Search

The effect of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the total (first and recurrent) burden of cardiovascular (CV) hospitalizations, including hospitalization for heart failure, myocardial infarction, and stroke, is poorly understood.To assess the effect of empagliflozin, an SGLT2i, on total CV hospitalizations among older adults with T2D.Using data from Medicare fee-for-service (08/2014-09/2017), we identified 1:1 propensity score-matched cohorts of patients with T2D initiating empagliflozin versus sitagliptin or empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA), balancing140 baseline covariates. We compared the risk of first and recurrent hospitalizations with any CV condition as the primary discharge diagnosis (ICD-9: 390-459; ICD-10: I00-I99), hospitalizations for heart failure (HHF), and myocardial infarctions (MI) or stroke. We estimated treatment effects based on the Ghosh-Lin semiparametric model for recurrent events as primary and joint frailty model as secondary analysis.We included 11,429 matched-pairs of empagliflozin and sitagliptin initiators and 17,502 matched-pairs of empagliflozin and GLP1-RA initiators with an average age of 72 years. Empagliflozin was associated with a reduced risk of total CV hospitalizations (0.80 [0.69-0.93] vs sitagliptin; 0.88 [0.77-1.00] vs GLP-1RA) and total HHF (0.70 [0.51-0.98] vs sitagliptin; 0.76 [0.56-1.03] vs GLP1-RA) over a mean follow up of 6.3 months. No differences between treatments were observed for MI or stroke. Results were consistent for joint frailty models.Empagliflozin, compared to sitagliptin or to a lesser extent GLP1-RA, was associated with a reduction in the burden of total CV hospitalizations and HHF in older patients with T2D.

The objective of this study was to quantify the value of early suppression of high-sensitivity C-reactive protein (hsCRP) levels as a biomarker of the protective role of canakinumab against future gout flares.We conducted a post hoc causal mediation analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study for gout flares. The 3-month change in the log hsCRP level was the mediator of interest. We used linear regression for the hsCRP level mediator and Cox or Weibull regression for gout-flare outcomes, combining them in causal mediation analysis. We examined the cohort overall, as well as stratified by prevalent gout at baseline.We analyzed 9,221 patients without prevalent gout and 747 with prevalent gout. The Cox regression hazard ratio (HR) for a gout flare was 0.50 (95% confidence interval [95% CI] 0.37-0.68) comparing canakinumab with placebo, of which 6% was explained by the mediated effect through hsCRP level reduction in the first 3 months. In the prevalent-gout subgroup, the HR was 0.58 (95% CI 0.36-0.95), of which 31% was explained by the mediated effect through hsCRP level reduction. The Weibull analysis gave a proportion-mediated estimate of 47%. The indirect effect via hsCRP level reductions was unclear in the subgroup without prevalent gout.The first 3-month reduction in hsCRP level was not a good biomarker for canakinumab's protective effect on future gout flares in the overall cohort. Among patients with prevalent gout, there may be a potential role for early hsCRP level reduction as a biomarker for interleukin-1β inhibitors' future gout-flare benefit.

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 (

Background High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. Methods In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Results Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. Conclusions Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)

ImportanceLimited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk.ObjectiveTo evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).Design, Setting, and ParticipantsThis retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score–matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score–matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2.ExposuresEmpagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2).Main Outcomes and MeasuresPrimary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching.ResultsAmong 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, −17.6 [95% CI, −24.9 to −10.4]; HHF: RD, −16.7 [95% CI, −21.7 to −11.9]), HF (modified MACE: RD, −41.1 [95% CI, −59.9 to −22.6]; HHF: RD, −50.4 [95% CI, −67.5 to −33.9]), or CKD (modified MACE: RD, −26.7 [95% CI, −41.3 to −12.3]; HHF: RD, −31.9 [95% CI, −43.5 to −20.8]).Conclusions and RelevanceIn this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

ImportanceSodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point.ObjectiveTo examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice.Design, Setting, and ParticipantsA population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021.ExposuresTo control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)–matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates.Main Outcomes and MeasuresThe primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups.ResultsNew users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, –3.7; 95% CI, –5.2 to –2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, –1.8; 95% CI, –3.2 to –0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses.Conclusions and RelevanceThe findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level–lowering agents in older adults with T2D.

The role of SGLT-2i in the primary prevention of atrial fibrillation (AF) remains unclear from clinical trials. We assessed the association of SGLT-2i use and incident AF in routine clinical practice. Using Medicare claims data 2013-2018, we identified patients with type 2 diabetes (T2D) and aged ≥66 years with no AF history (i.e., no diagnosis, procedure or medication codes suggestive of underlying AF at baseline) initiating an SGLT-2i or a comparator (a DPP-4i or a GLP-1RA) , in two pairwise comparisons (74,868 and 80,475 1:1 propensity score-matched pairs, respectively) . The primary outcome was AF hospitalization. Secondary outcomes were AF diagnosis in any care setting and AF treated with medications. We calculated hazard ratios (HRs) and rate differences (RDs, per 1000 patient-year) , in the matched groups, well-balanced across 138 baseline covariates. Over a median follow-up of approximately 6 months, the risk of AF hospitalization was lower in the SGLT-2i group than the DPP-4i group (HR, 0.82 [95%CI, 0.76-0.89]; RD, -3.7 [95%CI, -5.2, -2.2]) or the GLP-1RA group (HR, 0.90 [95%CI, 0.83-0.98]; RD, -1.8 [95%CI, -3.2, -0.3]) (Table) . Findings for secondary outcomes were consistent with the primary outcome. In routine care, SGLT-2i use was associated with a reduction in the risk of incident AF, compared to DPP-4i or GLP-1RA among older patients with T2D. Disclosure M.Zhuo: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. B.M.Everett: Consultant; Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Lilly, Provention Bio, Inc., UpToDate, Other Relationship; American Heart Association, Research Support; Novo Nordisk. E.D'andrea: None. R.Glynn: None. S.C.Kim: Research Support; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Roche Pharmaceuticals. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute.

Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes.In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations.Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection.SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

Objective Individuals with systemic lupus erythematosus (SLE) are at high risk for infections and SLE- and medication-related complications. The present study was undertaken to define a set of SLE-specific adverse outcomes that could be prevented, or their complications minimized, if timely, effective ambulatory care had been received. Methods We used a modified Delphi process beginning with a literature review and key informant interviews to select initial SLE-specific potentially preventable conditions. We assembled a panel of 16 nationally recognized US-based experts from 8 subspecialties. Guided by the RAND-UCLA Appropriateness Method, we held 2 survey rounds with controlled feedback and an interactive webinar to reach consensus regarding preventability and importance on a population level for a set of SLE-specific adverse conditions. In a final round, the panelists endorsed the potentially preventable conditions. Results Thirty-five potential conditions were initially proposed; 62 conditions were ultimately considered during the Delphi process. The response rate was 100% for both survey rounds, 88% for the webinar, and 94% for final approval. The 25 SLE-specific conditions meeting consensus as potentially preventable and important on a population level fell into 4 categories: vaccine-preventable illnesses (6 conditions), medication-related complications (8 conditions), reproductive health-related complications (6 conditions), and SLE-related complications (5 conditions). Conclusion We reached consensus on a diverse set of adverse outcomes relevant to SLE patients that may be preventable if patients receive high-quality ambulatory care. This set of outcomes may be studied at the health system level to determine how to best allocate resources and improve quality to reduce avoidable outcomes and disparities among those at highest risk.

OBJECTIVE Cardiovascular disease (CVD) risk is elevated in patients with systemic lupus erythematosus (SLE) and diabetes mellitus (DM), but whether risk of CVD in patients with SLE is as high as in those with DM is unknown. The present study was undertaken to compare CVD risks between patients with SLE and DM and general population US Medicaid recipients. METHODS In a cohort study, we identified age- and sex-matched adults (1:2:4) with SLE or DM and those from the general population using Medicaid Analytic eXtract, 2007-2010. We collected data on baseline sociodemographic factors, comorbidities, and medications. We used Cox regression models to calculate hazard ratios (HRs) of hospitalized nonfatal CVD events (combined myocardial infarction [MI] and stroke) and MI and stroke separately, accounting for competing risk of death and adjusting for covariates. We compared risks in age-stratified models. RESULTS We identified 40,212 SLE patients, 80,424 DM patients, and 160,848 general population patients; 92.5% were female, and the mean ± SD age was 40.3 ± 12.1 years. Nonfatal CVD incidence rate per 1,000 person-years was 8.99 for patients with SLE, 7.07 for those with DM, and 2.36 for the general population. Nonfatal CVD risk was higher in SLE compared to DM (HR 1.27 [95% confidence interval (95% CI) 1.15-1.40]), driven by excess risk at ages 18-39 years (HR 2.22 [95% CI 1.81-2.71]). Patients with SLE had higher risk of CVD compared to the general population (HR 2.67 [95% CI 2.38-2.99]). CONCLUSION SLE patients had a 27% higher risk of nonfatal CVD events compared to age- and sex-matched patients with DM and more than twice the risk of the Medicaid general population. The highest relative risk occurred at ages 18-39 years. These high risks merit aggressive evaluation for modifiable factors and research to identify prevention strategies.

Ty J. Gluckman, MD, FACC, Chair Niti R. Aggarwal, MD, FACC Nicole M. Bhave, MD, FACC Gregory J. Dehmer, MD, MACC Olivia N. Gilbert, MD, MSc, FACC Chayakrit Krittanawong, MD Dharam J. Kumbhani, MD, SM, FACC Andrea L. Price, CPHQ, RCIS, AACC Javier A. Sala-Mercado, MD, PhD David E.

Background Patients with systemic lupus erythematosus (SLE) have a similar risk of myocardial infarction as those with diabetes mellitus (DM). Whether the risk of heart failure (HF) in SLE is similar to the elevated risk in DM is unknown. We sought to estimate the rates and risks for HF hospitalization among US Medicaid patients with SLE and to compare them to those for DM and the general Medicaid population. Methods Using U.S. Medicaid data from 2007–2010, we identified patients with SLE or DM, and a matched cohort from the general Medicaid population and calculated incidence rates (IR), incidence rate ratios (IRR) and adjusted hazard ratios (HR) of a first HF hospitalization. Results We identified 37,902 SLE (93% female, mean age 40.1 ± 12.1), 76,657 DM (93% female, mean age 40.0 ± 12.1), and 158,695 general Medicaid patients (93% female, mean age 40.2 ± 12.1). The IR per 1000-person years was 6.9 (95% CI 6.3–7.5) for SLE, 6.6 (95% CI 6.2–7.0) for DM, and 1.6 (95% CI 1.5–1.8) for general Medicaid patients. The highest IRR compared to general Medicaid was seen among SLE patients in age group 18–39 (14.7, 95% CI 13.9–15.5). Multivariable-adjusted HRs for HF compared to general Medicaid population were similar for SLE (2.7, 95% CI 2.3–3.1) and DM (3.0, 95% CI 2.6–3.4). Conclusion The incidence of HF among SLE patients was 2.7-fold higher than general Medicaid patients, and similar to DM. Further investigation into the biologic mechanism of HF among SLE compared to non-SLE and DM patients may shed light on the findings of this study.

Introduction: The WATCH-DM score can predict risk of heart failure (HF) in patients with diabetes. Hypothesis: Addition of natriuretic peptide (NP) levels will improve WATCH-DM performance in individuals with dysglycemia. Methods: Adults with diabetes/pre-diabetes free of HF at baseline from 4 cohort studies (ARIC, CHS, FHS, and MESA) were included. The integer- [WATCH-DM(i)] and machine learning-based [WATCH-DM(ml)] 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, Brier score, and continuous net reclassification improvement (NRI). Results: Of the 8,938 participants included, 3,554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5-years. Among 5,384 (60.2%) participants with pre-diabetes, 647 (12.0%) developed incident HF. The WATCH-DM(ml) and (i) scores demonstrated high discrimination for predicting HF risk in diabetes (C-indices=0.76 and 0.69), pre-diabetes (0.83 and 0.72), and overall cohort (0.80 and 0.71), respectively, with no evidence of miscalibration (GND=P >0.10). A greater improvement in C-index was observed with the addition of NP-levels at lower WATCH-DM(i) scores with degradation of risk discrimination at higher scores (Fig. A). Calibration was also improved with addition of NP-levels at lower compared to higher WATCH-DM(i) scores (Fig. B). A greater improvement in reclassification was observed by combing WATCH-DM(i) score with selected NP-levels assessment in low (score Conclusions: The WATCH-DM risk score can accurately predict incident HF risk in community-based individuals with dysglycemia. The addition of NP-levels improves risk prediction among adults with low/intermediate but not high HF risk.

Background Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in placebo-controlled trials of patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). Objective To evaluate whether SGLT2 inhibitors and GLP-1 RAs are associated with differential cardiovascular benefit among T2D patients with and without CVD. Design Population-based cohort study. Setting Medicare and 2 U.S. commercial claims data sets (April 2013 to December 2017). Participants 1:1 propensity score-matched adult T2D patients with and without CVD (52 901 and 133 139 matched pairs) initiating SGLT2 inhibitor versus GLP-1 RA therapy. Measurements Primary outcomes were myocardial infarction (MI) or stroke hospitalization and hospitalization for heart failure (HHF). Pooled hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, with 95% CIs, controlling for 138 preexposure covariates. Results The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with a slightly lower risk for MI or stroke in patients with CVD (HR, 0.90 [95% CI, 0.82 to 0.98]; RD, -2.47 [CI, -4.45 to -0.50]) but similar risk in those without CVD (HR, 1.07 [CI, 0.97 to 1.18]; RD, 0.38 [CI, -0.30 to 1.07]). The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with reductions in HHF risk regardless of baseline CVD in patients with CVD (HR, 0.71 [CI, 0.64 to 0.79]; RD, -4.97 [CI, -6.55 to -3.39]) and in those without CVD (HR, 0.69 [CI, 0.56 to 0.85]; RD, -0.58 [CI, -0.91 to -0.25]). Limitation Treatment selection was not randomized. Conclusion Use of SGLT2 inhibitors versus GLP-1 RAs was associated with consistent reductions in HHF risk among T2D patients with and without CVD, although the absolute benefit was greater in patients with CVD. There were no large differences in risk for MI or stroke among T2D patients with and without CVD. Primary funding source Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.

Objective.Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory autoimmune disease with high prevalence of several risk factors for atrial fibrillation/flutter (AF). However, the incidence and risk of AF in SLE have not been well quantified.Methods.We used the United States Medicaid Analytic eXtract from 2007 to 2010 to identify beneficiaries aged 18–65 years, with prevalent SLE, each matched by age and sex to 4 non-SLE general Medicaid recipients. We estimated the incidence rates (IR) per 1000 person-years (PY) for AF hospitalizations and used multivariable Cox regression to estimate the HR for AF hospitalization.Results.We identified 46,876 US Medicaid recipients with SLE, and 187,504 age- and sex-matched non-SLE controls (93% female; mean age 41.5 ± 12.2 yrs). Known AF risk factors such as hypertension (HTN), cardiovascular disease (CVD), and kidney disease were more prevalent in patients with SLE. During a mean followup of 1.9 ± 1.1 years for SLE, and 1.8 ± 1.1 years for controls, the IR per 1000 PY for AF was 1.4 (95% CI 1.1–1.6) among patients with SLE and 0.7 (95% CI 0.6–0.8) among non-SLE controls. In age- and sex-matched and race-adjusted Cox models, the HR for AF was 1.79 (95% CI 1.43–2.24); after adjustment for baseline HTN and CVD, the adjusted HR was reduced to 1.17 (95% CI 0.92–1.48).Conclusion.SLE was associated with a doubled rate of hospitalization for AF compared to age- and sex-matched general Medicaid patients. In a race-adjusted model, the risk was 80% higher. However, the AF risk factors HTN and CVD were more prevalent among patients with SLE and accounted for the excess risk.

Objective Systemic lupus erythematosus (SLE), which is associated with increased stroke risk, is more prevalent and often more severe among Blacks, Asians, and Hispanics than Whites. We examined racial/ethnic variation in stroke rates and risks, overall and by hemorrhagic versus ischemic subtype, among SLE patients. Methods Within Medicaid (2000–2010), we identified patients aged 18–65 with SLE (≥ 3 ICD-9 710.0 codes, ≥ 30days apart) and ≥12 months of continuous enrollment. Subjects were followed from index date to first stroke event, death, disenrollment, or end of follow-up. Race/ethnicity-specific annual event rates were calculated for stroke overall and by subtypes (hemorrhagic vs. ischemic). We used Cox proportional hazard models to estimate hazard ratios (HR) of stroke by race/ethnicity, adjusting for comorbidities and the competing risk of death. Results Of 65,788 SLE patients, 93.1% were female. Racial/ethnic breakdown was 42% Black, 38% White, 16% Hispanic, 3% Asian, and 1% American Indian/Alaska Natives. Mean follow-up was 3.7 ± 3.0years. After multivariable adjustment, Blacks were at increased risk of overall stroke (HR 1.34 [95%CI 1.18–1.53), hemorrhagic stroke (HR 1.42 [1.00–2.01]), and ischemic stroke (HR 1.33 [1.15–1.52]) compared to Whites. Hispanics were at increased risk of overall stroke (HR 1.25 [1.06–1.47)] and hemorrhagic stroke (HR 1.79 [95% CI 1.22–2.61]), but not ischemic stroke, compared to Whites. Conclusion Among SLE patients enrolled in Medicaid, we observed elevated stroke risk (overall and by subtype) among Blacks and Hispanics compared to Whites, suggesting the importance of early recognition and screening for stroke risk factors among Blacks and Hispanics.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.)

Background: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure–related mortality. Methods: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure–related mortality. Results: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P P for trend=0.025). The composite of HHF or heart failure–related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78–1.29) for 50 mg, 0.88 (95% CI, 0.68–1.13) for 150 mg, and 0.78 (95% CI, 0.60–1.02) for 300 mg ( P for trend=0.042). Conclusions: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure–related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846.

Objective Cardiovascular disease (CVD) risks in systemic lupus erythematosus (SLE) are similar to those in diabetes mellitus (DM). We investigated whether the numbers of lipid tests and statin prescriptions in patients with SLE are comparable with those in patients with DM and those in individuals without either disease. Methods Using Analytic eXtract files from 29 states for 2007-2010, we identified a cohort of US Medicaid beneficiaries, ages 18-65 years, with prevalent SLE. Each SLE patient was matched for age and sex with 2 patients with DM and 4 individuals in the general Medicaid population who did not have either SLE or DM. We compared the proportions of patients in each cohort who received ≥1 lipid test and ≥1 statin prescription during 1-year follow-up. We used multivariable logistic regression to calculate the odds of lipid testing and receiving prescriptions for statins and conditional logistic regression to compare the matched cohorts. Results We identified 3 Medicaid cohorts: 25,950 patients with SLE, 51,900 patients with DM, and 103,800 Medicaid recipients without either condition. In these cohorts, lipid testing was performed in 24% of patients in the SLE group, 43% of patients in the DM group, and 16% of individuals in the group with neither condition, and statin prescriptions were dispensed in 11%, 33%, and 7% of these groups, respectively. SLE patients were 66% less likely (odds ratio [OR] 0.34, 95% confidence interval [95% CI] 0.34-0.35) to have lipid tests and 82% less likely (OR 0.18, 95% CI 0.18-0.18) to fill a statin prescription compared with DM patients. SLE patients were also less likely (OR 0.89, 95% CI 0.84-0.94) to fill a statin prescription compared with individuals in the general Medicaid population. Conclusion Despite having an elevated risk of CVD, SLE patients received less lipid testing and received fewer statin prescriptions compared with age- and sex-matched DM patients and individuals in the general Medicaid population; this gap should be a target for improvement.

James L. Januzzi, Jr, MD, FACC, Chair Tariq Ahmad, MD, MPH, FACC Brendan Everett, MD, FACC William Hucker, MD, PHD Dharam J. Kumbhani, MD, SM, FACC Joseph E. Marine, MD, FACC Pamela B. Morris, MD, FACC Robert N. Piana, MD, FACC Sunil V. Rao, MD, FACC Marielle Scherrer-Crosbie, MD, PhD

Objectives SLE patients have elevated cardiovascular disease (CVD) risk, but it is unclear whether this risk is affected by choice of immunosuppressive drug. We compared CVD risks among SLE patients starting MMF, CYC or AZA. Methods Using Medicaid Analytic eXtract (2000–2012), adult SLE patients starting MMF, CYC or AZA were identified and propensity scores (PS) were estimated for receipt of MMF vs CYC and MMF vs AZA. We examined rates of first CVD event (primary outcome), all-cause mortality, and a composite of first CVD event and all-cause mortality (secondary outcomes). After 1:1 PS-matching, Fine–Gray regression models estimated subdistribution hazard ratios (HRs.d.) for risk of CVD events. Cox regression models estimated HRs for all-cause mortality. The primary analysis was as-treated; 6- and 12-month intention-to-treat (ITT) analyses were secondary. Results We studied 680 PS-matched pairs of patients with SLE initiating MMF vs CYC and 1871 pairs initiating MMF vs AZA. Risk of first CVD event was non-significantly reduced for MMF vs CYC [HRs.d 0.72 (95% CI: 0.37, 1.39)] and for MMF vs AZA [HRs.d 0.88 (95% CI: 0.59, 1.32)] groups. In the 12-month ITT, first CVD event risk was lower among MMF than AZA new users [HRs.d 0.68 (95% CI: 0.47, 0.98)]. Conclusion In this head-to-head PS-matched analysis, CVD event risks among SLE patients starting MMF vs CYC or AZA were not statistically reduced except in one 12-month ITT analysis of MMF vs AZA, suggesting longer-term use may convey benefit. Further studies of potential cardioprotective benefit of MMF are necessary.

Introduction: While patients with dysglycemia and known CV disease face high risks of transition to HF and benefit from risk reduction strategies (such as SGLT-2 inhibitors), identification of at-risk patients without CV disease for allocation of primary prevention interventions is less clear. Biomarkers may improve risk stratification and inform targeted application of preventive strategies. Methods: Participants free of CV disease from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were included. A biomarker score was developed incorporating hs-cTnT ≥ 6 ng/L, NT-proBNP ≥ 100 pg/mL, hs-CRP ≥ 3 mg/L, and LVH by electrocardiogram. Among participants with dysglycemia, 5-year risks of incident HF and the number of HF events potentially prevented per 1,000 participants treated with an SGLT-2 inhibitor for 5-years were estimated. Results: Among 6,799 participants with prediabetes (66.8%) and diabetes (33.3%), there were 891 incident HF events over median follow-up of 17 years. The biomarker score alone demonstrated good discrimination and calibration for predicting 5-year HF risk [C-statistic 0.76 (0.71 to 0.81), calibration p value = 0.62]. Among those with dysglycemia, 5-year risk of HF in the very low (score = 0) and low biomarker score groups (score = 1) were similar to that observed among individuals with euglycemia (0.74%). The 5-year risk of HF increased in a graded fashion across increasing biomarker score groups. For every 1,000 participants with diabetes treated with an SGLT-2 inhibitor for 5-years, the estimated number of HF events prevented was estimated to be 4, 5, 14, and 41, respectively for individuals with scores of 0, 1, 2, and 3-4. Conclusions: Among adults with prediabetes and diabetes, a biomarker score can inform HF risk stratification. Individuals with diabetes and high biomarker scores face the highest risk of HF and are expected to benefit the most from SGLT-2 inhibitors.

Objective: Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among persons with type 2 diabetes mellitus (T2DM), but uptake in practice appears restricted to certain demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries. Methods: We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of non-insulin antihyperglycemic therapies. We used 2012-2017 National & State Medicaid data to compare prescription claims and costs between states that did (n=25) and did not expand (n=26) Medicaid by January 2014. Results: Following Medicaid expansion in 2014, average non-insulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in non-expansion states. For SGLT2i and GLP-1RA, quarterly growth rates per-1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for non-expansion states, respectively. Expansion states had faster utilization and total spending growth in SGLT2i and GLP-1RA than non-expansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion vs. non-expansion states was 1.68 (1.09 to 2.26;P Conclusion: Use of non-insulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and non-expansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.

Patients with established cardiovascular disease are at high risk for recurrent myocardial infarction, stroke, and cardiovascular death. The term residual risk refers to this risk that persists, even after optimal treatment. Considerable progress has been made to understand the biological basis of residual risk and to devise therapies that can safely and effectively reduce risk. The presence of ongoing subclinical vascular inflammation is known to be a marker of elevated residual risk, and reductions in measures of vascular inflammation predict improved outcome in these patients. Recent trials of anti-inflammatory agents have specifically tested the hypothesis that inflammation reduction reduces residual cardiovascular risk. Most prominent among these are the CANTOS, COLCOT, and CIRT trials. CANTOS enrolled patients with prior myocardial infarction (MI) and a high-sensitivity C-reactive protein ≥ 2 mg/L and reported a 15% reduction in major adverse cardiovascular events (MACE; HR 0.85, 95% CI 0.74–0.98) with the interleukin-1β inhibitor canakinumab. In COLCOT, colchicine 0.5 mg daily led to a 23% relative risk reduction (HR 0.77, 95% CI 0.61–0.96) in major vascular events in patients with recent acute coronary syndrome. By contrast, CIRT was stopped early for lack of benefit of low-dose methotrexate in preventing MACE in patients with coronary artery disease and either type 2 diabetes or the metabolic syndrome. Ongoing subclinical inflammation is an important marker of risk in patients with established cardiovascular disease, and novel therapies targeted at specific inflammatory pathways now demonstrate efficacy for the prevention of major adverse cardiovascular events.

ObjectiveTo estimate the rate of lower limb amputation among adults newly prescribed canagliflozin according to age and cardiovascular disease.DesignPopulation based, new user, cohort study.Data sourcesTwo commercial and Medicare claims databases, 2013-17.ParticipantsPatients newly prescribed canagliflozin were propensity score matched 1:1 with patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. Hazard ratios and rate differences per 1000 person years were computed for the rate of lower limb amputation in the following four groups: group 1, patients aged less than 65 years without baseline cardiovascular disease; group 2, patients aged less than 65 with baseline cardiovascular disease; group 3, patients aged 65 or older without baseline cardiovascular disease; group 4, patients aged 65 or older with baseline cardiovascular disease. Within each group, pooled hazard ratio and rate difference per 1000 person years were calculated by meta-analysis.InterventionCanagliflozin versus a GLP-1 agonist.Main outcome measuresLower limb amputation requiring surgery.ResultsAcross the three databases, 310 840 propensity score matched adults who started canagliflozin or a GLP-1 agonist were identified. The hazard ratio and rate difference per 1000 person years for amputation in adults receiving canagliflozin compared with a GLP-1 agonist for each group was: group 1, hazard ratio 1.09 (95% confidence interval 0.83 to 1.43), rate difference 0.12 (−0.31 to 0.55); group 2, hazard ratio 1.18 (0.86 to 1.62), rate difference 1.06 (−1.77 to 3.89); group 3, hazard ratio 1.30 (0.52 to 3.26), rate difference 0.47 (−0.73 to 1.67); and group 4, hazard ratio 1.73 (1.30 to 2.29), rate difference 3.66 (1.74 to 5.59).ConclusionsThe increase in rate of amputation with canagliflozin was small and most apparent on an absolute scale for adults aged 65 or older with baseline cardiovascular disease, resulting in a number needed to treat for an additional harmful outcome of 556 patients at six months (that is, 18 more amputations per 10 000 people who received canagliflozin). These results help to contextualize the risk of amputation with canagliflozin in routine care.

Objectives This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions. Background Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown. Methods Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4). Results The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group. Conclusions Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies.

Background: Certain antihyperglycemic therapies modify CV disease courses in DM, but their uptake in practice appears limited among low-income adults. Methods: We employed a difference-in-difference (DiD) design to study the association between Medicaid Expansion and non-insulin antihyperglycemic prescriptions. We used 2012-2017 National and State Medicaid data to compare prescription claims between states that did (n=25) and did not expand (n=26) Medicaid by Jan 2014. Results: Following Medicaid Expansion, average quarterly non-insulin antihyperglycemic therapies/1000 enrollees increased by 4% in expansion and 2% in non-expansion states (left panel) with modest variation (right panel). Use of SGLT2i and GLP-1RA grew faster in early expansion than non-expansion states. DiD estimates for prescription change after Medicaid Expansion between expansion vs. non-expansion states was 1.6 (1.00 to 2.20; P Conclusion: Medicaid Expansion was associated with greater access to non-insulin antihyperglycemic therapies, including GLP-1RA, among newly insured low-income adults, even after accounting for more DM detection. Future studies are needed to understand if policies facilitating these therapeutic changes impact CV health. Disclosure A. Sumarsono: None. L. Buckley: None. S.R. Machado: None. R.K. Wadhera: None. H. Warraich: None. R.J. Desai: Research Support; Self; Bayer AG, Novartis AG. B.M. Everett: Consultant; Self; Amarin Corporation, Amgen, Merck & Co., Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Roche Diagnostic USA. Consultant; Spouse/Partner; Sequana. Consultant; Self; U.S. Food and Drug Administration. Research Support; Self; National Heart, Lung, and Blood Institute. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. G.C. Fonarow: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Medtronic, Novartis Pharmaceuticals Corporation. J. Butler: Consultant; Self; Amgen, Array BioPharma, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife Co., Ltd., Janssen Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Relypsa, Inc., VIfor. A. Pandey: None. M. Vaduganathan: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Relypsa, Inc. Consultant; Self; Amgen, AstraZeneca, Baxter.

Background Inflammation reduction with the interleukin (IL)-1β inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown. Objectives This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events. Methods We randomized 10,061 patients to placebo or canakinumab 50 mg, 150 mg, or 300 mg once every 3 months and compared the rates of the composite of all serious cardiovascular events (MI, stroke, coronary revascularization, and cardiovascular death) in active versus placebo groups. We used negative binomial regression to account for correlations among repeated events in the same person and to estimate rate ratios and 95% confidence intervals. Results During a median of 3.7 years of follow-up, 3,417 total serious cardiovascular events occurred in 2,003 individuals among the 10,061 unique patients randomized. Canakinumab reduced the rates of total serious cardiovascular events, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 10.4, 8.4, 8.3, and 8.2, respectively. The corresponding rate ratios (95% confidence intervals) compared with placebo were 0.80 (0.69 to 0.93) for 50 mg, 0.79 (0.68 to 0.92) for 150 mg, and 0.78 (0.67 to 0.91) for 300 mg. Conclusions Anti-inflammatory therapy with canakinumab significantly reduced the total number of cardiovascular events in patients with prior MI and evidence of residual inflammatory risk. (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events] (CANTOS); NCT01327846

OBJECTIVE Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among patients with type 2 diabetes, but early uptake in practice appears restricted to particular demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries. RESEARCH DESIGN AND METHODS We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of noninsulin antihyperglycemic therapies. We used 2012–2017 national and state Medicaid data to compare prescription claims and costs between states that did (n = 25) and did not expand (n = 26) Medicaid by January 2014. RESULTS Following Medicaid expansion in 2014, average noninsulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in nonexpansion states. For sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA), quarterly growth rates per 1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for nonexpansion states, respectively. Expansion states had faster utilization of SGLT2i and GLP-1RA than nonexpansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion versus nonexpansion states was 1.68 (95% CI 1.09–2.26; P < 0.001) for all noninsulin therapies, 0.125 (−0.003 to 0.25; P = 0.056) for SGLT2i, and 0.12 (0.055–0.18; P < 0.001) for GLP-1RA. CONCLUSIONS Use of noninsulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and nonexpansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.

OBJECTIVE To 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 METHODS Using data from 8,756 patients free at baseline of HF, with RESULTS Over a median follow-up of 4.9 years, 319 patients (3.6%) developed incident HF. The RSF models demonstrated better discrimination than the best performing Cox-based method (C-index 0.77 [95% CI 0.75–0.80] vs. 0.73 [0.70–0.76] respectively) and had acceptable calibration (Hosmer-Lemeshow statistic χ2 = 9.63, P = 0.29) in the internal validation data set. From the identified predictors, an integer-based risk score for 5-year HF incidence was created: the WATCH-DM (Weight [BMI], Age, hyperTension, Creatinine, HDL-C, Diabetes control [fasting plasma glucose], QRS Duration, MI, and CABG) risk score. Each 1-unit increment in the risk score was associated with a 24% higher relative risk of HF within 5 years. The cumulative 5-year incidence of HF increased in a graded fashion from 1.1% in quintile 1 (WATCH-DM score ≤7) to 17.4% in quintile 5 (WATCH-DM score ≥14). In the external validation cohort, the RSF-based risk prediction model and the WATCH-DM risk score performed well with good discrimination (C-index = 0.74 and 0.70, respectively), acceptable calibration (P ≥0.20 for both), and broad risk stratification (5-year HF risk range from 2.5 to 18.7% across quintiles 1–5). CONCLUSIONS We developed and validated a novel, machine learning–derived risk score that integrates readily available clinical, laboratory, and electrocardiographic variables to predict the risk of HF among outpatients with T2DM.

Aims Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P

OBJECTIVE Current validated cardiovascular (CV) risk estimates were developed in populations with relatively stable levels of inflammation, whereas patients with rheumatoid arthritis (RA) routinely experience significant changes in inflammation. This study was undertaken to test whether changes in inflammation affect estimated CV risk as measured using validated population-based risk calculators. METHODS Participants in a prospective RA cohort who experienced a decrease or an increase of ≥10 mg/liter in the C-reactive protein (CRP) level at 2 consecutive time points 1 year apart (CRP decrease group and CRP increase group, respectively) were included in this study. We estimated 10-year CV risk using the following calculators: Framingham Risk Score, 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Score, Reynolds Risk Score (RRS), and QRISK2. Of these calculators, only the RRS includes a variable addressing the CRP level. Paired t-tests were performed to compare risk scores at baseline and 1-year follow-up. We calculated the correlations between the changes in risk scores and changes in pro-B-type natriuretic peptide (pro BNP), a surrogate marker of CV risk. RESULTS One hundred eighty RA patients were included in the study (mean age 57.8 years, 84% female, 80% seropositive). Of the calculators studied, only the RRS was sensitive to changes in inflammation; an increase in inflammation was associated with increased estimated CV risk (P < 0.0001), and only the RRS was correlated with changes in proBNP (r = 0.17, P = 0.03). CONCLUSION Our data showed no significant change in CV risk estimated using validated general population CV risk calculators except for the RRS. These findings suggest that CV risk may be modulated by changes in inflammation in RA, which is not typically considered when using existing CV risk calculators.

Background Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. Objectives The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD. Methods Stable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. Results Of 10,061 participants, 1,875 (18.6%) had baseline eGFR Conclusions IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).

Objective Systemic lupus erythematosus (SLE) is more prevalent and results in more severe outcomes among blacks, Asians, and Hispanics than among whites. Cardiovascular disease (CVD) is the leading cause of death among SLE patients. We undertook this study to examine racial/ethnic variations in risk of CVD events among SLE patients. Methods Within the Medicaid Analytic eXtract from 2000 to 2010, we identified patients ages 18–65 years with SLE (≥3 International Classification of Diseases, Ninth Revision 710.0 codes, ≥30 days apart) and with ≥12 months of continuous enrollment. Subjects were followed up from the index date to the first CVD event (myocardial infarction [MI] or stroke), death, disenrollment, loss to follow-up, or end of follow-up period. Race/ethnicity-specific annual CVD event rates were calculated. Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs), accounting for competing risk of death and adjusting for baseline demographics and comorbidities. Results Of 65,788 SLE patients, 93.1% were women and ∼42% were black, 38% were white, 16% were Hispanic, 3% were Asian, and 1% were American Indian/Alaska Native. Mean ± SD follow-up was 3.8 ± 3.1 years. CVD event rates were highest among blacks (incidence rate [IR] 10.57 [95% CI 9.96–11.22]) and lowest among Asians (IR 6.63 [95% CI 4.97–8.85]). After multivariable adjustment, risk of CVD events was increased among blacks (HR 1.14 [95% CI 1.03–1.26]) compared to whites. Hispanics and Asians had a lower risk of MI (HR 0.61 [95% CI 0.48–0.77] and HR 0.57 [95% CI 0.34–0.96], respectively), while blacks and Hispanics had a higher risk of stroke (HR 1.31 [95% CI 1.15–1.49] and HR 1.22 [95% CI 1.03–1.44], respectively). Conclusion Among SLE patients enrolled in Medicaid, the risk of MI was lower among Hispanics and Asians compared to whites, while the risk of stroke was elevated among blacks and Hispanics compared to whites.

This special issue of Clinical Chemistry includes multiple important studies on clinical and analytic aspects of established and emerging biomarkers for cardiovascular disease. Several biomarkers featured in these pages—cardiac troponin and measures of natriuretic peptides, as well as validated biomarkers such as high-sensitivity C-reactive protein (hsCRP)2 and coronary calcium scores—can improve the performance of risk prediction algorithms based solely on more traditional cardiovascular risk factors. Yet while patients and providers are interested in ever more “personalized” recommendations for risk prevention, the major guidelines from the American College of Cardiology, American Heart Association, European Society of Cardiology, and US Preventive Services Task Force remain focused on absolute risk based on epidemiologic modeling to determine when to give preventive treatments such as aspirin and statin therapy. Thus, considerable tension exists between traditional epidemiologic approaches to risk prediction for the “average patient” and the biologic reality that different pathophysiologic processes are highly relevant for the individual patients seen in daily practice. The biomarkers with the broadest application in cardiovascular medicine are cholesterol and blood pressure. These markers predict cardiovascular risk, identify patients for whom a particular therapy has benefit, and serve as treatment targets. As “factors of risk” for coronary heart disease, blood pressure and cholesterol are nearly as old as the specialty of cardiovascular medicine and were described by Dr. William B. Kannel and colleagues in their seminal publication from the Framingham Heart Study in 1961 (1). In the ensuing 55 years, there has been a steady year-over-year increase in the publications indexed with “cardiovascular biomarkers” in PubMed, both as an absolute number of publications (Figure 1A) and a proportion of all “cardiovascular” publications indexed (Figure 1B). And yet, despite the predictive accuracy or prognostic value of many of these biomarkers, none was found to offer sufficient new information …

Assays for cardiac troponin have become increasingly sensitive, and are now able to detect very low concentrations of circulating cardiac troponin in a substantial proportion of stable patients who are not suspected of having an acute myocardial infarction. These low concentrations of cardiac troponin are frequently well within the range of what is considered normal but are nonetheless associated with a significant increase in the risk of major cardiovascular events, including heart failure, myocardial infarction, and death in patients with and without established cardiovascular disease. The strength and consistency of these associations, and the fact that adding cardiac troponin to traditional risk factors improves the accuracy of existing cardiovascular risk prediction algorithms, raises the possibility of using cardiac troponin for therapeutic decision-making in ambulatory populations. Cardiac troponin is a powerful predictor of cardiovascular risk on the population level, but a specific intervention that can mitigate cardiac troponin-associated risk has not been identified. Thus, the therapeutic implications of cardiac troponin elevations for individual patients remain unclear. Ongoing research seeks to better understand the underlying cause of cardiac troponin release and to identify therapeutic interventions that can effectively mitigate cardiac troponin-associated cardiovascular risk. The development of high-sensitivity assays for cardiac troponin offers the opportunity to gain tremendous insight into the causes and consequences of chronic myocardial injury, and may, in the future, help guide therapy directed at improving the outcomes of ambulatory patients at high risk for cardiovascular events.

Article, see p 1435 Atherosclerotic peripheral artery disease (PAD) is a growing, yet underappreciated global health issue.1 PAD affects >200 million individuals worldwide,2 and atherosclerotic disease of the lower extremities confers a high risk of cardiovascular events and death.3 Patients with PAD have a 2.5-fold increased risk of myocardial infarction and a 3.1-fold increased risk of stroke in comparison with healthy individuals.3 In addition, individuals with PAD are at heightened risk for lower extremity ulceration, acute limb ischemia, surgical and percutaneous revascularization, and amputation. Given the prevalence and morbidity of PAD, there is a clear need for therapies that improve PAD-specific outcomes, such as amputation, and reduce the risk of other major cardiovascular events that are common among patients with atherosclerosis, as well. Current professional society guidelines recommend statin therapy for all individuals with PAD.4,5 Unfortunately, much of the data regarding lipid-lowering therapy for PAD have been extrapolated from studies of coronary artery disease, and few studies have specifically examined limb outcomes. The Heart Protection Study randomly assigned 20 536 subjects, 6748 of whom carried a diagnosis of PAD, to either simvastatin 40 mg daily or placebo with a mean follow-up of 5 years.6 In the overall study population, simvastatin was associated with a 16% relative risk reduction in peripheral vascular events, which was driven primarily by a 20% reduction in noncoronary revascularization. It is noteworthy that this end point included not only lower extremity arterial procedures, but …

In 2015, an estimated 107.7 million children and 603.7 million adults were classified as obese worldwide. In that year, obesity contributed directly to 4 million deaths and 120 million disability-adjusted life-years, and the majority of those deaths and that disability have been attributed to obesity-related cardiovascular disease (CVD)4 (1). Although some of the excess in obesity-related cardiovascular mortality is attributable to obesity's association with hypertension, hyperlipidemia, insulin resistance, type 2 diabetes mellitus, and obstructive sleep apnea, a significant portion is not mediated by these established CVD risk factors. The independent contribution of obesity to CVD risk, and the ways in which changes in weight and obesity status might alter this contribution, remains poorly understood. Because high-sensitivity assays for cardiac troponin can detect even small amounts of myocardial injury, they may serve as useful tools to help elucidate the effects of obesity on the myocardium. Numerous epidemiological studies suggest that obesity contributes to an increased risk of CVD, including heart failure, via mechanisms that are independent of traditional risk factors. In the Framingham Heart Study, obese individuals had double the risk of incident heart failure, and a recent metaanalysis of 23 prospective studies found that each 5-unit increase in body mass index (BMI) was associated with a 41% increase in the risk of heart failure incidence (relative risk, 1.41; 95% CI, 1.34–1.47) (2, 3). These associations were adjusted for possible mediating factors, including hypertension, type 2 diabetes mellitus, and dyslipidemia. Circulating concentrations of high-sensitivity cardiac troponin T (hs-cTnT) are sensitive measures of ongoing myocardial injury, and are closely associated with the risk of major adverse cardiovascular events (4–6). In the Dallas Heart Study, increased hs-cTnT concentrations were associated with left ventricular hypertrophy and left ventricular systolic …

Background While there exists significant inter-individual variability in low density lipoprotein cholesterol (LDL-C) response to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, predictors of this response remain uncertain. The Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) randomized control trials evaluated the efficacy of bococizumab, a humanized murine PCSK9 antibody, in patients at high cardiovascular risk. Purpose This study's purpose is to determine predictors of attenuated LDL-C response to bococizumab. Methods SPIRE 1 and 2 trial subjects allocated to bococizumab (n=13,675) were included. Subjects with an increase in LDL-C or non-compliance to bococizumab, or development of anti-drug or neutralizing antibodies were excluded. The remaining 8281 subjects were divided into quintiles of percent LDL-C reduction from baseline to 14 weeks. The first quintile (Q1) was considered an attenuated response. Multivariate logistic regression was used to discern significant predictors of attenuated response (Q1) compared to robust response (Q5). Results Q1 included 1657 subjects with median 35% LDL-C reduction (range 0.4% - 48%), whereas Q5 included 1658 subjects with median 83% LDL-C reduction (range 78% - 99%). Female sex, diabetes, white race, younger age, higher baseline non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) were significantly associated with an attenuated response compared to a robust response (each p Multivariate logistic regression for attenuated percent LDL-C response to bococizumab from baseline to 14 week Baseline characteristic Adjusted odds ratio (95% confidence interval) P-value Female 3.30 (2.72, 4.00) Conclusions In the SPIRE 1 and 2 trials, excluding subjects with anti-drug and neutralizing antibodies, significant predictors of an attenuated LDL-C response to PCSK9 inhibition with bococizumab included female sex, diabetes, younger age and white race. Acknowledgement/Funding Pfizer

OBJECTIVE: Systemic lupus erythematosus (SLE) severity, reflecting both disease intensity and duration, is heterogeneous making it challenging to study in administrative databases where severity may confound or mediate associations with outcomes. Garris et al developed an administrative claims-based algorithm employing claims over a 1-year period to classify SLE severity as mild, moderate or severe. We sought to compare this administrative algorithm to a measure of SLE activity, the SLE Disease Activity Index-2000 (SLEDAI-2K) score at clinical visits. METHODS: We identified 100 SLE patients followed in the Brigham and Women’s Hospital (BWH) Lupus Center (in 2008–2010) with SLEDAI-2K scores at each visit over a 1-year period per person. We obtained data for the Garris algorithm for the same year per subject. We compared Garris SLE severity to the highest SLEDAI-2K in that year, with SLEDAI-2K categories of mild 6. We compared classification using weighted kappa statistics, and positive and negative predictive values (PPV, NPV). We also assessed the binary comparison of mild vs. moderate/severe. We calculated sensitivity, specificity, and McNemar’s test. RESULTS: We analyzed 377 SLEDAI-2K assessments (mean 3.8 [SD 2.6] per subject/year). For classifying moderate/severe vs. mild SLE severity, the sensitivity was 85.7%, specificity 67.6%, PPV 81.8% and NPV 73.5%. CONCLUSION: The Garris algorithm for classifying SLE severity in administrative datasets had moderate agreement for classification of mild vs. moderate/severe SLE activity assessed by SLEDAI-2K assessments in an academic lupus center. It may be a useful tool for classifying SLE severity in administrative database studies.