Neha J. Pagidipati

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effects of adding once‐weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended‐release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person‐years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person‐years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention‐to‐treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338.)

Estimating Deaths From Cardiovascular Disease: A Review of Global Methodologies of Mortality Measurement

According to the National Center for Health Statistics, of 2 471 984 total deaths in the United States in 2008, 616 828 were caused by heart disease and 134 148 were caused by cerebrovascular disease (Table 1). By these statistics, heart disease is the leading cause of death in the United States.1 Worldwide, the Global Burden of Disease study estimated that in 2001, 12.45 million of >56 million total worldwide deaths were caused by cardiovascular disease (CVD) and cerebrovascular disease. Ischemic heart disease was the leading cause of global mortality, accounting for 1.4 million deaths in the developed world and 5.7 million deaths in developing regions.2 View this table: Table 1. Leading Causes of Death, United States, 2008 These impressive statistics are used for the design and subsequent evaluation of health policies and interventions, and increasingly, attention is being drawn to the need to redistribute funding on the basis of disease and mortality burden.3 But how much do practitioners know about the strength of data such as these? Many cardiovascular clinicians and researchers consider mortality data to be the most basic type of data on which to make interventions and policy decisions. Although the conclusions drawn from various clinical trials may be challenged, it is generally taken for granted that CVD mortality data in developed countries are valid. But mortality data, like all data, are subject to limitations based on how the data are collected. Furthermore, as the cardiology community begins to focus its attention on the prevalence of CVD in developing countries, it is important to determine how best to assess CVD-associated mortality in settings where most people die at home without death certificates or prior health records. The purpose of this review is to elucidate how mortality statistics are currently collected in both developed and developing countries, the various limitations …

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis

BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide. METHODS In this systematic review and meta-analysis, we analysed data from eligible trials that assessed the safety and efficacy of GLP-1 receptor agonists compared with placebo in adult patients (aged 18 years or older) with type 2 diabetes and had a primary outcome including, but not limited to, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. We searched PubMed and MEDLINE without language restrictions up to Sept 18, 2017, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) for cardiovascular efficacy outcomes and odds ratios for key safety outcomes. FINDINGS Of 12 articles identified in our search and screened for eligibility, four trials of cardiovascular outcomes of GLP-1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide). Compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity. No significant effect of GLP-1 receptor agonists was identified on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo. INTERPRETATION Our findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualised to each patients needs. FUNDING Amylin Pharmaceuticals (AstraZeneca).

Scaling Up Chronic Disease Prevention Interventions in Lower- and Middle-Income Countries

Chronic diseases are increasingly becoming a health burden in lower- and middle-income countries, putting pressure on public health efforts to scale up interventions. This article reviews current efforts in interventions on a population and individual level. Population-level interventions include ongoing efforts to reduce smoking rates, reduce intake of salt and trans-fatty acids, and increase physical activity in increasingly sedentary populations. Individual-level interventions include control and treatment of risk factors for chronic diseases and secondary prevention. This review also discusses the barriers in interventions, particularly those specific to low- and middle-income countries. Continued discussion of proven cost-effective interventions for chronic diseases in the developing world will be useful for improving public health policy.

Comparison of Recommended Eligibility for Primary Prevention Statin Therapy Based on the US Preventive Services Task Force Recommendations vs the ACC/AHA Guidelines

Importance There are important differences among guideline recommendations for using statin therapy in primary prevention. New recommendations from the US Preventive Services Task Force (USPSTF) emphasize therapy based on the presence of 1 or more cardiovascular disease (CVD) risk factors and a 10-year global CVD risk of 10% or greater. Objective To determine the difference in eligibility for primary prevention statin treatment among US adults, assuming full application of USPSTF recommendations compared with the American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Design, Setting, and Participants National Health and Nutrition Examination Survey (NHANES) data (2009-2014) were used to assess statin eligibility under the 2016 USPSTF recommendations vs the 2013 ACC/AHA cholesterol guidelines among a nationally representative sample of 3416 US adults aged 40 to 75 years with fasting lipid data and triglyceride levels of 400 mg/dL or less, without prior CVD. Exposures The 2016 USPSTF recommendations vs 2013 ACC/AHA guidelines. Main Outcomes and Measures Eligibility for primary prevention statin therapy. Results Among the US primary prevention population represented by 3416 individuals in NHANES, the median weighted age was 53 years (interquartile range, 46-61), and 53% (95% CI, 52%-55%) were women. Along with the 21.5% (95% CI, 19.3%-23.7%) of patients who reported currently taking lipid-lowering medication, full implementation of the USPSTF recommendations would be associated with initiation of statin therapy in an additional 15.8% (95% CI, 14.0%-17.5%) of patients, compared with an additional 24.3% (95% CI, 22.3%-26.3%) of patients who would be recommended for statin initiation under full implementation of the 2013 ACC/AHA guidelines. Among the 8.9% of individuals in the primary prevention population who would be recommended for statins by ACC/AHA guidelines but not by USPSTF recommendations, 55% would be adults aged 40 to 59 years with a mean 30-year cardiovascular risk greater than 30%, and 28% would have diabetes. Conclusions And Relevance In this sample of US adults from 2009-2014, adherence to the 2016 USPSTF recommendations for statin therapy, compared with the 2013 ACC/AHA guidelines, could lead to a lower number of individuals recommended for primary prevention statin therapy, including many younger adults with high mean long-term CVD risk.

Acute coronary syndromes in women and men

Evidence of sex-related disparities in the care and outcomes of patients with acute coronary syndrome (ACS) emerged >30 years ago, and yet the mechanisms behind these sex-specific differences remain unclear. In this Review, we discuss the current literature on differences between women and men in the clinical presentation, pathophysiology, evaluation, management, and outcomes of ACS. Although the symptoms of ACS and the benefits of therapy generally overlap between women and men, women continue to receive less-aggressive invasive and pharmacological therapy than men. In addition, young women in particular have worse short-term and long-term outcomes than men. To understand better the mechanisms behind these continued disparities, we have identified areas of future research that need to be urgently addressed in fields that range from clinical evaluation and management, to increasing representation of women in research.

Association between gender, process of care measures, and outcomes in ACS in India: results from the detection and management of coronary heart disease (DEMAT) registry.

Background Studies from high-income countries have shown that women receive less aggressive diagnostics and treatment than men in acute coronary syndromes (ACS), though their short-term mortality does not appear to differ from men. Data on gender differences in ACS presentation, management, and outcomes are sparse in India. Methods and Results The Detection and Management of Coronary Heart Disease (DEMAT) Registry collected data from 1,565 suspected ACS patients (334 women; 1,231 men) from ten tertiary care centers throughout India between 2007–2008. We evaluated gender differences in presentation, in-hospital and discharge management, and 30-day death and major adverse cardiovascular event (MACE; death, re-hospitalization, and cardiac arrest) rates. Women were less likely to present with STEMI than men (38% vs. 55%, p<0.001). Overall inpatient diagnostics and treatment patterns were similar between men and women after adjustment for potential confounders. Optimal discharge management with aspirin, clopidogrel, beta-blockers, and statin therapy was lower for women than men, (58% vs. 65%, p = 0.03), but these differences were attenuated after adjustment (OR = 0.86 (0.62, 1.19)). Neither the outcome of 30-day mortality (OR = 1.40 (0.62, 3.16)) nor MACE (OR = 1.00 (0.67, 1.48)) differed significantly between men and women after adjustment. Conclusions ACS in-hospital management, discharge management, and 30-day outcomes did not significantly differ between genders in the DEMAT registry, though consistently higher treatment rates and lower event rates in men compared to women were seen. These findings underscore the importance of further investigation of gender differences in cardiovascular care in India.

Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)

Background EXSCEL is a randomized, double‐blind, placebo‐controlled trial examining the effect of exenatide once‐weekly (EQW) versus placebo on time to the primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in patients with type 2 diabetes mellitus (DM) and a wide range of cardiovascular (CV) risk. Methods Patients were enrolled at 688 sites in 35 countries. We describe their baseline characteristics according to prior CV event status and compare patients with those enrolled in prior glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) outcomes trials. Results Of a total of 14,752 participants randomized between June 2010 and September 2015, 6,788 (46.0%) patients were enrolled in Europe; 3,708 (25.1%), North America; 2,727 (18.5%), Latin America; and 1,529 (10.4%), Asia Pacific. Overall, 73% had at least one prior CV event (70% coronary artery disease, 24% peripheral arterial disease, 22% cerebrovascular disease). The median (IQR) age was 63 years (56, 69), 38% were female, median baseline HbA1c was 8.0% (7.3, 8.9) and 16% had a prior history of heart failure. Those without a prior CV event were younger with a shorter duration of diabetes and better renal function than those with at least one prior CV event. Compared with prior GLP‐1RA trials, EXSCEL has a larger percentage of patients without a prior CV event and a notable percentage who were taking a dipeptidyl peptidase‐4 inhibitor at baseline (15%). Conclusions EXSCEL is one of the largest global GLP‐1RA trials, evaluating the safety and efficacy of EQW with a broad patient population that may extend generalizability compared to prior GLP‐1RA trials (ClinicalTrials.gov number, NCT01144338).

An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome

Background Studies have suggested a relationship between higher baseline serum uric acid (sUA) levels and an elevated risk of subsequent ischemic cardiovascular outcomes among acute coronary syndrome (ACS) patients; this relationship may be modified by a clinical history of gout and has not been studied in large patient cohorts. We sought to understand the effect of sUA and gout on ACS outcomes. Methods Using PLATO and TRACER data on 27,959 ACS patients, we evaluated baseline sUA levels in relation to a composite of cardiovascular death, myocardial infarction (MI), or stroke. We assessed interaction terms to determine if a baseline clinical diagnosis of gout modified this putative relationship; 46% (n = 12,882) had sUA levels elevated >6.0 mg/dL. Results Patients with elevated levels were more often male with a history of prior MI, diabetes, and heart failure compared with those with sUA <6.0 mg/dL. The unadjusted risk of the composite endpoint increased with corresponding elevations in sUA levels (per 1 mg/dL increase) (HR = 1.23 [95% CI: 1.20–1.26]) above the statistical inflection point of 5.0 mg/dL. After adjustment, the association between sUA level and the composite outcome remained significant (HR = 1.07 [95% CI: 1.04–1.10]), and baseline gout did not modify this relationship. Conclusions In patients with ACS, increasing levels of sUA are associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Further investigation is warranted to determine the mechanism behind this relationship and to delineate whether sUA is an appropriate therapeutic target to reduce cardiovascular risk.

Use of Prescription Smoking Cessation Medications After Myocardial Infarction Among Older Patients in Community Practice

Use of Prescription Smoking Cessation Medications After Myocardial Infarction Among Older Patients in Community Practice The immediate period after myocardial infarction (MI) represents a unique window of opportunity to encourage patients to quit smoking.1 Pharmacologic therapies, such as bupropion and varenicline, are effective2 and safe3; however, the prevalence of their use among patients with MI in community practice is unknown.