etc-1002 and Diabetes-Mellitus--Type-2

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss.. While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed.. ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Topics: ATP Citrate (pro-S)-Lyase; Cholesterol; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipogenesis; Randomized Controlled Trials as Topic

At the 2019 American College of Cardiology annual scientific sessions, major randomized clinical trials in cardiovascular disease (CVD) prevention were presented.. The CLEAR Wisdom trial examined the safety and efficacy of adding bempedoic acid to maximally tolerated statin for reducing low-density lipoprotein cholesterol. Post hoc analyses from the REDUCE-IT trial evaluated the efficacy of icosapent ethyl for lowering risk of total (first time and recurrent) CVD events. A sub-analysis of ODYSSEY OUTCOMES examined the effect of alirocumab on lipoprotein(a) lowering for reducing CVD risk. The CREOLE trial compared three different combination antihypertensive therapies for blood pressure lowering among black individuals in sub-Saharan Africa. The INFINITY trial examined the effect of intensive blood pressure control on progression of brain white matter changes and various components of mobility and cognitive function. Lastly, post hoc analyses from DECLARE-TIMI 58 evaluated the efficacy of dapagliflozin among patients with type 2 diabetes mellitus and heart failure or peripheral artery disease. These trials hold future promise for novel agents aimed at reducing CVD burden among high-risk patients who continue to experience CVD events despite treatment with currently available guideline-directed therapy.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Eicosapentaenoic Acid; Fatty Acids; Female; Glucosides; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; United States

To evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia.. A patient-level pooled analysis of four phase 3, randomized, double-blind, placebo-controlled trials evaluated changes in glycaemia, change from baseline in LDL-C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia).. The annual rate of new-onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P < .0001) reduced HbA1c by -0.12% and -0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significantly and consistently lowered LDL-C levels versus placebo, regardless of baseline glycaemic status (placebo-corrected difference range, -17.2% to -29.6%; P < .001 for each stratum). The safety of bempedoic acid was comparable with placebo and similar across glycaemic strata.. Bempedoic acid significantly lowered LDL-C across glycaemic strata and did not worsen glycaemic variables or increase the incidence of new-onset diabetes versus placebo over a median follow-up of 1 year.

Topics: Cholesterol, LDL; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Double-Blind Method; Fatty Acids; Glycemic Control; Humans; Prediabetic State; Treatment Outcome

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed.. A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed.. ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population.. http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

Topics: Aged; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; Blood Pressure; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Double-Blind Method; Fasting; Fatty Acids; Female; Humans; Hypercholesterolemia; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Treatment Outcome; Triglycerides

Topics: Diabetes Mellitus, Type 2; Dicarboxylic Acids; Fatty Acids; Humans

Topics: Anticholesteremic Agents; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Fatty Acids; Female; Humans; Hypercholesterolemia; Male