Major Atherosclerotic Cardiovascular Events Research Articles

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry.

The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH.

Association Between the Magnitude of Glycemic Control and Body Weight Loss With GLP-1 Receptor Agonists and Risk of Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-analyses of Randomized Diabetes Cardiovascular Outcomes Trials.

Reduction of major atherosclerotic cardiovascular events (MACE) has not been consistent among different glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the association between the magnitude of glycemic control, body weight loss, and reductions in systolic blood pressure (SBP)and low-density lipoprotein cholesterol (LDL-C) achieved through GLP-1 RA therapy and MACE. Electronic databases (MEDLINE, CENTRAL, SCOPUS) were searched through March 2023. Studies were eligible if they were cardiovascular outcome trials (CVOTs) comparing GLP-1 RAs versus placebo in T2DM patients. The outcome of interest was 3-point MACE - cardiovascular death, myocardial infarction, or stroke. Random-effects meta-regression analyses evaluated the associations between reductions of HbA1c, body weight, SBP and LDL-C and reduction of MACE. Overall, 8 CVOTs were included (60079 patients, 30693 with GLP-1 RAs). Reductions of HbA1C were associated with the reduction of 3P-MACE (Log RR -0.290 [95% CI -0.515;-0.064], p = 0.012), with an estimated RR reduction of 25% for each 1% absolute reduction in HbA1C levels. Body weight loss was associated with the reduction of 3P-MACE (Log RR -0.068 [95% CI -0.135;-0.001], p = 0.047), with an estimated RR reduction of 7% for each 1kg reduction in body weight. Reductions of SBP (Log RR -0.058 [95% CI -0.192;0.076], p = 0.396) and LDL-C (Log RR -0.602 [95% CI -4.157;2.953], p = 0.740) were not associated with the reduction of 3P-MACE. In T2DM patients, more potent GLP-1 RAs in reducing HbA1c and body weight were associated with greater reductions of MACE.

Immune checkpoint inhibitors and atherosclerotic cardiovascular events: a retrospective cohort study

Abstract Background Immune checkpoint inhibitors (ICI) are cancer therapies that have improved the prognoses of over 20 different tumour types (1). However, ICIs have been increasingly recognised to associate with major atherosclerotic cardiovascular events (MACE) in cancer survivorship (2). Purpose This study aimed to determine the incidence and predictors for MACE among cancer patients treated with ICIs. Methods We performed a single-centre retrospective analysis of consecutive ambulatory cancer patients treated with ICIs between 2018 and 2020. Demographics, baseline cardiovascular risk factors (CVRF), medication history, cancer history and ICI regimen were determined from electronic medical records. The primary endpoint of MACE, defined as a composite of acute myocardial infarction, coronary revascularization, ischaemic stroke, and acute limb ischaemia, was determined from case note review. Cox proportional multivariable modelling was performed to determine predictors for MACE using significant variables on univariate analysis (p&amp;lt;0.20) and variables of clinical relevance including CVRFs and use of dual ICI therapy. Time to first MACE analysis was undertaken; in those without MACE, date of death or last follow-up was used as the censoring date. Subgroup analysis was performed among patients with stage 1-3 cancer who were treated with (neo)adjuvant ICI therapy and expected to have favourable long-term prognoses. Results The study cohort included 366 patients (median age 66 years (58,73), 63% male). There were 238 patients (65%) with non-small cell lung cancer and 65 (17.8%) had prior history of atherosclerotic cardiovascular disease (ASCVD). A total of 26 patients (7.1%) experienced 27 MACE (7 myocardial infarction, 1 coronary revascularization, 13 ischaemic stroke, 6 acute limb ischaemia) over median follow up of 1.9 years (0.6,3.2). During the study, there were 226 (61.8%) cancer-related deaths; there were no cardiac deaths. On multivariable analysis, MACE was independently associated with history of ASCVD (hazard ratio [HR] 4.49, 95% CI 1.92-10.49, p&amp;lt;0.01) and hypertension (HR 2.57, 95% CI 1.07-6.17, p=0.04). When limited to those with stage 1-3 cancer, 16 patients (11.0%) developed MACE among a cohort of 145 patients. History of ASCVD was the only variable associated with MACE on subgroup analysis (HR 3.79, 95% 1.25-11.49, p=0.02). Conclusion Among an unselected cohort of cancer patients treated with ICIs, an increased risk of MACE was observed among patients with a history of ASCVD or hypertension. Patients undergoing ICI therapy with concomitant ASCVD or hypertension should be identified and their modifiable CVRFs aggressively treated.

Serum adiponectin concentrations as a risk factor for cardiovascular complications in type 1 diabetes

AimBy analyzing data from DCCT/EDIC study, we investigated the associations of serum adiponectin concentrations with macrovascular complications and cardiovascular events in T1D. Materials and MethodsAdiponectin concentrations were measured in EDIC year 8. The participants (n = 1040) were divided into four groups by quartiles of adiponectin concentrations. The association of macrovascular complications and cardiovascular events were analyzed by using multivariable regression and Cox proportional hazards models. ResultsHigh adiponectin concentrations were associated with decreased risk of peripheral artery disease represented by ankle brachial index (ORs (95% CI): 0.22 (0.07–0.72), 0.48 (0.18–1.25), and 0.38 (0.14–0.99) in fourth, third, and second quartiles compared with first quartile), with reduced carotid intima-media thickness, and with increased LVEDV index. Moreover, high adiponectin concentrations were also associated with increased risk of any cardiovascular events (HRs (95% CI): 2.59 (1.10–6.06), 2.03 (0.90–4.59), and 1.22 (0.52–2.85)) and major atherosclerotic cardiovascular events (HRs (95% CI): 11.37 (2.04–63.43), 5.68 (1.04–31.07), and 3.76 (0.65–21.77) in fourth, third, and second quartiles compared with first quartile), however, after adjustments with LVEDV index, these associations were diminished. ConclusionsAdiponectin may protect carotid atherosclerosis and peripheral artery disease in T1D. It may be associated with increased cardiovascular events, depending on cardiac structural changes.

Impact of Post-Transplant Diabetes Mellitus on Survival and Cardiovascular Events in Kidney Transplant Recipients.

Post-transplant diabetes mellitus (PTDM) is a risk factor for poor outcomes after kidney transplantation (KT). However, the outcomes of KT have improved recently. Therefore, we investigated whether PTDM is still a risk factor for mortality, major atherosclerotic cardiovascular events (MACEs), and graft failure in KT recipients. We studied a retrospective cohort of KT recipients (between 1994 and 2017) at a single tertiary center, and compared the rates of death, MACEs, overall graft failure, and death-censored graft failure after KT between patients with and without PTDM using Kaplan-Meier analysis and a Cox proportional hazard model. Of 571 KT recipients, 153 (26.8%) were diagnosed with PTDM. The mean follow-up duration was 9.6 years. In the Kaplan- Meier analysis, the PTDM group did not have a significantly increased risk of death or four-point MACE compared with the non-diabetes mellitus group (log-rank test, P=0.957 and P=0.079, respectively). Multivariate Cox proportional hazard models showed that PTDM did not have a negative impact on death or four-point MACE (P=0.137 and P=0.181, respectively). In addition, PTDM was not significantly associated with overall or death-censored graft failure. However, patients with a long duration of PTDM had a higher incidence of four-point MACE. Patient survival and MACEs were comparable between groups with and without PTDM. However, PTDM patients with long duration diabetes were at higher risk of cardiovascular disease.

Immune checkpoint inhibitors and the risk of major atherosclerotic cardiovascular events in patients with high-risk or advanced melanoma: a retrospective cohort study

BackgroundImmune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations.ObjectiveTo characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population.MethodsWe conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015–2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization.ResultsThe study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1–6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9–112.3, p = 0.01).ConclusionPatients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.

SGLT2 Inhibitors: Benefits for CKD and Cardiovascular Disease in Type 2 Diabetes.

Over the past few decades, multiple glucose lowering therapies have been developed, but until now, no single drug has proven to both decrease cardiovascular mortality and improve renal outcomes. The purpose of this review is to outline the key findings of the recent major outcome clinical trials on SGLT2 inhibitors, review the indications for their use, and improve adoption of these medications in patients with type 2 diabetes mellitus (T2DM). Recent studies have shown a benefit for SGLT2 inhibitors in patients with heart failure (HF) and kidney disease both in the presence and absence of T2DM. Additional benefits also include improvements in fluid status, blood pressure, serum uric acid levels, and weight loss. Available data suggests that SGLT2 inhibitors should be used in all eligible patients with HFrEF and/or CKD with albuminuria to decrease progression of CKD, hospitalizations for heart failure, major atherosclerotic cardiovascular events, and cardiovascular death, with and without T2DM.

Rationale for Expanding the Use of Low-Dose Aspirin for Primary Cardiovascular Prevention during the COVID-19 Pandemic

The COVID-19 pandemic has decreased life-expectancy in the United States in 2021, causing over one million deaths especially in elderly persons with medical co-morbidities. While now waning, this epidemic continues to cause more than 500 fatalities per week mostly in individuals over70 years of age who are unvaccinated. Since viral epidemics have been shown to increase mortality due to atherosclerotic coronary heart disease and low-dose aspirin has been shown to reduce first myocardial infarctions by 44%, we recommend consideration of expanding the use of aspirin for primary cardiovascular prevention to reduce the cardiac morbidity and excess mortality associated with COVID-19 infections. Such aspirin use may be seen as especially appropriate for vulnerable elderly persons who qualify for treatment with Paxlovid (ritonavir-boosted nirmatrelvir) but are currently excluded for such in primary prevention guidelines of subspecialty societies. The rationale for this approach is further supported by recent proof of concept that vaccination, an alternative intervention for primary cardiovascular prevention, reduces the excess mortality associated with COVID-19 infection. Can greater use of aspirin for primary cardiovascular prevention mitigate the excess cardiac mortality associated with COVID-19 as shown with prior viral epidemics 1-3? Recommendations from the 2019 ACC/AHA and 2021 ESC guidelines currently advise limited aspirin use for primary prevention except in persons aged 40 to 59 years with elevated ASCVD risk scores (10-year risk ≥10%) and for those aged 60 to 69 years only with risk ≥20% in the context of no excess risk of bleeding (Figure 1) 4,5. These guidelines have been endorsed by the United States Preventive Services Task Force, which acknowledge that low-dose aspirin in the primary prevention setting reduces the risk of major atherosclerotic cardiovascular events including myocardial infarction and ischemic stroke offset by an increased risk of gastrointestinal bleeding 7,8. Currently endorsed guidelines specifically recommend against aspirin use in individuals at age 70 and beyond.

Plasma biomarkers outperform echocardiographic measurements for cardiovascular risk prediction in kidney transplant recipients: results of the HOME ALONE study.

ABSTRACTBackgroundSince kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain.MethodsThe prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed.ResultsAmong all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02–17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75–24.18)] analysis.ConclusionOur data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction.

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

BackgroundFamilial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH‐causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long‐term response to therapy and the risk of atherosclerosis.Methods and ResultsA cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low‐density lipoprotein‐rising genetic risk score >0.69 to identify polygenic cause. Medical records were reviewed to estimate the response to lipid‐lowering therapies and the occurrence of major atherosclerotic cardiovascular events during a median follow‐up of 31.0 months. A subgroup of patients (n=119) also underwent coronary computed tomographic angiography for the evaluation of coronary artery calcium score and severity of coronary stenosis as compared with 135 controls. Two hundred nine (56.5%) patients with hypercholesterolemia were classified as monogenic (FH/M+), 89 (24.1%) as polygenic, and 72 (19.5%) genetically undefined (FH/M−). The response to lipid‐lowering therapy was poorest in monogenic, whereas it was comparable in patients with polygenic hypercholesterolemia and genetically undetermined. Mean coronary artery calcium score and the prevalence of coronary artery calcium >100 units were significantly higher in FH/M+ as compared with both FH/M− and controls. Finally, after adjustments for confounders, we observed a 5‐fold higher risk of incident major atherosclerotic cardiovascular events in FH/M+ (hazard ratio, 4.8; 95% CI, 1.06–21.36; P adj=0.041).ConclusionsMonogenic cause of FH is associated with lower response to conventional cholesterol‐lowering therapies as well as with increased burden of coronary atherosclerosis and risk of atherosclerotic‐related events. Genetic testing for hypercholesterolemia is helpful in providing important prognostic information.

Gaps in Evidence-Based Therapy Use in Insured Patients in the United States With Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease.

BackgroundEvidence‐based therapies are generally underused for cardiovascular risk reduction; however, less is known about contemporary patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.Methods and ResultsPharmacy and medical claims data from within Anthem were queried for patients with established atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Using an index date of April 18, 2018, we evaluated the proportion of patients with a prescription claim for any of the 3 evidence‐based therapies on, or covering, the index date ±30 days: high‐intensity statin, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, and sodium glucose cotransporter‐2 inhibitor or glucagon‐like peptide‐1 receptor agonist. The potential benefit of achieving 100% adoption of all 3 evidence‐based therapies was simulated using pooled treatment estimates from clinical trials. Of the 155 958 patients in the sample, 24.7% were using a high‐intensity statin, 53.1% were using an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, and 9.9% were using either an sodium glucose cotransporter‐2 inhibitor or glucagon‐like peptide‐1 receptor agonists. Overall, only 2.7% of the population were covered by prescriptions for all 3 evidence‐based therapies, and 37.4% were on none of them. Over a 12‐month period, 70.6% of patients saw a cardiologist, while only 18% saw an endocrinologist. Increasing the use of evidence‐based therapies to 100% over 3 years of treatment could be expected to reduce 4546 major atherosclerotic cardiovascular events (myocardial infarction, stroke, or cardiovascular death) in eligible but untreated patients.ConclusionsAlarming gaps exist in the contemporary use of evidence‐based therapies in this large population of insured patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.

The use of activated vitamin D and risks of hospitalization for infection and amputation in incident hemodialysis patients in Taiwan: a nationwide population-based cohort study

BackgroundHemodialysis patients have a high risk of mortality. The most common causes of death are cardiovascular disease and infection. The potential hazard or benefit associated with vitamin D use and cardiovascular or infection outcome is poorly characterized.MethodsWe conducted a retrospective observational cohort study by recruiting 52,757 patients older than 20 years from Taiwan National Health Insurance Research Database (NHIRD) who initiated maintenance hemodialysis between 2001 and 2009. Patients who were prescribed activated vitamin D before the 360th day from hemodialysis initiation were defined as vitamin D users. The primary outcome of interest includes occurrence of acute myocardial infarction (AMI), ischemic stroke, lower limb amputation, and hospitalization for infection, respectively, while death events are treated as competing events. We conducted competing risk analysis using subdistribution hazard regression model to estimate subdistribution hazard ratios (SHRs) in relation to various outcomes.ResultsDuring the median follow-up of 1019 days, the vitamin D users had a lower crude mortality rate, lower incidences of AMI, ischemic stroke, amputation, and hospitalization for infection compared with non-users. Taking into consideration competing events of death, vitamin D users were associated with a lower hazard of lower limb amputation (SHR 0.84 [95% CI, 0.74–0.96]) and hospitalization for infection (SHR 0.90 [95% CI, 0.87–0.94]), but not AMI or ischemic stroke, after adjustment for potential confounders. Subgroup analyses and dose response evaluation both showed a consistent association of activated vitamin D treatment with decreased risk of amputation and infection.ConclusionThe findings suggest that therapeutic activated vitamin D use in hemodialysis patients may be beneficial for decreasing infection events and amputation, of which the latter is a complication of peripheral vascular disease, rather than reducing major atherosclerotic cardiovascular events such as AMI or ischemic stroke.

A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.

P0676CHOLESTEROL ABSORPTION JUGDED BY CAMPESTEROL / LATHOSTEROL RATIO AND OUTCOMES IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may partly be explained by a shift from cholesterol synthesis, which is inhibited by statin treatment, towards cholesterol absorption, which is inhibited by ezetimibe. In line, markers of cholesterol absorption – such as campesterol - better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis – such as lathosterol - in dialysis patients. We now investigated in our CARE FOR HOMe study whether a similar shift towards cholesterol absorption occurs in non-dialysis chronic kidney disease (CKD), and whether the campesterol / lathosterol ratio predicts outcome in non-dialysis CKD patients. Method Since 2008, 599 participants suffering from chronic kidney disease have been included into the CARE FOR HOME study, an observational cohort study. 555 patients had baseline samples available for analyses of the lathosterol / cholesterol ratio as a marker for cholesterol synthesis, and the campesterol / cholesterol ratio as a marker for cholesterol absorption. We excluded those participants who were currently treated with statins or other lipid lowering drugs, leaving 251 patients for this analysis. Participants were followed annually for major atherosclerotic cardiovascular events (MACE), defined as non-fatal acute myocardial infarction, non-fatal ischemic stroke, cerebrovascular / peripheral arterial or coronary revascularization, major amputation above the ankle and cardiovascular death. Additionally, all-cause death and the composite endpoint MACE and all-cause death were explored. We performed univariate (Model 1) and multivariate Cox regression analysis, adjusting for age, gender (Model 2), estimated glomerular filtration rate (eGFR), log-transformed albuminuria (Model 3), prevalent cardiovascular disease, current smoking, diabetes mellitus, systolic blood pressure and body mass index (Model 4). The primary hypothesis was that patients with a high campesterol / lathosterol ratio had a higher event rate. Results Neither lathosterol / cholesterol ratio (r = 0.022, p = 0.730), nor campesterol / cholesterol ratio (r = 0.042; p = 0.519) nor the campesterol / lathosterol ratio (r = -0.103; p = 0.105) correlated significantly with eGFR. During follow-up of 5.1 ± 2.1 years, 47 participants suffered from MACE, 46 participants died and 61 participants reached the composite endpoint of MACE or all-cause death. In univariate Cox regression analysis, campesterol / lathosterol ratio did not significantly predict atherosclerotic cardiovascular events (HR 0.740; 0.368 – 1.487), all-cause death (HR 0.564; 0.277 – 1.145) or the composite endpoint (HR 0.652; 0.355 – 1.196). After full adjustment, results were not different: Campesterol / lathosterol ratio was not significantly associated with all three endpoints: MACE (HR 1.064; 0.507 – 2.231), all-cause death (HR 0.818; 0.420 – 1.594) and MACE and all-cause death (HR 0.956; 0.525 – 1.744). Conclusion We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol / lathosterol ratio did not predict future MACE or all-cause death in non-dialysis CKD. These findings do not support the concept that CKD patients may preferentially benefit from ezetimibe rather than from statin treatment.

285-OR: Long-Term HbA1c Trajectories and Mortality and Major Atherosclerotic Cardiovascular Events (MACE) in Type 1 Diabetes (T1D)

While poor glycemic control is a well-established risk factor for mortality and MACE in T1D, specific patterns of control over time have not been well-studied. Thus, we sought to identify long-term trajectories of HbA1c and examine associated participant characteristics, mortality, and MACE incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a prospective observational cohort with childhood-onset (&amp;lt;17 years) T1D. These data were analyzed as part of a DNA methylation sub-study (currently in progress), where n=422 (baseline mean T1D duration 21 yrs, 53% male) have been followed for outcomes, including 28-year mortality and MACE. Beginning in 1988, HbA1c was measured at baseline, 2, 4, 6, 8, 15, and 22 yrs. HbA1c trajectories were identified using latent class growth modeling. Five HbA1c trajectories were identified (Figure). There were no significant differences in age, T1D duration, age at T1D onset, sex, education, or insulin dose between groups. Both mortality and MACE were significantly increased in IMPROVED (p&amp;lt;0.02) and even more so in HIGH (p&amp;lt;.0001) compared to LOW. MODERATE and WORSENED did not have increased risk of either outcome compared to LOW. These results demonstrate that, despite improvement, past high HbA1c remains associated with increased long-term mortality and MACE risk in this T1D cohort. Disclosure R.G. Miller: None. T. Costacou: None. T.J. Orchard: None. Funding American Diabetes Association (1-19-JDF-109 to R.G.M.)

Serum apolipoproteins and apolipoprotein-defined lipoprotein subclasses: a hypothesis-generating prospective study of cardiovascular events in T1D

APOB, APOC3, and APOE and apolipoprotein-defined lipoprotein subclasses (ADLSs; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and CVD. Our main objective was to define associations of serum apolipoproteins and ADLSs with "any CVD" and "major atherosclerotic cardiovascular events" (MACEs) in a prospective study of T1D. Serum apolipoproteins and ADLSs (14 biomarkers in total) were measured in sera (obtained between 1997 and 2000) from a subset (n = 465) of the Epidemiology of Diabetes Interventions and Complications cohort. Prospective associations of "any CVD" (myocardial infarction, stroke, confirmed angina, silent myocardial infarction, revascularization, or congestive heart failure) and MACEs (fatal or nonfatal myocardial infarction or stroke), over 5,943 and 6,180 patient-years follow-up, respectively, were investigated using Cox proportional hazards models that were unadjusted and adjusted for risk factors. During 15 years of follow-up, 50 "any CVD" events and 24 MACEs occurred. Nominally significant positive univariate associations with "any CVD" were APOB, APOC3 and its subfractions [heparin precipitate, heparin-soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACEs were APOC3 and its subfractions and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjusting for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLSs with either "any CVD" or MACEs. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for any CVD and MACEs in adults with T1D.

88-OR: hsTroponin and NT-proBNP in Type 1 Diabetes (T1D): Association with Incident Cardiovascular Disease (CVD) and Major Atherosclerotic Cardiovascular Events (MACE)

High-sensitivity troponin T (hsTnT), a marker of CVD, and N-Terminal pro B-Type Natriuretic Peptide (NT-proBNP), a marker of heart failure, have not been widely studied in type 1 diabetes. We thus assessed the ability of these markers to independently predict CVD and MACE in a cohort with childhood-onset T1D (n=583, mean age 29 and duration 21 years) during a median follow-up of 21 years. CVD was defined as CVD death, myocardial infarction, revascularization, angina, or ischemia, and MACE as CVD death, myocardial infarction, or stroke. hsTnT and NT-proBNP were assessed with electrochemiluminescence immunoassays. Median hsTnT was 5.0 ng/L (IQR: 2.0, 10.0) and median NT-proBNP was 22.0 pg/mL (7.0, 61.0). In Cox proportional hazards models allowing for diabetes duration, gender, BMI, smoking status, HbA1c, hypertension status, HDL and non-HDL cholesterol, white blood cell count, estimated glomerular filtration rate and albumin excretion rate, both log hsTnT (HR=1.30, 95% CI: 1.06-1.59) and log NT-proBNP (HR=1.29, 95% CI: 1.13-1.48) independently predicted CVD. However, the prediction of CVD between models with and without these two markers improved only marginally (Uno’s concordance statistic p=0.06). Furthermore, log hsTnT was a slightly weaker predictor of MACE (HR=1.22, 95% CI: 0.97-1.55) compared with log NT-proBNP (HR=1.28, 95% CI: 1.11-1.47). The addition of these two markers to models already including traditional risk factors did not enhance MACE prediction (p=0.39). In conclusion, although hsTnT and NT-proBNP independently predicted both CVD and MACE, they marginally increased the area under the curve only for CAD in this type 1 diabetes cohort. Disclosure T. Costacou: None. A.K. Saenger: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. Funding National Institutes of Health (DK34818); Rossi Memorial Fund

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

Smoking cessation and risk of recurrent cardiovascular events and mortality after a first manifestation of arterial disease

To quantify the relation between smoking cessation after a first cardiovascular (CV) event and risk of recurrent CV events and mortality. Data were available from 4,673 patients aged 61 ± 8.7 years, with a recent (≤1 year) first manifestation of arterial disease participating in the SMART-cohort. Cox models were used to quantify the relation between smoking status and risk of recurrent major atherosclerotic cardiovascular events (MACE including stroke, MI and vascular mortality) and mortality. In addition, survival according to smoking status was plotted, taking competing risk of non-vascular mortality into account. A third of the smokers stopped after their first CV event. During a median of 7.4 (3.7-10.8) years of follow-up, 794 patients died and 692 MACE occurred. Compared to patients who continued to smoke, patients who quit had a lower risk of recurrent MACE (adjusted HR 0.66, 95% CI 0.49-0.88) and all-cause mortality (adjusted HR 0.63, 95% CI 0.48-0.82). Patients who reported smoking cessation on average lived 5 life years longer and recurrent MACE occurred 10 years later. In patients with a first CV event >70 years, cessation of smoking had improved survival which on average was comparable to former or never smokers. Irrespective of age at first CV event, cessation of smoking after a first CV event is related to a substantial lower risk of recurrent vascular events and all-cause mortality. Since smoking cessation is more effective in reducing CV risk than any pharmaceutical treatment of major risk factors, it should be a key objective for patients with vascular disease.

Risk Factor Modeling for Cardiovascular Disease in Type 1 Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison With the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC).

In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study report, mean HbA1c was the strongest predictor of cardiovascular disease (CVD) after age. In DCCT/EDIC, mean diabetes duration was 6 years (median 4) at baseline and those with high blood pressure or cholesterol were excluded. We now replicate these analyses in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (at <17 years of age) type 1 diabetes, with similar age (mean 27 years in both studies) but longer diabetes duration (mean 19 years and median 18 years) and no CVD risk factor exclusion at baseline. CVD incidence (CVD death, myocardial infarction (MI), stroke, revascularization, angina, or ischemic electrocardiogram) was associated with diabetes duration, most recent albumin excretion rate (AER), updated mean triglycerides, baseline hypertension, baseline LDL cholesterol, and most recent HbA1c Major atherosclerotic cardiovascular events (CVD death, MI, or stroke) were associated with diabetes duration, most recent AER, baseline systolic blood pressure, baseline smoking, and updated mean HbA1c Compared with findings in DCCT/EDIC, traditional risk factors similarly predicted CVD; however AER predominates in EDC and HbA1c in DCCT/EDIC. Thus, the relative impact of HbA1c and kidney disease in type 1 diabetes varies according to diabetes duration.