N-Glycosylation Profiles of Immunoglobulin G and Future Cardiovascular Events.

BACKGROUND: Posttranslational glycosylation of IgG can modulate its inflammatory capacity through structural variations. We examined the association of baseline IgG N-glycans and an IgG glycan score with incident cardiovascular disease (CVD). METHODS: IgG N-glycans were measured in 2 nested CVD case-control studies: JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681; primary prevention; discovery; Npairs=162); and TNT trial (Treating to New Targets; NCT00327691; secondary prevention; validation; Npairs=397). Using conditional logistic regression, we investigated the association of future CVD with baseline IgG N-glycans and a glycan score adjusting for clinical risk factors (statin treatment, age, sex, race, lipids, hypertension, and smoking) in JUPITER. Significant associations were validated in TNT, using a similar model further adjusted for diabetes. Using least absolute shrinkage and selection operator regression, an IgG glycan score was derived in JUPITER as a linear combination of selected IgG N-glycans. RESULTS: Six IgG N-glycans were associated with CVD in both studies: an agalactosylated glycan (IgG-GP4) was positively associated, while 3 digalactosylated glycans (IgG glycan peaks 12, 13, 14) and 2 monosialylated glycans (IgG glycan peaks 18, 20) were negatively associated with CVD after multiple testing correction (overall false discovery rate <0.05). Four selected IgG N-glycans comprised the IgG glycan score, which was associated with CVD in JUPITER (adjusted hazard ratio per glycan score SD, 2.08 [95% CI, 1.52-2.84]) and validated in TNT (adjusted hazard ratio per SD, 1.20 [95% CI, 1.03-1.39]). The area under the curve changed from 0.693 for the model without the score to 0.728 with the score in JUPITER (PLRT=1.1×10-6) and from 0.635 to 0.637 in TNT (PLRT=0.017). CONCLUSIONS: An IgG N-glycan profile was associated with incident CVD in 2 populations (primary and secondary prevention), involving an agalactosylated glycan associated with increased risk of CVD, while several digalactosylated and sialylated IgG glycans associated with decreased risk. An IgG glycan score was positively associated with future CVD.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

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.).

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Effectiveness and safety of empagliflozin: final results from the EMPRISE study.

AIMS/HYPOTHESIS: Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases. METHODS: We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure. RESULTS: We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD -2.08 [95% CI (-3.26, -0.90]), HHF (HR 0.50 [0.44, 0.56]; RD -5.35 [-6.22, -4.49]), MACE (HR 0.73 [0.62, 0.86]; RD -6.37 [-8.98, -3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD -10.36 [-12.63, -8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD -2.39 [-3.08, -1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD -2.46 [-3.32, -1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD -9.49 [-16.97, -2.10]); and similar risks of other safety events. CONCLUSIONS/INTERPRETATION: Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer.

Effect of Daily Vitamin D Supplementation on Risk of Upper Respiratory Infection in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. RESULTS: Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI}, .86-1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI, .28-1.30]). Statistical power to assess effect modification in other subgroups was limited. CONCLUSIONS: In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259.

Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials.

BACKGROUND: Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins. METHODS: We did a collaborative analysis of patients with-or at high risk of-atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment. FINDINGS: 31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20-1·43; p<0·0001), cardiovascular mortality (2·68, 2·22-3·23; p<0·0001), and all-cause mortality (2·42, 2·12-2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98-1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07-1·50; p=0·0086) and all-cause death (1·16, 1·03-1·32; p=0·025). INTERPRETATION: Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk. FUNDING: Kowa Research Institute, Amarin, AstraZeneca.

Plasma Biomarker Profiles for Premature and Nonpremature Coronary Heart Disease in Women.

BACKGROUND: Premature coronary heart disease (CHD) is a major cause of death in women. We aimed to characterize biomarker profiles of women who developed CHD before and after age 65 years. METHODS: In the Women's Health Study (median follow-up 21.5 years), women were grouped by age and timing of incident CHD: baseline age <65 years with premature CHD by age 65 years (25 042 women; 447 events) and baseline age ≥65 years with nonpremature CHD (2982 women; 351 events). Associations of 44 baseline plasma biomarkers measured using standard assays and a nuclear magnetic resonance (NMR)-metabolomics assay were analyzed using Cox models adjusted for clinical risk factors. RESULTS: Twelve biomarkers showed associations only with premature CHD and included lipoprotein(a), which was associated with premature CHD [adjusted hazard ratio (HR) per SD: 1.29 (95% CI 1.17-1.42)] but not with nonpremature CHD [1.09(0.98-1.22)](Pinteraction = 0.02). NMR-measured lipoprotein insulin resistance was associated with the highest risk of premature CHD [1.92 (1.52-2.42)] but was not associated with nonpremature CHD (Pinteraction <0.001). Eleven biomarkers showed stronger associations with premature vs nonpremature CHD, including apolipoprotein B. Nine NMR biomarkers showed no association with premature or nonpremature CHD, whereas 12 biomarkers showed similar significant associations with premature and nonpremature CHD, respectively, including low-density lipoprotein (LDL) cholesterol [1.30(1.20-1.45) and 1.22(1.10-1.35)] and C-reactive protein [1.34(1.19-1.50) and 1.25(1.08-1.44)]. CONCLUSIONS: In women, a profile of 12 biomarkers was selectively associated with premature CHD, driven by lipoprotein(a) and insulin-resistant atherogenic dyslipoproteinemia. This has implications for the development of biomarker panels to screen for premature CHD.

Semiparametric Allocation of Subjects to Cohort Strata.

BACKGROUND: We illustrate a method for stratum assignment in small cohort studies that avoids modeling assumptions. METHODS: Off-the-shelf software ( rgenoud ) made stratum assignments to minimize a loss function built on within-stratum and population-adjusted Euclidean distances. RESULTS: In 100 trials using simulated data of 300 records with a binary treatment and four dissimilar covariate treatment predictors, minimizing a loss based on Euclidean distance reduced covariate imbalance by a median of 99%. Stratification by propensity score and weighting records by the inverse of their probability of treatment reduced imbalance by 76%-89% and 83%-94%, respectively. Loss minimization applied to a cohort of 361 children undergoing immunotherapy achieved nearly complete elimination of covariate differences for important treatment predictors. CONCLUSION: With the availability of semiparametric stratum-assignment algorithms, analysts can tailor loss functions to meet design goals. Here, a loss function that emphasized covariate balance performed well under limited testing.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Intake of Blueberries, Anthocyanins, and Risk of Eye Disease in Women.

BACKGROUND: Blueberries and anthocyanins, their key bioactive component, may improve eye health. However, few long-term studies have examined blueberries and anthocyanins with cataract and age-related macular degeneration (AMD). OBJECTIVES: To investigate the prospective association between blueberry and anthocyanin intake with incident cataract, total AMD, and visually significant AMD among middle-aged and older women. METHODS: A total of 36,653 and 35,402 women initially free of AMD and cataract, respectively, aged ≥45 y from the Women's Health Study provided semiquantitative food frequency questionnaire data on blueberry intake categorized as none, 1-3 servings/mo, 1 serving/wk, or ≥2 servings/wk, plus a combined category of ≥1 serving/wk. Total anthocyanin intake and major subclasses were energy-adjusted and categorized into quintiles. Self-reported risk factors of eye disease were adjusted in multivariable hazard ratios (HRs) (95% confidence intervals [CIs]) of confirmed cataract, AMD, and visually significant AMD with mean follow-up of 11 y. RESULTS: Among the participants, 10.5% consumed ≥1 serving/wk of blueberries, with mean total anthocyanin intake of 11.2 mg/d. Compared to no blueberry intake, women consuming 1-3 servings/mo, 1 serving/wk, and ≥2 servings/wk had corresponding multivariable HRs of total AMD of 0.90 (95% CI: 0.73, 1.11), 0.71 (95% CI: 0.50, 1.00), and 0.36 (95% CI: 0.14, 0.93) (Ptrend = 0.011); those consuming ≥1 servings/wk had an HR of 0.68 (95% CI: 0.47, 0.98). A similar magnitude of HRs were found for visually significant AMD (Ptrend = 0.012) but not for cataract. There were no significant associations between increasing total anthocyanin quintiles and total and visually significant AMD, but there was a modest inverse association with cataract (Ptrend = 0.022), driven by a 10% reduction in cataract in the upper 2 quintiles. CONCLUSIONS: Greater blueberry intake significantly reduced total AMD, but not visually significant AMD or cataract. However, the magnitude of effect for visually significant AMD was similar to total AMD. There was a modest but significant inverse association between dietary anthocyanin intake with cataract but not AMD.

Stratified analysis in comparative effectiveness studies that emulate randomized trials.

PURPOSE: For observational cohort studies that employ matching by propensity scores (PS), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre-stratification in two real-life examples. For both, prior evidence from placebo-controlled randomized clinical trials (RCTs) suggested small or no risk reduction, but observational analysis suggested protection, presumably the result of confounding bias. STUDY DESIGN AND SETTING: The study populations consisted of Medicare beneficiaries (2014-18) with type 2 diabetes initiating either (i) empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or (ii) empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA). The outcome was myocardial infarction or stroke. We estimated hazard ratios (HR) and rate differences (RD) after controlling for 143 pre-exposure covariates via 1:1 PS matching after (1) PS estimation in the total cohort (total-cohort PS-matching) and (2) PS estimation separately by baseline cardiovascular disease (stratified PS matching). RESULTS: Stratified PS matching resulted in HRs that exceeded those from total-cohort PS-matching by 13% and 9%, respectively, for the comparisons of empagliflozin to DPP-4i and GLP-1RA. Against both comparators, HRs and RDs after stratified PS matching were closer to the null, with slightly higher variances (2%-3%) than those after total-cohort PS matching. CONCLUSION: Stratified PS matching produced effect estimates closer to the expected trial findings than total-cohort PS matching. The price paid in increased variance was minimal.

Risk of fall or fracture with concomitant use of prescription opioids and other medications in osteoarthritis patients.

BACKGROUND: Osteoarthritis (OA) patients taking prescription opioids for pain are at increased risk of fall or fracture, and the concomitant use of interacting drugs may further increase the risk of these events. AIMS: To identify prescription opioid-related medication combinations associated with fall or fracture. MATERIALS & METHODS: We conducted a case-crossover-based screening of two administrative claims databases spanning 2003 through 2021. OA patients were aged 40 years or older with at least 365 days of continuous enrollment and 90 days of continuous prescription opioid use before their first eligible fall or fracture event. The primary analysis quantified the odds ratio (OR) between fall and non-opioid medications dispensed in the 90 days before the fall date after adjustment for prescription opioid dosage and confounding using a case-time-control design. A secondary analogous analysis evaluated medications associated with fracture. The false discovery rate (FDR) was used to account for multiple testing. RESULTS: We identified 41 693 OA patients who experienced a fall and 24 891 OA patients who experienced a fracture after at least 90 days of continuous opioid therapy. Top non-opioid medications by ascending p-value with OR > 1 for fall were meloxicam (OR 1.22, FDR = 0.08), metoprolol (OR 1.06, FDR >0.99), and celecoxib (OR 1.13, FDR > 0.99). Top non-opioid medications for fracture were losartan (OR 1.20, FDR = 0.80), alprazolam (OR 1.14, FDR > 0.99), and duloxetine (OR 1.12, FDR = 0.97). CONCLUSION: Clinicians may seek to monitor patients who are co-prescribed drugs that act on the central nervous system, especially in individuals with OA.

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1ß, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. METHODS: Serum levels of interleukin-1ß, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator. RESULTS: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1ß (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1ß (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. CONCLUSIONS: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01492361.

Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis.

OBJECTIVE: Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent. METHODS: Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. RESULTS: 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups-ΔTNFi: -0.24 (SD=0.51), Δtriple therapy: -0.19 (SD=0.51)-without difference between groups (difference in Δs: -0.02, 95% CI -0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (ß=0.04, 95% CI -0.03 to 0.10). CONCLUSION: We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy. TRIAL REGISTRATION NUMBER: NCT02374021.

Effect Measure Modification by Covariates in Mediation: Extending Regression-based Causal Mediation Analysis.

Existing methods for regression-based mediation analysis assume that the exposure-mediator effect, exposure-outcome effect, and mediator-outcome effect are constant across levels of the baseline characteristics of patients. However, investigators often have insight into how these underlying effects may be modified by baseline characteristics and are interested in how the resulting mediation effects, such as the natural direct effect (NDE), the natural indirect effect. (NIE), and the proportion mediated, are modified by these baseline characteristics. Motivated by an empirical example of anti-interleukin-1 therapy's benefit on incident anemia reduction and its mediation by an early change in an inflammatory biomarker, we extended the closed-form regression-based causal mediation analysis with effect measure modification (EMM). Using a simulated numerical example, we demonstrated that naive analysis without considering EMM can give biased estimates of NDE and NIE and visually illustrated how baseline characteristics affect the presence and magnitude of EMM of NDE and NIE. We then applied the extended method to the empirical example informed by pathophysiologic insights into potential EMM by age, diabetes, and baseline inflammation. We found that the proportion modified through the early post-treatment inflammatory biomarker was greater for younger, nondiabetic patients with lower baseline level of inflammation, suggesting differential usefulness of the early post-treatment inflammatory biomarker in monitoring patients depending on baseline characteristics. To facilitate the adoption of EMM considerations in causal mediation analysis by the wider clinical and epidemiologic research communities, we developed a free- and open-source R package, regmedint.

Comparative Safety of Gout Treatment Strategies on Cardiovascular Outcomes Using Observational Data: Clone-censor-weight Target Trial Emulation Approach.

BACKGROUND: We sought to examine the cardiovascular safety of intensive treat-to-target serum urate strategies for gout using Medicare claims data linked to electronic health record laboratory data. METHODS: We selected patients with gout who initiated urate-lowering therapy. We emulated a hypothetical trial comparing the rate of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) among seven different strategies over 24 months. Three aspects were considered in defining increasingly intensive strategies: (1) continuation of urate-lowering therapy, (2) serum urate monitoring, and (3) modification of urate-lowering therapy when serum urate >6 mg/dl. We applied the "clone-censor-weight" method to account for baseline and time-varying confounding. RESULTS: We identified 4402 patients with gout who initiated urate-lowering therapy (mean age 77; male 60%). During a total of 6611 person-years (PY) of follow-up under usual care, the rate of major cardiovascular events (first and recurrent) was 4.5/100 PY (95% CI = 4.0, 5.1). The rate ratios (RRs) suggested reductions (RR point estimates 0.88-0.84) compared with usual care. All 95% CIs were imprecise, but their upper bounds excluded substantial increase in RRs. RRs were closer to 1.0 for the analysis focusing on the first major adverse cardiovascular event during follow-up and on comparison to the strategy requiring continuation of urate-lowering therapy (but not necessarily titration). CONCLUSIONS: Our treatment strategy trial emulation did not find increased risk of major adverse cardiovascular events with intensive urate-lowering strategies. Results may provide reassurance of the cardiovascular safety of intensive treat-to-target serum urate strategies recommended by rheumatology societies.

Relationship between Claims-Based Frailty Index and Eye Care Utilization among Medicare Beneficiaries with Glaucoma.

PURPOSE: To determine differences in eye care utilization by frailty levels among Medicare beneficiaries with glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare fee-for-service beneficiaries over 65 years of age with glaucoma, identified using International Classification of Diseases codes before July 1, 2014. METHODS: By using a validated claims-based frailty index (range, 0-1), beneficiaries were classified as nonfrail/prefrail (0-0.19), mildly frail (0.20-0.29), and moderate-to-severely frail (≥ 0.30). Negative binomial regression analyses were used to estimate incident rate ratios (IRRs) of eye care utilization by frailty levels between July 1, 2014, and December 31, 2016. MAIN OUTCOME MEASURES: Current Procedural Terminology codes for eye examinations and eye care-related office visits; eye care-related inpatient and emergency department (ED) encounters; eye care-related nursing facility and home-visit encounters; visual field (VF) and retinal nerve fiber layer (RNFL) OCT tests; and selective laser trabeculoplasties (SLTs) and glaucoma surgeries. RESULTS: Among 76 260 Medicare beneficiaries with glaucoma, the mean age was 78.9 years (standard deviation, 7.8), female beneficiaries constituted 60.5%, and 78.7% of beneficiaries self-identified as non-Hispanic White. According to a claims-based frailty index, 79.5% of beneficiaries were nonfrail/prefrail, 17.1% were mildly frail, and 3.4% were moderate-to-severely frail. Moderate-to-severely frail beneficiaries were less likely than nonfrail/prefrail beneficiaries to have outpatient encounters (IRR, 0.85, 95% confidence interval [CI], 0.83-0.88); VF tests (IRR, 0.64, 95% CI, 0.60-0.67); RNFL OCT tests (IRR, 0.77, 95% CI, 0.73-0.81); SLT (IRR, 0.74, 95% CI, 0.60-0.92); and glaucoma surgery (IRR, 0.74, 95% CI 0.55-0.99), after adjusting for age, gender, glaucoma severity, race, and socioeconomic status. Compared with nonfrail/prefrail beneficiaries, moderate-to-severely frail beneficiaries had higher rates of inpatient/ED encounters (IRR, 5.03, 95% CI, 2.36-10.71) and nursing facility/home-visit encounters (IRR, 34.89, 95% CI, 14.82-82.13). CONCLUSIONS: Compared with nonfrail/prefrail Medicare beneficiaries with glaucoma, beneficiaries with moderate-to-severe frailty had lower rates of eye care utilization in the outpatient setting and higher rates of utilization in acute care settings. This suggests that frail patients may receive less disease monitoring and fewer interventions for their glaucoma management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Risk of malignant melanoma and non-melanoma skin cancer in rheumatoid arthritis patients initiating methotrexate versus hydroxychloroquine: a cohort study.

OBJECTIVES: To characterise the incidence rate of skin cancer associated with methotrexate and hydroxychloroquine in older adults with rheumatoid arthritis (RA). METHODS: RA patients aged ≥65 years who initiated methotrexate or hydroxychloroquine as their first disease modifying antirheumatic drugs (DMARDs). The primary outcome was new occurrence of any skin cancer (i.e. malignant melanoma or non-melanoma skin cancer; NMSC) based on validated algorithms (positive predictive value >83%). Secondary outcomes were malignant melanoma, NMSC, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We estimated the incidence rates (IRs) and hazard ratios (HRs) for each outcome in the 1:1 propensity score (PS)-matched methotrexate and hydroxychloroquine groups. RESULTS: We included 24,577 PS-matched pairs of methotrexate and hydroxychloroquine initiators. Compared with hydroxychloroquine (IR 25.20/1,000 person-years), methotrexate initiators (IR 26.21/1,000 person-years) had a similar risk of any skin cancer [HR 1.03 -(95%CI 0.92, 1.14)] over a mean follow-up of 388 days. The HR (95%CI) associated with methotrexate was 1.39 (0.87, 2.21) for malignant melanoma, 1.01(0.90, 1.12) for NMSC, 1.37 (1.13, 1.66) for BCC, and 0.79 (0.63, 0.99) for SCC compared with hydroxychloroquine. CONCLUSIONS: In this large cohort of older RA patients initiating methotrexate or hydroxychloroquine as their first DMARD, we found no difference in the risk of skin cancer including malignant melanoma and NMSC. However, for specific components of NMSC, methotrexate initiators had higher risk of BCC but lower risk of SCC compared with hydroxychloroquine initiators.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

BACKGROUND: Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. OBJECTIVE: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. DESIGN: Population-based cohort study. SETTING: Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). PARTICIPANTS: Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. INTERVENTION: First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. MEASUREMENTS: Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. RESULTS: Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. LIMITATION: Treatment selection was not randomized. CONCLUSION: As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. PRIMARY FUNDING SOURCE: Brigham and Women's Hospital and Harvard Medical School.

Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses: Results of 32 Clinical Trials.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates. Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs. Design, Setting, and Participants: New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022. Exposures: Therapies for multiple clinical conditions were included. Main Outcomes and Measures: Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference. Results: In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement). Conclusions and Relevance: Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.