Aruna D. Pradhan

Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial

BACKGROUND In view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use. METHODS In the randomised, double-blind JUPITER trial, 17,603 men and women without previous cardiovascular disease or diabetes were randomly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation, or cardiovascular death) and the protocol-prespecified secondary endpoints of venous thromboembolism, all-cause mortality, and incident physician-reported diabetes. In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m(2) or higher, or glycated haemoglobin A(1c) greater than 6%. The trial is registered at ClinicalTrials.gov, NCT00239681. FINDINGS Trial participants with one or more major diabetes risk factor (n=11,508) were at higher risk of developing diabetes than were those without a major risk factor (n=6095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio [HR] 0·61, 95% CI 0·47-0·79, p=0·0001), a 36% reduction in venous thromboembolism (0·64, 0·39-1·06, p=0·08), a 17% reduction in total mortality (0·83, 0·64-1·07, p=0·15), and a 28% increase in diabetes (1·28, 1·07-1·54, p=0·01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0·48, 95% CI 0·33-0·68, p=0·0001), a 53% reduction in venous thromboembolism (0·47, 0·21-1·03, p=0·05), a 22% reduction in total mortality (0·78, 0·59-1·03, p=0·08), and no increase in diabetes (0·99, 0·45-2·21, p=0·99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1·25, 95% CI 1·05-1·49, p=0·01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0·63, 95% CI 0·25-1·60) was consistent with that for the trial as a whole (0·56, 0·46-0·69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5·4 weeks (84·3 [SD 47·8] weeks on rosuvastatin vs 89·7 [50·4] weeks on placebo). INTERPRETATION In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes. FUNDING AstraZeneca.

Platelet Expression Profiling and Clinical Validation of Myeloid-Related Protein-14 as a Novel Determinant of Cardiovascular Events

Background— Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. Methods and Results— We profiled platelet mRNA from patients with acute ST-segment–elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 &mgr;g/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. Conclusions— The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.

Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.

BACKGROUND Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. DESIGN The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. SUMMARY CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.

Relationship of total and abdominal adiposity with CRP and IL-6 in women

PURPOSE To examine the relationship between different measures of adiposity as predictors of C-reactive protein (CRP) and interleukin-6 (IL-6) levels. METHODS A cross-sectional study of 733 women free from preexisting cardiovascular disease or cancer at baseline. MEASUREMENTS Total adiposity, as measured by body mass index (BMI). Abdominal adiposity, as measured by waist circumference (WC) and waist/hip ratio (WHR). High sensitivity CRP levels and IL-6 levels. RESULTS BMI, WHR, and WC were all significantly correlated with CRP and IL-6, throughout the anthropometric spectrum. After adjustment for risk factors, the odds ratios (ORs) were 12.2 (95% CI, 6.44-23.0) for elevated CRP (>/=75th percentile) and 4.13 (95% CI, 2.37-7.18) for elevated IL-6 (>/=75th percentile) in comparisons of extreme BMI quartiles. Among women in the highest WC quartile, the OR for elevated CRP and IL-6 were 8.57 (95% CI, 4.59-16.0) and 4.40 (95%CI, 2.46-7.89), while ORs for the highest WHR quartile were 2.88 (95% CI, 1.60-5.19) and 1.76 (95% CI, 1.03-3.01), respectively. Compared with lean nonusers, women in the highest BMI quartile who did not use hormone therapy (HT) had an OR for elevated CRP of 7.79 (95% CI, 2.08-29.2) vs. 31.6 (95% CI, 7.97-125.6) for current hormone users. CONCLUSIONS Indices of both total and abdominal adiposity were strongly associated with significant increased levels of CRP and IL-6. This association was evident across the entire spectrum of BMI.

Soluble Intercellular Adhesion Molecule-1, Soluble Vascular Adhesion Molecule-1, and the Development of Symptomatic Peripheral Arterial Disease in Men

Background—Elevated levels of soluble cellular adhesion molecules have been linked to the development of occlusive coronary events in otherwise healthy individuals. It is not certain, however, whether similar relationships exist for the development of early systemic atherosclerosis. Methods and Results—In a prospective, nested case-control study conducted among 14 916 middle-aged men, we evaluated the relationship between baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and the subsequent development of symptomatic peripheral arterial disease (PAD) during a 9-year follow-up period. Median levels of sICAM-1 but not sVCAM-1 were significantly higher at baseline among men who developed PAD than among those who did not (285.2 versus 267.8 ng/mL [P =0.005] for sICAM-1 and 701.0 versus 709.3 ng/mL [P =0.8] for sVCAM-1). In analyses adjusted for age and smoking, the odds ratio in the highest compared with the lowest quartile of sICAM-1 was 3.9 (95% CI 1.7 to 8.6;Ptrend=0.001). After additional adjustment for lipid and nonlipid risk factors, including C-reactive protein, elevated sICAM-1 remained significantly associated with subsequent PAD (OR 3.5, 95% CI 1.4 to 8.5, Ptrend=0.008). Whereas a monotonic dose-response relationship was evident over the full spectrum of ICAM-1 levels, elevated sVCAM-1 was not associated with future PAD in either age- and smoking-adjusted or fully adjusted models. Conclusions—Elevated levels of sICAM-1 are independently associated with the development of accelerated atherosclerosis among otherwise healthy men even in the absence of acute coronary occlusion.

C-Reactive Protein Is Independently Associated With Fasting Insulin in Nondiabetic Women

Objective—Insulin resistance is associated with chronic subclinical inflammation, and both conditions are linked with increased risk for type 2 diabetes mellitus and atherothrombotic cardiovascular disease. Methods and Results—In a cross-sectional study conducted among participants in the Women’s Health Study, an ongoing US primary prevention trial of cardiovascular disease and cancer, we evaluated the correlates of elevated fasting insulin, a marker of insulin resistance, among 349 healthy, nondiabetic women who remained free from clinically diagnosed type 2 diabetes mellitus during a 4-year period from biomarker assessment. Fasting insulin was strongly associated with body mass index (BMI) (r =0.53, P <0.001), C-reactive protein (CRP) (r =0.38, P <0.001), and interleukin-6 (r =0.33, P <0.001). Physical activity level, alcohol consumption, and use of hormone replacement therapy were also related to fasting insulin. However, in multivariable linear regression analysis, BMI and CRP were the only independent correlates of log-normalized fasting insulin. Overall, the final model explained 32% of the variance in log insulin level. In multivariable logistic regression, the fully adjusted odds ratio (OR) for elevated fasting insulin (≥51.6 pmol/L) increased with tertile of BMI, CRP, and IL-6, such that the ORs in the highest versus lowest tertile of each parameter were 9.0 (95% confidence interval [CI], 4.4 to 18.7), 4.4 (95% CI, 1.9 to 10.1), and 2.0 (95% CI, 0.9 to 4.2), respectively. Furthermore, increasing levels of CRP were associated with a stepwise gradient in odds for elevated fasting insulin among both lean and overweight women. Conclusions—CRP is independently associated with fasting hyperinsulinemia in nondiabetic women. These data provide additional support for previously reported associations between subclinical inflammation and the risk of type 2 diabetes and cardiovascular disease.

Lipoprotein Particle Size and Concentration by Nuclear Magnetic Resonance and Incident Type 2 Diabetes in Women

OBJECTIVE Diabetic dyslipoproteinemia is characterized by low HDL cholesterol and high triglycerides. We examined the association of lipoprotein particle size and concentration measured by nuclear magnetic resonance (NMR) spectroscopy with clinical type 2 diabetes. RESEARCH DESIGN AND METHODS This was a prospective study of 26,836 initially healthy women followed for 13 years for incident type 2 diabetes (n = 1,687). Baseline lipids were measured directly and lipoprotein size and concentration by NMR. Cox regression models included nonlipid risk factors (age, race, smoking, exercise, education, menopause, blood pressure, BMI, family history, A1C, and C-reactive protein). NMR lipoproteins were also examined after further adjusting for standard lipids. RESULTS Incident diabetes was significantly associated with baseline HDL cholesterol, triglycerides, and NMR-measured size and concentration of LDL, IDL, HDL, and VLDL particles. The associations of these particles differed substantially by size. Small LDLNMR and small HDLNMR were positively associated with diabetes (quintile 5 vs. 1 [adjusted hazard ratios and 95% CIs], 4.04 [3.21–5.09] and 1.84 [1.54–2.19], respectively). By contrast, large LDLNMR and large HDLNMR were inversely associated (quintile 1 vs. 5, 2.50 [2.12–2.95] and 4.51 [3.68–5.52], respectively). For VLDLNMR, large particles imparted higher risk than small particles (quintile 5 vs. 1, 3.11 [2.35–4.11] and 1.31 [1.10–1.55], respectively). Lipoprotein particle size remained significant after adjusting for standard lipids and nonlipid factors. CONCLUSIONS In this prospective study of women, NMR lipoprotein size and concentrations were associated with incident type 2 diabetes and remained significant after adjustment for established risk factors, including HDL cholesterol and triglycerides.

Sensitive Cardiac Troponin T Assay and the Risk of Incident Cardiovascular Disease in Women With and Without Diabetes Mellitus The Women's Health Study

Background— Very low levels of cardiac troponin T are associated with an increased risk of cardiovascular death in patients with stable chronic coronary disease. Whether high-sensitivity cardiac troponin T levels are associated with adverse cardiovascular outcomes in individuals without cardiovascular disease (CVD) has not been well studied. Methods and Results— Using 2 complementary study designs, we evaluated the relationship between baseline cardiac troponin and incident CVD events among diabetic and nondiabetic participants in the Womens Health Study (median follow-up, 12.3 years). All diabetic women with blood specimens were included in a cohort study (n=512 diabetic women, n=65 events), and nondiabetic women were sampled for inclusion in a case-cohort analysis (n=564 comprising the subcohort, n=479 events). High-sensitivity cardiac troponin T was detectable (≥0.003 &mgr;g/L) in 45.5% of diabetic women and 30.3% of nondiabetic women (P<0.0001). In models adjusted for traditional risk factors and hemoglobin A1c, detectable high-sensitivity cardiac troponin T was associated with subsequent CVD (myocardial infarction, stroke, cardiovascular death) in diabetic women (adjusted hazard ratio, 1.79; 95% confidence interval, 1.04 to 3.07, P=0.036) but not nondiabetic women (adjusted hazard ratio, 1.13; 95% confidence interval, 0.82 to 1.55; P=0.46). Further adjustment for amino-terminal pro-B-type natriuretic peptide and estimated renal function did not substantially alter this relationship among diabetic women (hazard ratio, 1.76; 95% confidence interval, 1.00 to 3.08; P=0.0499), which appeared to be driven by a 3-fold increase in CVD death that was not observed in nondiabetic women. Conclusions— Very low but detectable levels of cardiac troponin T are associated with total CVD and CVD death in women with diabetes mellitus. Among healthy nondiabetic women, detectable compared with undetectable troponin was not associated with CVD events.

Effects of Initiating Insulin and Metformin on Glycemic Control and Inflammatory Biomarkers Among Patients With Type 2 Diabetes: The LANCET Randomized Trial

CONTEXT As diabetes is in part an inflammatory condition, the initiation of insulin and/or metformin may beneficially reduce levels of inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP). OBJECTIVE To determine whether insulin alone or combined with metformin lowers levels of hsCRP, IL-6, and soluble tumor necrosis factor receptor 2 (sTNFr2) in patients with recent-onset type 2 diabetes mellitus. DESIGN, SETTING, AND PARTICIPANTS Randomized 2 x 2 factorial trial of open-label insulin glargine and placebo-controlled metformin in 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels. Patients were recruited from US office-based practices between October 2006 and December 2008. INTERVENTION Random allocation to 1 of 4 treatments (placebo metformin only, placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine) with dose titration targeting fasting blood glucose less than 110 mg/dL. MAIN OUTCOME MEASURES Change in hsCRP level (primary end point) and change in IL-6 and sTNFr2 levels (secondary end points) from baseline to 14 weeks. RESULTS Levels of glucose and glycated hemoglobin (HbA(1c)) were significantly reduced with active treatment vs placebo (all P values <.001). Levels of hsCRP were reduced in all 4 groups. There was no significant difference in hsCRP reduction among those allocated to insulin (-11.8%; 95% CI, -18.7% to -4.4%) or to no insulin (-17.5%; 95% CI, -23.9% to -10.5%) (P for difference = .25), or among those allocated to active metformin (-18.1%; 95% CI, -24.4% to -11.1%) or placebo metformin (-11.2%; 95% CI, -18.1% to -3.7%) (P for difference = .17). In the individual treatment groups, despite a differential impact on glucose control, reductions in hsCRP in the metformin (-16.1%; 95% CI, -25.1% to -6.1%) and metformin plus insulin (-20.1%; 95% CI, -28.8% to -10.4%) groups were no different than reductions with placebo alone (-19.0%; 95% CI, -27.8% to -9.1%; P = .67 and .87 vs placebo, respectively). By contrast, hsCRP reduction was attenuated with insulin alone (-2.9%, 95% CI, -13.2% to 8.6%; P = .03 vs placebo). Similar findings were noted for levels of IL-6 and sTNFr2. CONCLUSION In patients with recent-onset type 2 diabetes, treatment with insulin or metformin compared with placebo did not reduce inflammatory biomarker levels despite improving glucose control. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00366301.

Symptomatic Peripheral Arterial Disease in Women Nontraditional Biomarkers of Elevated Risk

Background— Most investigations of novel biomarkers for prediction of cardiovascular disease pertain to coronary artery disease. Few large-scale prospective studies have critically assessed plasma-based factors as predictors of peripheral arterial disease (PAD), and comparative data between individual biomarkers and lipid levels are sparse, especially among women. Methods and Results— We evaluated the relationship between baseline levels of several novel biomarkers and confirmed incident symptomatic PAD (n=100) in a prospective cohort study (median follow-up, 12.3 years) involving 27 935 US female health professionals ≥45 years of age without diagnosed vascular disease at baseline. Biomarkers assessed were high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), homocysteine, lipoprotein(a), hemoglobin A1c, creatinine, and conventional lipid levels. In univariate analyses, levels of high-sensitivity C-reactive protein, fibrinogen, sICAM-1, homocysteine, lipoprotein(a), creatinine clearance, high-density lipoprotein cholesterol (HDL-C), non–HDL-C, and the ratio of total cholesterol to HDL-C (TC:HDL-C) were significantly related to PAD (all P<0.05). However, after multivariable adjustment, risk associations were significant only for high-sensitivity C-reactive protein (adjusted hazard ratio [HR] extreme tertiles, 2.1; 95% confidence interval, 1.2 to 3.7), sICAM-1 (adjusted HR, 4.0; 95% confidence interval, 1.9 to 8.6), HDL-C (adjusted HR, 0.4; 95% confidence interval, 0.3 to 0.8), and TC:HDL-C (adjusted HR, 2.2; 95% confidence interval, 1.2 to 3.9). In a model simultaneously controlling for traditional risk factors plus these significant biomarkers, sICAM-1 remained independently predictive of PAD (adjusted HR in each tertile, 1.0 [reference], 2.3, and 3.5). Conclusions— Among a broad range of biomarkers of cardiovascular risk, only 4 factors, sICAM-1, high-sensitivity C-reactive protein, HDL-C, and TC:HDL-C, were significantly associated with incident symptomatic PAD in women. Findings pertaining to novel biomarkers provide clinical confirmation of a prominent role of endothelial activation and leukocyte recruitment in lower-extremity arterial disease.