150 mg/dL, blood pressure >or=130/85 mm Hg, or use of antihypertensive therapy, or body mass index >or=27. Death, myocardial infarction, or stroke was assessed at 6 months, 1 year, then annually. Cox proportional hazards models were generated to compare mortality and cardiovascular events between groups. The primary cohort consisted of 5744 patients; 1831 (31.9%) had DM, 2491 (43.4%) had MetSyn, and 1422 (24.7%) had no DM/MetSyn. Median follow-up was 5 years. Compared with no DM/MetSyn patients, DM patients had a higher adjusted risk for mortality (hazard ratio, 1.47; 95% CI, 1.28 to 1.69) but MetSyn patients did not (hazard ratio, 0.94; 95% CI, 0.81 to 1.08). Similar results were found for the combined end points of death or myocardial infarction, and death, myocardial infarction, or stroke. Conclusions: In a population of consecutive patients with a new diagnosis of coronary artery disease by angiography, MetSyn without DM was not an independent predictor of mortality or cardiovascular events. [ABSTRACT FROM AUTHOR]

Disorders of glucose metabolism are associated with increased risk for cardiovascular disease (CVD) complications, including coronary, peripheral and cerebral arterial disease, that account for the majority of morbidity and mortality among patients with diabetes mellitus (DM). These associations between glucose and CVD risk extend continuously well below the glycaemic thresholds established for the diagnosis of diabetes, including significantly increased risk associated with impaired fasting glucose, impaired glucose tolerance, and even high normal glucose concentrations. While these epidemiological observations have established a clear association between cardiovascular disease and dysglycaemia and suggest a direct causal link, the mechanisms by which hyperglycaemia may contribute to the development, progression and instability of atherosclerosis remain unclear. A number of recent advances in the realm of vascular biology have identified several novel, plausible pathways that might link hyperglycaemia with atherosclerosis, individually or in aggregate. Key among them are the interaction between advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE), which exists as a trans-membrane signalling receptor and as a circulating form, soluble RAGE (sRAGE).The purpose of this review is to provide an overview of the present understanding of RAGE and sRAGE, their plausible role linking perturbed glucose metabolism with the development, progression and instability of atherosclerosis, and the potential therapeutic implications of modulation of this biological system. [ABSTRACT FROM PUBLISHER]

Type 2 diabetes mellitus (DM) is increasing around the world, and the public health impact of DM, driven largely by cardiovascular disease complications, underpins the importance of continued efforts toward primary prevention of DM. Only a few interventions have been shown to prevent DM, with none of them yet proven to improve cardiovascular risk commensurately. Accumulating evidence suggest that drugs that block the renin-angiotensin-aldosterone system (RAAS), many of which have proven cardiovascular disease (CVD) benefit, also have favourable effects on parameters of glucose metabolism and incident diabetes. Here we review the evidence accumulated to date from animal studies, clinical mechanistic studies and clinical trials regarding the effect of RAAS inhibition and incident DM. [ABSTRACT FROM PUBLISHER]

Objective: The aims of this study were to investigate the prognostic influence of diabetes after an episode of unstable angina pectoris or non-Q-wave myocardial infarction (MI) and to investigate whether diabetes is independently associated with increased short- and long-term mortality risk following these episodes.Design: Consecutive patients with a diagnosis of unstable angina pectoris or non-Q-wave MI, admitted to the Coronary Care Unit at Ostra Hospital, Göteborg, Sweden during 1988-1998 were included. The primary endpoint was 2-year mortality collected from the Swedish cause-specific mortality register.Results: The study included 4341 patients, 722 (17%) had diabetes. Diabetes was associated with increased mortality during initial hospitalization (10.2% vs 5.7%, p < 0.0001), after 30 days (13% vs 7.5%, p < 0.0001), and at 2 years (33.7% vs 20.2%, p < 0.0001). After adjustment for potentially confounding factors, diabetes remained an independent predictor of 2-year mortality following unstable coronary syndromes, the hazard ratio (HR) of death (HR = 1.6; 95% CI 1.4-1.9).Conclusions: Among patients with unstable coronary syndromes, diabetes is an independent risk factor associated with increased mortality during hospitalization, short- and long-term follow-up. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to evaluate the associations between plasma levels of soluble CD40 ligand (sCD40L), atherosclerosis risk factors, and evidence of subclinical atherosclerosis. Methods and results. Plasma levels of sCD40L were measured in 2811 subjects from the Dallas Heart Study, a multiethnic population-based cross-sectional study. Electron Beam Computed Tomography measurements of coronary artery calcium (CAC) and MRI measurements of aortic plaque were performed in 2198 and 1965 subjects, respectively. No association was observed between quartiles of sCD40L and age, sex, race, body mass index, diabetes, smoking, creatinine clearance, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or C-reactive protein. In contrast, weak but statistically significant associations were observed between sCD40L and total cholesterol and triglycerides. The prevalence of detectable CAC (CAC score ≥10) and aortic plaque did not differ across sCD40L quartiles, and individuals with CAC scores <10, ≥10 to 100, >100 to 400, and >400 had similar sCD40L levels. Conclusions. In a large and representative multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or with subclinical atherosclerosis. These findings suggest that sCD40L will not be useful as a tool to screen for the presence of subclinical atherosclerosis in the population. Further evaluation of this biomarker should focus on settings in which platelet activation is common, such as following acute coronary syndromes or coronary revascularization procedures.

OBJECTIVE--To evaluate the relationship between A1C and glucose therapy intensification (GTI) in patients with diabetes mellitus (DM) hospitalized for acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODSdA1C was measured as part of routine care (clinical A1C) or in the core laboratory (laboratory A1C, results unavailable to clinicians). GTI predictors were identified using hierarchical Poisson regression. RESULTS--Of 1,274 patients, 886 (70%) had clinical A1C and an additional 263 had laboratory A1C measured. Overall, A1C was <7% in 419 (37%), 7-9% in 415 (36%), and >9% in 315 patients (27%). GTI occurred in 31% of patients and was more frequent in those with clinical A1C both before (34 vs. 24%, P < 0.001) and after multivariable adjustment (relative risk 1.34 [95% CI 1.12-1.62] vs. no clinical A1C). CONCLUSIONS--Long-term glucose control is poor in most AMI patients with DM, but only a inority of patients undergo GTI at discharge. Inpatient A1C assessment is strongly associated with intensification of glucose-lowering therapy. [ABSTRACT FROM AUTHOR]

Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. This study sought to determine the effect of ticagrelor on limb events. Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P interaction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P interaction = 0.40) or TIMI major bleeding (P interaction = 0.3239). Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved.Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models.Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min-1·1.73 m-2). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease.Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886. [ABSTRACT FROM AUTHOR]

We appreciate the letter written by Drs Mordi, Mohan, and Lang describing their findings of reduced left ventricular mass index in patients with coronary artery disease and insulin resistance or pre-diabetes mellitus randomized to 12 months of treatment with metformin compared with placebo. 2019, 140, 1004-1014, doi: 10.1161/CIRCULATIONAHA.119.040144 2 Sambe T, Mason RP, Dawoud H, Bhatt DL, Malinski T. Metformin treatment decreases nitroxidative stress, restores nitric oxide bioavailability and endothelial function beyond glucose control. [Extracted from the article]

Patients who have diabetes mellitus have 2 times the incidence of an acute coronary syndrome (ACS) and 2 times the mortality rate after ACS compared with patients who do not have diabetes. Poor patient understanding of diabetes is believed to impede appropriate self-management, thus accelerating cardiovascular complications. We investigated the relation between patients'' diabetes-related knowledge (DRK) and measurements of risk factor control and cardiac outcomes. Two hundred patients who had diabetes mellitus and ACS and were admitted to a university hospital were enrolled over a 9-month period. At enrollment, clinical and demographic data were recorded, and each patient completed a previously validated DRK assessment. Clinical outcomes data were obtained 6 months after enrollment. Years of education and DRK assessment score were moderately correlated (r = 0.496, p &#60;0.0001). Glycosylated hemoglobin, low-density lipoprotein cholesterol, and body mass index showed no correlation with DRK assessment score (r = −0.045, −0.005, and 0.175, respectively), even after multivariable adjustment for differences in age, race, insulin requirement, duration of diabetes, and years of education. Rates of 6-month death (6.2% vs 9.7%) and death or myocardial infarction (15.5% vs 19.4%) were not significantly different between groups of patients stratified by DRK assessment scores (high vs low scoring groups). Thus, among patients who have diabetes and ACS, there is a moderate correlation between years of education and DRK. We found no correlation between DRK and measurements of risk factor control or 6-month clinical outcomes. New strategies must be developed to translate understanding of disease into better risk factor modification among patients who have diabetes and ACS. [Copyright &y& Elsevier]

We investigated the use of different antithrombotic therapies at baseline among patients with a history of atrial fibrillation (AF), type 2 diabetes, and established atherosclerotic cardiovascular disease (ASCVD) enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). TECOS participants with a history of AF were stratified by CHA 2 DS 2 -VASc score and their antithrombotic use evaluated. Cox proportional hazards models were employed to explore possible associations between history of AF and prespecified clinical outcomes after adjusting for key baseline characteristics. Of the 14,671 TECOS participants, 1167 (8%) had a history of AF, of whom 51.6% were using vitamin K antagonists (VKA); 31.2% used VKA alone, 16.9% used aspirin plus VKA, 1.8% used clopidogrel plus VKA, and 1.7% used aspirin and clopidogrel plus VKA. Aspirin was used by 56.8%: 30.9% used aspirin alone and 7.3% aspirin plus clopidogrel. Clopidogrel alone was used by 2.9%, and 7.3% were not using any antithrombotic medication. Participants with a history of AF had a higher risk of cardiovascular events, including hospitalization for heart failure and all-cause mortality, than those without AF. White, older men with prior myocardial infarction, heart failure, peripheral artery disease, or prior stroke were more likely to develop new-onset AF than others without these characteristics. Almost half of high-risk AF patients with diabetes and established ASCVD in TECOS were not treated with anticoagulation therapy despite clear guideline recommendations for such therapy, highlighting the challenge and potential for clinical improvements in managing these patients in clinical practice. Clinical Trial Registration : URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205. • Afib and type 2 diabetes are associated with adverse cardiovascular outcomes. • We examined OAC use by TECOS patients with Afib, ASCVD, and type 2 diabetes. • OAC use by these high-risk patients is much less than guideline recommendations. [ABSTRACT FROM AUTHOR]

Background: The strength of association and optimal levels for risk factors related to excess risk of death and cardiovascular outcomes in type 1 diabetes mellitus have been sparsely studied.Methods: In a national observational cohort study from the Swedish National Diabetes Register from 1998 to 2014, we assessed relative prognostic importance of 17 risk factors for death and cardiovascular outcomes in individuals with type 1 diabetes mellitus. We used Cox regression and machine learning analyses. In addition, we examined optimal cut point levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. Patients with type 1 diabetes mellitus were followed up until death or study end on December 31, 2013. The primary outcomes were death resulting from all causes, fatal/nonfatal acute myocardial infarction, fatal/nonfatal stroke, and hospitalization for heart failure.Results: Of 32 611 patients with type 1 diabetes mellitus, 1809 (5.5%) died during follow-up over 10.4 years. The strongest predictors for death and cardiovascular outcomes were glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol. Glycohemoglobin displayed ≈2% higher risk for each 1-mmol/mol increase (equating to ≈22% per 1% glycohemoglobin difference), whereas low-density lipoprotein cholesterol was associated with 35% to 50% greater risk for each 1-mmol/L increase. Microalbuminuria or macroalbuminuria was associated with 2 to 4 times greater risk for cardiovascular complications and death. Glycohemoglobin <53 mmol/mol (7.0%), systolic blood pressure <140 mm Hg, and low-density lipoprotein cholesterol <2.5 mmol/L were associated with significantly lower risk for outcomes observed.Conclusions: Glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol appear to be the most important predictors for mortality and cardiovascular outcomes in patients with type 1 diabetes mellitus. Lower levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than contemporary guideline target levels appear to be associated with significantly lower risk for outcomes. [ABSTRACT FROM AUTHOR]

Background: There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission.Methods: In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m2) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264.Findings: Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054).Interpretation: Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health.Funding: Eisai. [ABSTRACT FROM AUTHOR]

Background: Intensive risk factor modification significantly improves outcomes for patients with diabetes mellitus and cardiovascular disease. However, the degree to which secondary prevention treatment goals are achieved in international clinical practice is unknown.Methods: Attainment of 5 secondary prevention parameters-aspirin use, lipid control (low-density lipoprotein cholesterol <70 mg/dL or statin therapy), blood pressure control (<140 mm Hg systolic, <90 mm Hg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and nonsmoking status-was evaluated among 13 616 patients from 38 countries with diabetes mellitus and known cardiovascular disease at entry into TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin). Logistic regression was used to evaluate the association between individual and regional factors and secondary prevention achievement at baseline. Cox proportional hazards regression analysis was used to determine the association between baseline secondary prevention achievement and cardiovascular death, myocardial infarction, or stroke.Results: Overall, 29.9% of patients with diabetes mellitus and cardiovascular disease achieved all 5 secondary prevention parameters at baseline, although 71.8% achieved at least 4 parameters. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of ≈25%. Individually, blood pressure control (57.9%) had the lowest overall attainment, whereas nonsmoking status had the highest (89%). Over a median 3.0 years of follow-up, a higher baseline secondary prevention score was associated with improved outcomes in a step-wise graded relationship (adjusted hazard ratio, 0.60; 95% confidence interval, 0.47-0.77 for those patients achieving all 5 measures versus those achieving ≤2).Conclusions: In an international trial population, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes mellitus and cardiovascular disease, which in turn could lead to reduced risk of downstream cardiovascular events.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205. [ABSTRACT FROM AUTHOR]

Background: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.Methods: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.Results: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).Conclusions: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .). [ABSTRACT FROM AUTHOR]

Background: Individuals with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular complications, but it is unknown to what extent fulfilling all cardiovascular treatment goals is associated with residual risk of mortality and cardiovascular outcomes in those with T1DM compared with the general population.Methods: We included all patients ≥18 years of age with T1DM who were registered in the Swedish National Diabetes Register from January 1, 1998, through December 31, 2014, a total of 33 333 patients, each matched for age and sex with 5 controls without diabetes mellitus randomly selected from the population. Patients with T1DM were categorized according to number of risk factors not at target: glycohemoglobin, blood pressure, albuminuria, smoking, and low-density lipoprotein cholesterol. Risk of all-cause mortality, acute myocardial infarction, heart failure hospitalization, and stroke was examined in relation to the number of risk factors at target.Results: The mean follow-up was 10.4 years in the diabetes group. Overall, 2074 of 33 333 patients with diabetes mellitus and 4141 of 166 529 controls died. Risk for all outcomes increased stepwise for each additional risk factor not at target. Adjusted hazard ratios for patients achieving all risk factor targets compared with controls were 1.31 (95% confidence interval [CI], 0.93-1.85) for all-cause mortality, 1.82 (95% CI, 1.15-2.88) for acute myocardial infarction, 1.97 (95% CI, 1.04-3.73) for heart failure hospitalization, and 1.17 (95% CI, 0.51-2.68) for stroke. The hazard ratio for patients versus controls with none of the risk factors meeting target was 7.33 (95% CI, 5.08-10.57) for all-cause mortality, 12.34 (95% CI, 7.91-19.48) for acute myocardial infarction, 15.09 (95% CI, 9.87-23.09) for heart failure hospitalization, and 12.02 (95% CI, 7.66-18.85) for stroke.Conclusions: A steep-graded association exists between decreasing number of cardiovascular risk factors at target and major adverse cardiovascular outcomes among patients with T1DM. However, risks for all outcomes were numerically higher for patients with T1DM compared with controls, even when all risk factors were at target, with risk for acute myocardial infarction and heart failure hospitalization statistically significantly higher. [ABSTRACT FROM AUTHOR]

Increasing rates of obesity and diabetes have driven corresponding increases in related cardiorenal and metabolic diseases. In many patients, these conditions occur together, further increasing morbidity and mortality risks to the individual. Yet all too often, the risk factors for these disorders are not addressed promptly in clinical practice, leading to irreversible pathologic progression. To address this gap, we convened a Task Force of experts in cardiology, nephrology, endocrinology, and primary care to develop recommendations for early identification and intervention in obesity, diabetes, and other cardiorenal and metabolic diseases. The recommendations include screening and diagnosis, early interventions with lifestyle, and when and how to implement medical therapies. These recommendations are organized into primary and secondary prevention along the continuum from obesity through the metabolic syndrome, prediabetes, diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), atherosclerotic cardiovascular disease (ASCVD) and atrial fibrillation, chronic kidney disease (CKD), and heart failure (HF). The goal of early and intensive intervention is primary prevention of comorbidities or secondary prevention to decrease further worsening of disease and reduce morbidity and mortality. These efforts will reduce clinical inertia and may improve patients' well-being and adherence. • Diabetes, obesity and cardiorenal/metabolic disease often occur in the same patient. • Suboptimal metabolic control has not improved in past 20 years despite new medications. • Traditional, stepwise treatment often leads to inertia and morbidity and mortality. • Early intensive combination intervention can prevent disease progression and events. • Recommendations cover early intervention in both primary and secondary prevention. [ABSTRACT FROM AUTHOR]

Background--Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results--A total of 16492 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 12301 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 12monthswere 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. Conclusions--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. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to examine the efficacy of ranolazine versus placebo on weekly angina frequency and sublingual nitroglycerin use in subjects with type 2 diabetes mellitus, coronary artery disease (CAD), and chronic stable angina who remain symptomatic despite treatment with up to 2 antianginal agents. Background: Patients with diabetes have more extensive CAD than those without diabetes, and a high burden of angina. Ranolazine is not only effective in treating angina but also may improve glycemic control, thus providing several potential benefits in this high-risk group. We conducted a randomized trial to test the antianginal benefit of ranolazine in patients with diabetes and stable angina. Methods: TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina) was an international, randomized, double-blind trial of ranolazine versus placebo in patients with diabetes, CAD, and stable angina treated with 1 to 2 antianginals. After a single-blind, 4-week placebo run-in, patients were randomized to 8 weeks of double-blind ranolazine (target dose 1000 mg bid) or placebo. Anginal episodes and nitroglycerin use were recorded with daily entry into a novel electronic diary. Primary outcome was the average weekly number of anginal episodes over the last 6 weeks of the study. Results: A total of 949 patients were randomized across 104 centers in 14 countries. Mean age was 64 years, 61% were men, mean diabetes duration was 7.5 years, and mean baseline HbA1c was 7.3%. Electronic diary data capture was 98% in both groups. Weekly angina frequency was significantly lower with ranolazine versus placebo (3.8 [95% confidence interval (CI): 3.6 to 4.1] episodes vs. 4.3 [95% CI: 4.0 to 4.5] episodes, p = 0.008), as was the weekly sublingual nitroglycerin use (1.7 [95% CI: 1.6 to 1.9] doses vs. 2.1 [95% CI: 1.9 to 2.3] doses, p = 0.003). There was no difference in the incidence of serious adverse events between groups. Conclusions: Among patients with diabetes and chronic angina despite treatment with up to 2 agents, ranolazine reduced angina and sublingual nitroglycerin use and was well tolerated. (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina [TERISA]; NCT01425359) [Copyright &y& Elsevier]

A response from the author of the article "Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations From the SAVOR-TIMI 53 Randomized Trial" in the previous issue is presented.