Cardiovascular Outcome Studies Research Articles

#3115 Effectiveness of SGLT2 inhibitors in patients with glomerulonephritis: a single center experience

Abstract Background and Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors have become widely used in recent years because of favorable outcomes on kidney function in people with diabetes mellitus and chronic kidney disease (CKD). The main effect of SGLT2 inhibitors is inhibiting sodium and glucose reabsorption, acting precisely in the early proximal tubule of the renal nephron. Although these drugs developed as glucose-lowering agents for their capability to induce glycosuria, cardiovascular outcome studies found that the reduction in kidney function was significantly delayed, and the incidence of severe decline in kidney function was reduced in patients taking SGLT2 inhibitors. Later on, these outcomes were confirmed by the results of the DAPA-CKD, EMPA-KIDNEY, and CREDENCE studies, which were specific outcome trials in patients with CKD. However, data about the use of SGLT2 inhibitors in patients with glomerulonephritis at routine clinical practice are still limited. The purpose of this study is to investigate the impact of SGLT2 inhibitors use in patients with glomerulonephritis. Method Patients diagnosed with biopsy-proven GN who continued their routine follow-up in Etlik City Hospital nephrology clinic were retrospectively examined. Patients with a steroid treatment history for GN were excluded from this study. We identified 29 patients who were treated with SGLT2 inhibitors for proteinuria. We analyzed the baseline characteristics, comorbidities, GN types, and laboratory parameters (baseline, sixth and twelfth months at the follow-up). Each patient was matched to the control with a similar baseline feature under conservative therapy (n = 29). Both patient groups were treated in line with the KDIGO glomerulonephritis guideline and were received RAAS blockers at the maximum tolerated dose. According to baseline levels, the reduction rate in proteinuria and eGFR of the sixth and twelfth months were calculated as percentages. The study was performed in accordance with the Declaration of Helsinki. The local ethical committee approved the study design. Results Our study involved 58 patients diagnosed with 32 (55%) IgA nephropathy, 16 (28%) with membranous nephropathy, and 10 (17%) with focal segmental glomerulosclerosis. In the treatment group, 23 (79%) patients used dapagliflozin, and 6 (21%) used empagliflozin as SGLT2 inhibitors. Baseline proteinuria levels at [1940 (1780-2700 mg/d) vs. 1890 (1670-2400 mg/d); p = 0.8], eGFRs [60 (44-82) vs. 64 (46-80) ml/min/1.73 m2; p = 0.8] and serum albumin levels (39.6 ± 0.3 vs. 39.1 ± 0.2; p = 0.4) were similar between both groups. The proteinuria reduction rate in the sixth month was 34% (27.3-40.5) for the treatment group and 12% (6.9-20.7) for the control group (<0.0001). Besides, the reduction rate was still higher in the treatment group at the 12th month [50.5% (39-52.6) vs. 26.3% (17.2-35.4); p ≤ 0.0001]. eGFR declining rate at 6th months and 12th months were lower in SGLT2 group than the control group [3.1% (0-6.2) vs. 8.6% (4.1-16.6); p = 0.004 and 0.8% (0-5) vs. 5.9% (3.3-15.2); 0.005, respectively] (Table 1). Proteinuria levels at 6th months were 1170 (970-1890) mg/d and 1730 (1180-2100) mg/d for treatment and control group, respectively. At 12th months, median proteinuria level of SGLT2 group was 940 (840-1480) mg/d and control group was 1250 (1120- 2040) mg/d (Fig. 1). Conclusion In this study with a well-matched control group, we found that SGLT2 inhibitors demonstrate efficacy in mitigating the decline in estimated GFR and reducing albuminuria in patients with GN. However, randomized-controlled trials are still required specific to patients with GN.

Abstract PO3-19-04: The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. The CROWN study (CaRdiac Outcomes With Near complete estrogen deprivation) will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. A total of 17 patients are enrolled as of 07/2023. NCT05309655 Study Procedures XX- XX Citation Format: Susan Dent, Emily Douglas, Sarah Hatcher, Katherine Ansley, Carolyn Park, Nathaniel O'Connell, Mary Hackney, Ralph D'Agostino, Rani Bansal, Renee Avecilla, Monica Brown, Kacey Clayton-Stiglbauer, Igor Klem, Jennifer Jordan, Alexandra Thomas. The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-04.

The Effect of Surgical Therapy for Obstructive Sleep Apnea on Blood Pressure and Peripheral Arterial Tonometry.

To determine the effect of upper airway surgery on cardiovascular function in patients with obstructive sleep apnea (OSA). A prospective, self-controlled study from 2018 to 2023. Two academic medical centers. Seventy-four patients underwent surgery for OSA, including: tonsillectomy, adenoidectomy, epiglottidectomy, modified uvulopalatopharyngoplasty, maxillary expansion, and maxillomandibular advancement. Twenty-four-hour ambulatory blood pressure (BP), peripheral arterial tonometry (PAT)-based home sleep study, and sleep-related patient-reported outcomes (PROs) were captured preoperatively and at 6 months postoperatively. Paired T-tests evaluated changes in outcomes after surgery. Forty-one patients successfully completed preoperative and postoperative assessments. Patients were generally middle-aged (43.8 ± 12.5 years), obese (BMI 33.0 ± 5.8 kg/m2), male (68%), White (71%), and had severe OSA (apnea-hypopnea index [AHI] 33.9 ± 29.5 events/h). The 4% oxygen desaturation index (ODI) decreased from 30.7 ± 27.1 to 12.2 ± 13.6 events/h(P < .01) after surgery. There was no significant difference in 24-hBP following surgery, though clinically meaningful reductions in nocturnal systolic (-1.95 [-5.34, 1.45] mmHg) and nocturnal diastolic (-2.30 [-5.11, 0.52] mmHg) blood pressure were observed. Stratified analysis showed patients undergoing skeletal surgery (n = 17) demonstrated larger average reductions compared to those undergoing soft tissue surgery in nocturnal systolic (-4.12 [-7.72, -0.51] vs-0.10 [-5.78, 5.58] mmHg) and nocturnal diastolic (-3.94 [-7.90, 0.01] vs-0.90 [-5.11, 3.31] mmHg) pressures. No meaningful changes were observed in PAT Autonomic Index (PAI) measurements. Surgical therapy for OSA did not demonstrate statistically significant improvements in 24-hBP. However, clinically meaningful reductions in nocturnal BP were observed, particularly in skeletal surgery patients, supporting the need for larger studies of cardiovascular outcomes following OSA surgery.

Efficacy and Safety of Bempedoic Acid in Patients with High Cardiovascular Risk: An Update.

Statins play a significant role in the prevention of cardiovascular (CV) diseases (CVDs); however, non-adherence with statin treatment or statin intolerance (mainly attributed to muscleassociated side effects) is not uncommon. New agents such as bempedoic acid (BA) can provide more treatment options. BA is administered orally, once daily, at a dose of 180 mg in current clinical practice. It can decrease circulating low-density lipoprotein cholesterol (LDL-C) levels by nearly 30% as monotherapy or by 20% as an add-on to statins. CV outcome studies have shown that BA decreases major adverse CV event risk in patients with established CVD or high CV risk by 13%. When patients with high CV risk were analyzed alone, the risk reduction was 30%. Its side effects include a rise in serum uric acid levels and liver enzyme activity, whereas it does not increase diabetes risk as statins do. BA can be used as adjunctive therapy to statins in patients at high CV risk in whom lipid targets cannot be achieved or as an alternative to statins in patients with statin intolerance.

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin

Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. To evaluate the associations between hypoglycemia and CV outcomes. This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023. Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial. The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze. This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both. ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA).

Are We Using Ezetimibe As Much As We Should?

Lipid-lowering therapies, particularly non-statin regimens, are underutilized as ~2/3 of patients with atherosclerotic cardiovascular (CV) disease (CVD) are not optimally managed, and do not attain target low-density lipoprotein cholesterol (LDL-C) concentrations, despite statin treatment. Statins have been the mainstay of hypolipidemic therapies; however, they are plagued by adverse effects, which have partly hindered their more widespread use. Ezetimibe is often the first added mode of treatment to attain LDL-C goals as it is efficacious and also allows the use of a smaller dose of statin, while the need for more expensive therapies is obviated. We herein provide a comprehensive review of the effects of ezetimibe in lipid lowering and reducing CV events and improving outcomes. Of the hypolipidemic therapies, oral ezetimibe, in contrast to newer agents, is the most convenient and/or affordable regimen to be utilized as mono- or combined therapy supported by data from CV outcomes studies attesting to its efficacy in reducing CVD risk and events. When combined with a statin, the statin dose could be lower, thus curtailing side-effects, while the hypolipidemic effect is enhanced (by ~20%) as the percentage of patients with target level LDL-C (<70 mg/dL) is higher with combined treatment versus a high-intensity statin. Ezetimibe could also serve as an alternative treatment in cases of statin intolerance. In conclusion, ezetimibe has an excellent safety/tolerability profile; it is the first added treatment to a statin that can attain LDL-C targets. In the combined therapy, the hypolipidemic effect is enhanced while the dose of statin could be lower, thus limiting the occurrence of side-effects. Ezetimibe could also serve as an alternative mode of treatment in cases of statin intolerance.

Abstract 13756: The Role of Glucagon Like Peptide-1 Receptor Agonists on Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Chronic Heart Failure: A Meta-Analysis From Cardiovascular Outcome Trials

Introduction: Meta-analyses on glucagon-like peptide-1 (GLP-1) receptor agonists have shown beneficial effects in reducing major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. However, it is unclear if they have similar beneficial effects in patients with type 2 diabetes mellitus and chronic heart failure. Methods: A search was performed on online databases - MEDLINE (via PubMed) and ClinicalTrials.gov, using the search words GLP-1 receptor agonist and cardiovascular outcomes. The references from the search results were also reviewed for potential studies that can be included. We identified four cardiovascular outcome studies with GLP-1 receptor agonists on patients with type 2 diabetes mellitus with data on patients with chronic heart failure, and included them in our meta-analysis. Results: 6189 patients were evaluated in this meta-analysis, with 3053 in the GLP-1 receptor agonist group and 3136 in the placebo group. Among them, 475 (15.56%) major adverse cardiovascular events (i.e., cardiovascular death, stroke, or myocardial infarction) occurred in the GLP-1 receptor agonist group and 536 events (17.09%) in the placebo group with a hazard ratio (HR) of 0.90, 95% confidence interval (CI) of 0.79 to 1.01 and a p-value of 0.08, indicating a favorable effect with GLP1 agonists though statistically not significant. Conclusion: In patients with type 2 diabetes mellitus and chronic heart failure, GLP-1 receptor agonists may have a favorable effect in reducing major adverse cardiovascular events, though statistically not significant.

Recent studies of Aircraft Noise and Cardiovascular Outcomes in the UK

Recent studies of Aircraft Noise and Cardiovascular Outcomes in the UK

Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials.

Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD). Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models. The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83). In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors. URL: https://www. gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

Primary disorders of lipid metabolism: their place in current dyslipidemia guidelines and treatment innovations

According to current guidelines, the selection and intensity of lipid-effective therapies are based on the risk to be treated. The sole clinical categories of primary and secondary prevention of cardiovascular diseases result in over- and under-treatment, which may be acontributory cause of incomplete implementation of current guidelines in everyday practice. For the extent of benefit in cardiovascular outcome studies with lipid-lowering drugs, the importance of dyslipdemia for the pathogenesis of atherosclerosis-related diseases is crucial. Primary lipid metabolism disorders are characterized by life-long increased exposure to atherogenic lipoproteins. This article describes the relevance of new data for low density lipoprotein-effective therapy: inhibition of proprotein convertase subtilisin/kexin type9 (PCSK9), adenosine triphosphate (ATP) citrate lyase with bempedoic acid, and ANGPTL3 with special consideration of primary lipid metabolism disorders, which are insufficiently taken into account, or not taken into account at all, in current guidelines. This is due to their apparently low prevalence rate and thus the lack of large outcome studies. The authors also discuss the consequences of increased lipoprotein(a), which cannot be sufficiently reduced until the ongoing intervention studies examining antisense oligonucleotides and small interfering RNA (siRNA) against apolipoprotein(a) are completed. Another challenge in practice is the treatment of rare, massive hypertriglyceridemia, especially with the aim of preventing pancreatitis. For this purpose, the apolipoprotein C3 (ApoC3) antisense oligonucleotide volenasorsen is available, which binds to the mRNA for ApoC3 and lowers triglycerides by around three quarters.

The CROWN study (CaRdiac outcomes with near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor.

TPS12142 Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. Taken together with the CV morbidity associated with other aspects of BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. Present accrual is 4. Clinical trial information: NCT05309655 . [Table: see text]

Discordance between LDL cholesterol and apolypoprotein B. Which to prefer to guide treatment?

Abstract Funding Acknowledgements Type of funding sources: None. Current cardiovascular risk guidelines recommend target values of low-density lipoprotein cholesterol (LDLc) &amp;lt; 55 mg/dL and apolipoprotein B (apoB) &amp;lt; 65 mg/dL. However, they don’t clarify what the attitude should be when one of the two targets is not achieved. Our objective was to establish the prevalence of LDLc and ApoB discordance in a secondary prevention population in our cardiac rehabilitation unit and describe the size of LDLc particles in this cohort of patients. We conducted a retrospective observational study including patients with previous ischemic heart disease with lipid-lowering treatment in secondary prevention followed up in our cardiac rehabilitation unit between February 2022 and September 2022. We present a series of 100 patients with a mean age of 60.5 years (S.D. 9.7), 79% male, with high prevalence of cardiovascular risk factors (59% hypertension, 26% diabetes mellitus, 52% smokers). All patients received lipid-lowering therapies, with statins alone or in combination with Ezetimibe. 30 patients (30%) had LDLc &amp;gt; 55 mg/dL and ApoB &amp;lt; 65 mg/dL, 37 (37%) reached target LDL and ApoB levels (LDLc &amp;lt; 55 mg/dL and ApoB &amp;lt; 65 mg/dL), and 33 (33%) did not reach any of the target levels (LDLc &amp;gt; 55mg/dL and ApoB &amp;gt; 65 mg/dL). No patient had LDLc &amp;lt; 55mg/dL and ApoB &amp;gt; 65mg/dL. Among patients with ApoB target level achieved and LDLc &amp;gt; 55mg/dL, the mean LDLc/ApoB ratio was 1.1 (S.D. 0.1). The mean ratios stratified by LDLc level are represented in Figure 1 and specified in Table 1. The conclusion of our study is that in clinical practice we find a group of patients with discrepancy between LDLc and ApoB levels that is not represented in the main studies of cardiovascular outcomes. Therefore, we do not know what therapeutic approach we should take. It is known that these relatively high LDLc values when apoB is in range correspond to larger and less dense particles, and therefore less atherogenic, and it has been suggested that ApoB levels better reflect residual risk than LDLc in statin-treated patients. At this point, the question that arises is: should we take these patients to an LDL &amp;lt; 55mg/dL or is their lipid risk controlled?

Prevention of Cardiovascular Events in Patients With Chronic Kidney Disease.

To examine the evidence base for lifestyle and pharmacologic interventions to reduce the risk of cardiovascular events in patients with chronic kidney disease, with an emphasis on reporting available data in distinct subtypes. A PubMed search (origin to February 2023) was conducted and references for selected studies were reviewed to identify additional articles. Search terms included chronic kidney disease, major adverse cardiovascular events, and heart failure hospitalization. English language studies reporting cardiovascular outcomes data in patients with chronic kidney disease were included. Much of the data on interventions to prevent cardiovascular events in patients with chronic kidney disease are derived from observational studies or subgroup analyses of trials of broader populations. Some common recommendations, such as weight loss, may be harmful in certain patients. Others may only offer benefits in subgroups, such as those with albuminuria. Newer agents, such as SGLT2 inhibitors and finerenone, have clearer evidence of cardiovascular benefit, but these may also apply only to specific subgroups. Given the prevalence of chronic kidney disease and its attendant cardiovascular risk, it is important to understand which interventions offer the greatest benefit. Patients diagnosed with chronic kidney disease have markedly increased risk of cardiovascular events, including myocardial infarction, stroke, heart failure, and cardiovascular death. However, until recently, there were few cardiovascular outcome studies that targeted enrollment specifically to those patients. Certain drugs now have shown benefits to cardiovascular end points in this population.

The growing clinical effect of SGLT2 inhibitors

In September, 2015, the results of EMPA-REG OUTCOME, the first cardiovascular outcomes study based on a sodium-glucose co-transporter-2 (SGLT2) inhibitor, empagliflozin, were announced at the Annual Meeting of the European Association for the Study of Diabetes. It was the first of a series of cardiovascular outcome studies confirming a significant risk reduction of the three-point MACE (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke) in people with type 2 diabetes and established atherosclerotic cardiovascular disease. It was also the first clinical trial to show potential renal protection: empagliflozin was associated with reduced loss of estimate glomerular filtration rate compared with placebo. Moreover, the trial reported a significant reduction in the risk of hospitalisation for heart failure. 1 Zinman B Wanner C Lachin JM et al. Investigators E-ROEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128 Crossref PubMed Scopus (7211) Google Scholar The cardiorenal protective effects of SGLT2 inhibitors have been confirmed in subsequent cardiovascular outcomes studies done in people with type 2 diabetes 2 McGuire DK Shih WJ Cosentino F et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021; 6: 148-158 Crossref PubMed Scopus (339) Google Scholar and without diabetes. 3 Vaduganathan M Docherty KF Claggett BL et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022; 400: 757-767 Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar Because of these results, current guidelines recommend the use of a SGLT2 inhibitor with proven beneficial effect for people with type 2 diabetes with chronic kidney disease and a history of heart failure. 4 Davies MJ Aroda VR Collins BS et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022; 65: 1925-1966 Crossref PubMed Scopus (32) Google Scholar Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trialDapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition. Full-Text PDF

Abstract P6-05-09: Cardiovascular Risk Evaluation for Breast Cancer Survivors: A Pilot Study

Abstract Introduction: Breast cancer (BC) is the most common cancer in women in the United States (US). With advances in screening and treatment, there are increasing numbers of BC survivors. Preexisting or emerging cardiovascular (CV) risk factors and some cancer therapies put BC survivors at risk for long-term CV disease (CVD). ASCO clinical practice guidelines for prevention and monitoring of cardiac dysfunction recommend treatment of CV risk factors in cancer survivors, however, the application of these guidelines in clinical practice presents several challenges. In this pilot study, we describe the feasibility of performing CVD risk assessment in a cohort of BC survivors in a single institution in an urban area that serves mostly Black/African American (AA) populations. Methods: We identified patients with early-stage BC treated between 2015 and 2022. Patients underwent CVD risk assessment including vital signs, hemoglobin A1c, lipid panel, transthoracic echocardiogram (TTE), 6-minute walk test (6MWT), troponin T, and B-type natriuretic peptide (NT-ProBNP). The primary objective of the study was to describe the feasibility of performing a CVD risk assessment. Results: Out of 69 eligible patients who were approached for the study, 50 were enrolled and completed the CVD risk assessment (72%). Among 19 patients who did not enroll or complete the risk assessment, time constraints to complete the work up was the predominant factor. The median age was 60.5 years (SD = 13.65; range 34-86), 76% self-identified as Black/AA, 14% as White, and 95% as Non-Hispanic. Half of the patients had hormone-receptor-positive BC, 34% human epidermal growth factor receptor 2 (HER2) positive disease (and received HER2-targeted therapies), and 28% triple-negative breast cancer (TNBC). In terms of treatment, 34% received anthracycline-containing regimens. CVD risk assessment results are shown in Table 1. Twenty-four (48%) of the patients had metabolic syndrome defined as the presence of 3 out of 5 CV risk factors (waist circumference, hypertension, low HDL, high triglycerides, insulin resistance). Although all patients had an ejection fraction (EF) above 55%, 7 patients (14%) had an abnormal global longitudinal strain (GLS). The median number of meters in the 6MWT was 369 (SD 94.46, range 67-531); 74% of patients walked a shorter distance than predicted by age and body mass index, indicating significant physical impairment. All patients had a troponin T value below the 99th percentile. The most frequent modifiable CVD-risk factors included obesity and hypertension. Conclusion: Performing a low-cost CVD risk assessment in a population of mostly Black/AA BC survivors was feasible in this pilot study. We identified a high prevalence of CVD risk factors, with 48% of patients meeting metabolic syndrome criteria and the majority of patients demonstrated a very high level of functional impairment measured by 6MWT. Our findings underscore the importance of survivorship care focused on CVD risk in BC survivors. Limitations include the small sample size, single-institution study, and lack of CV and BC-related outcomes. The higher incidence of TNBC could be explained by a selection bias of patients receiving cytotoxic chemotherapy and the higher incidence of TNBC in the Black/AA population. Future research will focus on implementing this assessment in the survivorship clinic and establishing interventions to decrease CVD risk in cancer survivors. Table 1. Clinical Measurements &amp; Outcomes (n=50). Citation Format: Ilana Schlam, Dipanjan Debnath, Christopher Gallagher, Asma A. Dilawari, Shruti R. Tiwari, Malate Aschalew, Hiwot Guebre-Xabiher, Stacy Malloy, Kristi Graves, Ana Barac, Ami Chitalia. Cardiovascular Risk Evaluation for Breast Cancer Survivors: A Pilot Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-09.

Abstract OT2-01-05: The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) therapy to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in the non-cancer population is associated with CV disease, including atherosclerosis and coronary artery disease, which can be detected pre-clinically by myocardial perfusion imaging and coronary artery plaques. This, together with the CV morbidity associated with other aspects of BC treatment and future life-years of these women, warrants further investigation with the goal of identifying pre-clinical markers of myocardial compromise. We seek to do this with the following specific aims: 1. Characterize and quantify the extent of coronary microvascular injury and perfusion changes experienced during early NCED therapy. 2. Characterize and quantify the extent of structural and functional alterations to the aorta and left ventricle while on NCED therapy. 3. Identify potential biomarkers and additional risk factors for CV morbidity in patients receiving NCEDTrial Design: This is a federally funded (NHLBI) prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary outcome is myocardial perfusion reserve (MPR) as measured by CMR imaging stress studies. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors, including an emphasis on racial disparities, on study outcomes, and dynamic change in modifiable and treatment related risk factors. Statistical Methods: We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group) for Aims 1 and 2. Comparisons will be made using longitudinal mixed models to examine effects on outcomes measured. The second analyses, for Aim 3, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with MPR. The sample size allows 80% power to address specific aims for between and within group comparisons, including a between group difference of 2.8% in our primary outcome, MPR. Present Accrual: 0 Target Accrual: 90 Contact information: Emily Douglas, MD; edouglas@wakehealth.edu Table 1: Study Procedures Citation Format: Emily Douglas, Nathaniel O’Connell, Mary Hackney, Wendy Bottinor, John Grizzard, Igor Klem, Carolyn Park, Sujethra Vasu, Karl Richardson, Susan Dent, Ralph D’Agostino, Gregory Hundley, Jennifer Jordan, Alexandra Thomas. The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-05.

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods: ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214). Conclusion: This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data.

Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study. The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.

S-32-3: RECENT IDACO ANALYSIS ON THE RISK OF PROGRESSION TO SUSTAINED HYPERTENSION FROM WHITE-COAT HYPERTENSION OR MASKED HYPERTENSION

In the general population, the cardiovascular risk is increased in patients with masked hypertension (MH), whereas in individuals with white-coat hypertension (WCH) it is virtually the same as in the normotensive individuals. However, no conclusive evidence exists as to whether WCH and MH are accompanied by a greater rate of development of a sustained hypertensive state, i.e. hypertension both in and outside the clinical environment. We investigated the risk of progression to sustained hypertension in initially untreated participants of cohort studies included in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcome (IDACO) study. Within the IDACO, 5 populations comprising 1081 individuals had ambulatory (ABP) and conventional (CBP) blood pressure measured at baseline and at follow up. We excluded from the analysis subjects on BP-lowering treatment at baseline (n = 252) and individuals with untreated sustained hypertension at baseline (n = 80), leaving 749 subjects included in the current analysis. The cut-off value for elevated CBP was &gt; = 140/90 mm Hg and for daytime ABP &gt; = 135/85 mm Hg. At baseline, 110 individuals (14.7%) was defined as MH, 64 subjects as WCH (8.5%), and 575 (76.8%) as normotensives. MH patients were older (50 vs 45 years compared to normotensives, P &lt; 0.01) and more frequently male (50.9 vs 31.5% compared to normotensives, P &lt; 0.01). During median follow-up of 9.7 years, there were 264 incident cases of sustained hypertension. In the analyses adjusted for cohort, sex, age, body mass index, smoking and drinking, both MH (HR 2.23, 95%CI 1.57 to 3.17) and WCH (HR 1.84, 95%CI 1.37 to 2.47) significantly increased risk of progression to sustained hypertension. In conclusion, long-term risk of progression to sustained hypertension is 2-fold higher in individuals with masked hypertension or white coat hypertension at baseline as compared to normotensive subjects at baseline. However, this observation might be due to more frequent initiation of antihypertensive therapy in both groups.

Emerging Evidence for the Use of Antidiabetic Drugs, Glucagon-like Peptide 1 Receptor Agonists, for the Treatment of Alzheimer's Disease.

From an epidemiological and pathophysiological point of view, Alzheimer's disease (AD) and type 2 diabetes (T2DM) should be considered 'sister' diseases. T2DM significantly increases the risk of developing AD, and the mechanisms of neuronal degeneration themselves worsen peripheral glucose metabolism in multiple ways. The pathophysiological links between the two diseases, particularly cerebral insulin resistance, which causes neuronal degeneration, are so close that AD is sometimes referred to as 'type 3 diabetes'. Although the latest news on the therapeutic front for AD is encouraging, no treatment has been shown to halt disease progression permanently. At best, the treatments slow down the progression; at worst, they are inactive, or cause worrying side effects, preventing their use on a larger scale. Therefore, it appears logical that optimizing the metabolic milieu through preventive or curative measures can also slow down the cerebral degeneration that characterizes AD. Among the different classes of hypoglycaemic drugs, glucagon-like peptide 1 receptor agonists, which are widely used in the treatment of T2DM, were shown to slow down, or even prevent, neuronal degeneration. Data from animal, preclinical, clinical phase II, cohort and large cardiovascular outcomes studies are encouraging. Of course, randomized clinical phase III studies, which are on-going, will be essential to verify this hypothesis. Thus, for once, there is hope for slowing down the neurodegenerative processes associated with diabetes, and that hope is the focus of this review.