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In a randomized trial of patients with primary biliary cholangitis, bezafibrate and ursodeoxycholic acid resulted in a higher rate of complete biochemical response than ursodeoxycholic acid alone. Bezafibrate was associated with increases in creatinine and myalgias.

Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects (\"statin-intolerant\" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

Background Whereas European guidelines recommend adjusting lipid-lowering therapy (LLT) to meet prespecified targets (‘treat-to-target’) for low-density lipoprotein cholesterol (LDL-C), other guidelines do not (‘fire and forget’). In a large observational prospective cohort, we sought to evaluate which strategy could be associated with better cardiovascular outcomes in chronic kidney disease (CKD). Methods In CKD-REIN, patients (CKD stages 3 and 4) on LLT were categorized according to achievement of LDL-C targets for high and very high cardiovascular risk (< 2.6 and < 1.8 mmol/L, respectively) at baseline. Primary outcome was fatal/non-fatal atheromatous cardiovascular disease (CVD). Secondary outcomes were non-atheromatous CVD, atheromatous or non-atheromatous CVD, and major adverse cardiovascular events. Results The population comprised 1521 patients (68 ± 12 years, 31% women, mean estimated glomerular filtration rate [eGFR] 35 mL/min/1.73 m 2 ). Overall, 523 (34%) met their LDL-C targets at baseline. Median follow-up was 2.9 years (interquartile range 2.2–3.0). Incidence rates per 100 patient-years were 6.2% (95% confidence interval [CI] 5.5–7.0) for atheromatous CVD, 9.2% (8.3–10.1) for non-atheromatous CVD, 15.2% (14.0–16.4) for atheromatous/non-atheromatous CVD, and 6.3% (5.5–7.1) for major adverse cardiovascular events. Corresponding rates in patients who achieved targets were 6.6%, 9.8%, 16.1%, and 6.3%, respectively. Target achievement was not associated with risk of fatal/non-fatal atheromatous CVD (adjusted hazard ratio 1.04, 95% CI 0.76–1.44, p  = 0.77) or fatal/non-fatal atheromatous or non-atheromatous CVD (0.98, 0.78–1.23, p  = 0.91). Conclusions These findings do not appear to support a treat-to-target approach in CKD patients on LLT, and may favor the hypothesis of an advantage of fire-and-forget. Randomized trials are needed to confirm this theory. Graphic abstract

Elevated levels of lipoprotein(a) in the plasma are a risk factor for cardiovascular disease, and lowering levels can be achieved with antisense oligonucleotide targeting LPA messenger RNA, which encodes lipoprotein(a). This trial tested whether the same effect can be achieved in persons with established cardiovascular disease.

Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate) and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C). PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD) which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil) and myopathy should also be acknowledged.

Key Points The liver X receptors (LXRs) are sterol-sensitive transcription factors that regulate cholesterol homeostasis. LXRs control the expression of genes that are linked to lipid synthesis, transport and excretion in many tissues. LXRs are crucial regulators of the reverse cholesterol transport pathway and are important determinants of whole-body cholesterol content. Pharmacological activation of LXRs inhibits the development of atherosclerosis in animal models. Subtype-selective LXR agonists and tissue-selective agonists are promising strategies for the development of targeted modulators of lipid metabolism. Alterations in LXR-dependent gene expression and cholesterol metabolism have been associated with the development of neurological diseases, including Alzheimer's disease. LXR is a promising therapeutic target but the development of novel drugs faces many challenges, including undesirable hepatic side effects. The liver X receptors (LXRs) are key regulators of lipid homeostasis. Here, the authors highlight tissue-specific aspects of LXR function with a focus on the liver, intestine and brain, and discuss the implications of recent advances in the understanding of LXR activity for drug development. The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.

In a phase 2b trial involving patients with hypertriglyceridemia, the use of olezarsen (which targets APOC3 mRNA) for 6 months reduced triglyceride levels by approximately 50% as compared with placebo.

The effects on lipid profiles of pharmacologic inhibition of ATP citrate lyase, an enzyme in the cholesterol–biosynthesis pathway upstream of HMGCR (the target of statins), are similar to those of statins. This inhibition may lower the risk of cardiovascular disease.

The development of osteoarthritis (OA) correlates with a rise in the number of senescent cells in joint tissues, and the senescence-associated secretory phenotype (SASP) has been implicated in cartilage degradation and OA. Age-related mitochondrial dysfunction and associated oxidative stress might induce senescence in joint tissue cells. However, senescence is not the only driver of OA, and the mechanisms by which senescent cells contribute to disease progression are not fully understood. Furthermore, it remains uncertain which joint cells and SASP-factors contribute to the OA phenotype. Research in the field has looked at developing therapeutics (namely senolytics and senomorphics) that eliminate or alter senescent cells to stop disease progression and pathogenesis. A better understanding of how senescence contributes to joint dysfunction may enhance the effectiveness of these approaches and provide relief for patients with OA.The development of osteoarthritis (OA) correlates with an increase in the number of senescent cells in joint tissues and the senescence-associated secretory phenotype is implicated in cartilage degradation and OA. Eliminating or altering senescent cells with senolytics or senomorphics could stop OA progression and pathogenesis.

In a randomized trial, patients with type 2 diabetes, hypertriglyceridemia, and low HDL cholesterol who received pemafibrate did not have fewer cardiovascular events, although some lipid levels decreased.