Patients with type 2 diabetes mellitus (T2DM) are at high cardiovascular risk. National and international guidelines recommend aggressive low-density lipoprotein cholesterol (LDL-C) lowering with statin therapy; however, statins may increase glucose levels. This phase 2 study was the first to

Importance:Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant. Objective:To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo. Design, Setting, and Participants:This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance. Interventions:Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks. Main Outcomes and Measures:Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins. Results:In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was -16.0% with bempedoic acid vs 1.8% with placebo (difference, -17.8%; 95% CI, -19.5% to -16.0%; P < .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were -23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, -24.5%; 95% CI, -27.8% to -21.1%; P < .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of -12.7% at week 52; patients with statin intolerance, difference of -22.2% at week 24). Decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs <0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%). Conclusions and Relevance:Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients. Trial Registration:ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115.

This study was funded by IONIS/Akcea Therapeutics; Gaudet D: Received research grant support from FH Canada, Aegerion (Novelion Therapeutics), Amgen, Akcea Therapeutics a subsidiary of IONIS Pharmaceuticals, Astra Zenca, Chiesi, Cymabay, DalCor Pharma, Esperion, GlaxoSmithKiline, Gemphire, Ionis, Pfizer, Regeneron and Sanofi. Served as a consultant for Amgen, Aegerion, Akcea, Chiesi, Cymabay, IONIS, Regeneron, Sanofi and Uniqure; Digenio A: Employee of Akcea Therapeutics a subsidiary of IONIS Pharmaceuticals; Alexander, VJ: Employee of IONIS Pharmaceuticals; Arca M: Received grants/ honoraria from AMGEN, SANOFI, PFIZER, AEGERION, MSD, MYLAN and IONIS; Jones A: None; Stroes E: Received lecturing fees from Amgen, Sanofi, Chiesi, Novartis and Merck; Bergeron J: Received honoraria/fees as Advisory Board Member from Aegerion, Amgen and Sanofi; Clinical trial investigator for Amarin, Amgen, Akcea, Esperion, Ionis, Pfizer, Regeneron, Sanofi and the Medicines Company; Civeira F: None; Hemphill L: Consultant to Aegerion and Regeneron; Clinical trial investigator for IONIS/Akcea Therapeutics, Regeneron and Sanofi; Blom DJ: Advisor and clinical trial investigator for IONIS/Akcea Therapeutics; Flaim J: Ionis Pharmaceuticals stockholder; Hughes S: Employee of IONIS Pharmaceuticals; Geary R: Employee of IONIS Pharmaceuticals; Tsimikas S: Employee of IONIS Pharmaceuticals; Witztum JL: Consultant for IONIS/Akcea Therapeutics, Intercept, Cymabay and Prometheus; Bruckert E: Received honoraria from AstraZeneca, AMGEN, Genfit, MSD, Sanofi and Regeneron, Unilever, Institut Benjamin Delessert, Danone, Aegerion, Chiesi, Rottapharm-MEDA, Lilly, Ionis Pharmaceuticals.

Dr. Gaudet has been the principal investigator for this trial and has received funding from Isis Pharmaceuticals to conduct this study.

Background: Apolipoprotein C-III (apoC-III), a CV risk factor, plays a pivotal role in regulating plasma triglyceride (TG) levels. Elevated TG and its nonesterified fatty acid (NEFA) derivatives are associated with insulin resistance and type 2 diabetes. ISIS-APOCIII Rx selectively inhibits apoC-III protein synthesis in the liver and studies show it may improve insulin sensitivity in patients with type 2 diabetes. Treatment with ISIS-APOCIII Rx results in significant dose-dependent decreases in apoC-III and TG levels (Table) in patients with severe hypertriglyceridemia (SHTG) as monotherapy or add on to a stable dose of fibrate. The present study assessed the potential resulting change in NEFA levels in these patients. Methods: Adult patients with SHTG treated or untreated with fibrate were enrolled in a double-blind Phase 2 study to receive ISIS-APOCIII Rx (up to 300 mg) or placebo as weekly SC injections for 13 weeks. Baseline and end-of-treatment fasting serum samples were analyzed for NEFA levels. Results: Results show significant reductions in NEFA levels in line with reductions in TG levels at the 300 mg/week dose (the Phase 3 dose) of ISIS-APOCIII Rx (Table). ISIS-APOCIII Rx was generally safe and well tolerated. There were no clinically meaningful changes in liver tests or other laboratory values. Conclusions: Treatment with ISIS-APOCIII Rx reduces NEFA levels together with decreases in TG in patients with treated or untreated SHTG suggesting the potential for improvement in peripheral insulin sensitivity in these patients.

ApoC-III plays a pivotal role in regulating plasma triglyceride (TG) levels by inhibiting the hydrolysis of TG-rich lipoproteins and the receptor-mediated uptake of lipoprotein remnants by the liver and is recognized as a CV risk factor. ISIS-ApoCIIIRx selectively inhibits apoC-III protein synthesis