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Background/Introduction Both major adverse cardiovascular events (MACE) and non-alcoholic fatty-liver disease (NAFLD) are highly prevalent in patients with high BMI and long-standing type 2 diabetes (T2DM). NAFLD is characterized by an augmented hepatic inflammation and fat deposition and is strongly associated with metabolic syndrome. Patients with NAFLD are at an increased risk of cardiovascular (CV) events, and MACE is the leading cause of death for patients with NAFLD. Apabetalone (APB) is a novel selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. In the Phase 3 BETonMACE trial treatment of 2,425 T2DM patients post ACS with APB, resulted in hazard ratios (HR) of 0.82 (p=0.11) for the primary endpoint of ischemic MACE (CV death, non-fatal MI or stroke) and 0.59 (p=0.03) for the secondary endpoint of heart failure hospitalization (HFH) vs placebo (PBO). Transient elevations of alanine aminotransferase greater than 5xULN occurred in 3.3% of APB treated patients. Purpose In this exploratory post hoc analysis of BETonMACE we evaluated risk modification for a composite of MACE+HFH by APB based on the Angulo NAFLD fibrosis score (FS) using 6 variables (age, BMI, hyperglycemia/diabetes, AST/ALT ratio, platelet count, and albumin). The NAFLD FS categorizes individuals into groups that correlate with differing levels of fibrosis in biopsy studies: (FS F0-F2, no significant fibrosis; FS ID, indeterminant; and FS F3-F4, significant fibrosis). Methods Baseline characteristics and blood measurements were used to determine NAFLD FS at baseline. The incidence of MACE+HHF was compared between treatment groups. Results Based on FS, there were 618 pts were classified as FS F0-F2 (n=328 APB, n=290 PBO), 1,440 pts were classified as FS ID (n=708 APB, n=732 PBO) and 289 pts were classified as FS F3-F4 (n=144 APB, n=145). MACE+HHF in the PBO group was higher in FS ID and FS F3-F4 compared to FS F0-F2 (17.2% vs 15.0% vs 9.7%) and therefore the former two groups were combined into an elevated risk FS+ group. FS+ pts were older (63 vs 56), had longer duration of T2DM (9.0 vs 7.3 yrs), and higher BMI (30.8 vs 28.6) compared to FS- pts. Overall, APB was associated with fewer MACE+HHF (HR 0.78, 95% CI 0.60–1.01, p=0.06) compared to PBO in the FS+ pts with adjustment for age, duration of T2DM and BMI. Conclusions Patients with T2DM and ACS may share common risk factors with patients with NAFLD. Apabetalone appears to exert a favorable effect on MACE in patients with risk factors for NAFLD. Whether apabetalone has a modulatory effect on the development and progression of NAFLD is an important question requiring further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Resverlogix Corp.

Background and Aims The burden of disease associated with FSGS has not been well characterized, especially with regard to health care resource utilization (HCRU) and related costs. The aim of this study was to evaluate all-cause HCRU and estimate associated costs in patients with FSGS compared with a matched non-FSGS cohort; a secondary aim was to evaluate the impact of nephrotic range proteinuria on these outcomes. Method Data were from the Optum Clinformatics® Data Mart Database. Patients with ≥ 1 claim (1st claim = index event) for FSGS between April 2016 and December 2018 were identified based on ICD-10-CM codes and matched 1:2 (FSGS:controls) on index date, age, sex, and race to non-FSGS controls; continuous enrollment 6 months pre- and 12 months post-index was required. FSGS nephrotic range (either UPCR >3000 mg/g or ACR >2000 mg/g) and non-nephrotic subpopulations were also identified. Quan-Charlson Comorbidity Index (CCI) and individual comorbidities at baseline, and 12-month post-index all-cause HCRU and associated costs (per patient per year [PPPY]) as well as medication prescriptions related to FSGS treatment were compared between the matched cohorts and between the FSGS subpopulations; t-tests were used for continuous variables and chi-square tests for categorical variables. Results 844 patients with FSGS were matched with 1688 non-FSGS controls; 57.4% male, 56.9% white, mean (SD) age 54.7 (18.4) years. Mean (SD) CCI was higher in the FSGS cohort relative to matched controls (2.72 [2.12] vs 0.55 [1.29]; P < .0001), with prevalence of most individual comorbidities higher in the FSGS cohort. Only 308 FSGS patients (36.5%) had UPCR or ACR tests with available results during the review period; 112 (36.4%) were in the nephrotic range and 196 were non- nephrotic (63.6%). The FSGS cohort was characterized by higher rates of all-cause HCRU across resource categories (all P < .0001) (Table 1); outpatient visits was the most frequently used category (99.1% vs 69.0%), followed by prescription medications. Among patients who used these resources, units of use were significantly higher in FSGS vs matched controls except for length of stay (Table 1). Readmission rates following 1st post-index hospitalization were higher in the FSGS cohort vs matched controls at 30 days (16.1% vs 6.0%; P < .05) and 365 days (39.1% vs 22.9%; P < .05). Glucocorticoids were the most frequently prescribed FSGS-related medication in both cohorts, with a higher rate in FSGS vs matched controls (50.6% vs 23.3%; P < .0001); other FSGS-related medications were infrequently prescribed (< 14%). Inpatient, outpatient, and prescription costs were higher in the FSGS cohort vs matched controls (all P < .0001) resulting in mean total annual medical costs of $59,753 vs $8,431 PPPY (P < .0001) that were driven by outpatient costs (Fig. 1A). Nephrotic range proteinuria was associated with higher all-cause inpatient, outpatient, and prescription costs vs non-nephrotic patients (all P < .0001; Fig. 1B), resulting in higher total costs ($70,481 vs $36,099 PPPY; P < .0001). A higher proportion of nephrotic range patients were prescribed FSGS-modifying medications (73.2% vs 54.1%; P = 0.001), with glucocorticoids the most frequent medication. However, 26.8% of nephrotic range patients were not prescribed any FSGS-related medications. Conclusion FSGS is associated with significant clinical and economic burdens with total annual medical costs > 7-fold higher than matched controls that were driven by outpatient costs. The presence of nephrotic range proteinuria substantially and significantly increased the economic burden. New treatment modalities leading to lower rates of proteinuria may help improve patient outcomes while reducing HCRU and their associated costs.

Background Despite established treatments, patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS) are at higher risk of ischemic cardiovascular (CV) events and hospitalization for heart failure (HHF) compared to those without T2DM. LDL-C lowering or use of GLP-1 agonists predominantly affects ischemic CV events, with little effect on HHF. Conversely, treatment with SGLT-2 inhibitors reduces HHF, with less effect on ischemic CV events. Preclinical studies indicate that bromodomain and extra-terminal (BET) proteins coordinate gene transcription for pathways that promote atherothrombotic events as well as heart failure. We assessed the clinical effect of apabetalone (APB), a novel BET protein inhibitor, on a composite of non-fatal ischemic CV events, HHF, and CV death in a post hoc analysis of the BETonMACE trial Methods BETonMACE was a double-blind, placebo-controlled phase 3 study in patients with T2DM and recent acute coronary syndrome receiving standard of care risk factor management. In 13 countries, 2425 patients were enrolled. We conducted a time-to-event analysis for first adjudicated CV death or non-fatal MI, stroke, or HHF using a log-rank test and Cox proportional hazards model. Results At baseline median age was 62 years, 25.6% were female, 87.6% white, and use of high intensity statin, ACE inhibitors/ angiotensin II blockers, dual antiplatelet therapy and beta blocker were 90, 88, 92 and 91% respectively. A total of 312 subjects had an endpoint event, with 139 (11.5%) patients in the ABP group and 173 (14.3%) among PBO (HR 0.78, 95% CI 0.63–0.98, p=0.03, Figure). At 26 months, the absolute risk reduction was 3.2% and number needed to treat was 31. Numerically favorable HRs were observed for each component endpoint except for stroke (Table). Conclusion This present analysis suggests that BET inhibition with APB may be a novel pathway through which to reduce both HHF and ischemic CV events in high risk patients with T2DM thus impacting broader clinical outcomes with potentially large benefits for patients and healthcare systems. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Resverlogix Corp

Background and Aims Patients with type 2 diabetes (T2D) and acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular (CV) events, particularly in the presence of chronic kidney disease (CKD). Apabetalone (APB) is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Its cardiovascular efficacy and safety were evaluated in a phase 3 trial, BETonMACE. Method BETonMACE was a randomized, double-blind, comparison of effects of ABP or placebo (PBO) on major adverse CV events (MACE) defined as CV-death, non-fatal myocardial infarct or stroke, in 2425 pts with T2D and recent ACS. Here we report MACE plus CHF hospitalization in subjects with or without CKD Stage 3. Results Baseline characteristics: median age 62 years, 25.6% female, 87.6% white, 90% high intensity statin use, mean LDL-C 70.3 and HDL-C 33.3 mg/dl, median HbA1c 7.3%, and 11% with CKD Stage 3. Overall in the trial, MACE plus CHF hospitalization occurred in 139 (11.5%) patients with ABP and 173 (14.3%) with PBO (HR 0.78, 95% CI 0.63-0.98). In the subgroup with CKD, MACE plus CHF hospitalization occurred in 16 (12.9%) on APB and 41 (25%) on PBO (HR 0.48, 95% CI 0.26-0.89). In the subgroup without CKD, MACE plus CHF hospitalization occurred in 123 (11.3%) and 132 (12.7%) with APB or PBO, respectively (HR 0.89, 95% CI 0.70-1. Conclusion Patients with T2D, ACS, and Stage 3 CKD have a very high risk of subsequent MACE plus CHF hospitalization. The BET protein inhibitor ABP may reduce this risk.

Background Diabetes (DM) is associated with increased risk of macro/microvascular disease and cognitive decline. Inflammation and vascular calcification may be contributing factors. Bromodomain and extraterminal (BET) proteins coordinate gene transcription and modify the transcriptional response to hyperglycemia, and inflammation. Apabetalone competitively and selectively inhibits binding between BET proteins and acetyl-lysine marks on histone tails: normalizing transcriptional profiles to physiological levels; reducing in vitro alkaline phosphatase (ALP) transcription and in vivo plasma ALP in a dose-dependent manner. Phase 2 trials with apabetalone show improved renal function in the chronic kidney disease (CKD) subgroups. Furthermore, treatment showed a 55% reduction in CVD events with more pronounced benefit among patients with DM, low HDL-cholesterol (HDL-C) and high sensitivity C-reactive protein (hsCRP). Methods The double-blind, placebo controlled phase 3 BETonMACE trial is testing the hypothesis that apabetalone 100 mg b.i.d., added to standard care, reduces major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction or stroke) in patients with DM, acute coronary syndrome (ACS) within the preceding 7–90 days, low HDL-C (30 mL/min/1.7m2. The trial will continue until at least 250 MACE, providing 80% power to detect a 30% reduction. Secondary endpoints include changes in eGFR in patients with baseline eGFR 30 to Results Enrollment of 2425 patients across 13 countries and 195 centers is now complete. Baseline characteristics [median (IQR)] include LDL-C 65.0 (36) mg/dL, HDL-C 33.0 (7) mg/dL, HbA1c 7.3 (2.3) %, hsCRP 2.8 (4.9) mg/L, mean blood pressure 129/76 mmHg, and CKD in 266 patients (10.8%). Background care was based on guideline recommendations. Diabetes medications include metformin (79%), insulin (36%), sulfonylureas (28%), DPP4 inhibitors (11%), SGLT2 inhibitors (9.7%) and GLP1 receptor agonists (0.3%). The CKD subpopulation vs. total population differed significantly from the whole population with regard to age (71 vs. 62 y. o.), male sex (58% vs. 75%), history of hypertension (46% vs. 88%), history of stroke (1.5% vs. 7.5%), and current smokers (6.1% vs. 13%). In the 70 year and older (n=466, 19%) population 54% (n=243) showed a baseline MoCA score 25 and lower suggesting cognitive impairment. Summary The BETonMACE trial is testing the hypothesis that selective BET-inhibition with apabetalone, added to established, evidence-based treatment, reduces MACE in high-risk patients with DM, recent ACS, and low HDL-C. The study will also assess apabetalone's effect on renal function and cognition.

Author(s): Qader, Hemn; Streja, Elani; Obi, Yoshitsugu; Rhee, Connie M; Moradi, Hamid; Kovesdy, Csaba; Mehrotra, Rajnish; Kalantar-Zadeh, Kam

Author(s): Kalantar-Zadeh, Kam; Lerner, Lorena; Nicoletti, Richard; Feng, Bin; Soohoo, Melissa; Streja, Elani; Rhee, Connie M; Moradi, Hamid; Jing, Jennie; Nakata, Tracy; Kovesdy, Csaba; Gyuris, Jeno

Author(s): Feng, Ming; Streja, Elani; Obi, Yoshitsugu; Wang, Jialin; Soohoo, Melissa; Rhee, Connie; Lau, Wei Ling; Kovesdy, Csaba; Mehrotra, Rajnish; Kalantar-Zadeh, Kam

Author(s): Kim, Taehee; Streja, Elani; Obi, Yoshitsugu; Rhee, Connie; Moradi, Hamid; Kovesdy, Csaba; Mehrotra, Rajnish; Kalantar-Zadeh, Kam