Leptin treatment has vasculo-protective effects in lipodystrophic mice.

Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-ß2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr-/-; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.

Proprotein convertase subtilisin/kexin type 9-inhibition across different patient populations.

PURPOSE OF REVIEW: Monoclonal antibodies (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been established in cardiovascular risk prevention. The purpose of this review is to summarize the effects of PCSK9 inhibitors across different patient populations. RECENT FINDINGS: Long-term data on the use of evolocumab and alirocumab shows persisting low- density lipoprotein cholesterol (LDL-C) lowering and good tolerability. PCSK9 inhibitors are effective and safe in both sexes, in pediatric patients as well as in the elderly. Initiation of PCSK9 mAb during acute myocardial infarction is safe and leads to beneficial morphological plaque changes. The PCSK9 inhibitors evolocumab, alirocumab and inclisiran lower LDL-C in patients with heterozygous familial hypercholesterolemia (FH), while the response of patients with homozygous FH is heterogeneous. New areas of application beyond lipid lowering are currently investigated. SUMMARY: PCSK9 inhibitors are safe, well tolerated, and effective in primary and secondary prevention in a wide range of patient populations.

[Statin intolerance and statin-associated muscular pain]. / Statinintoleranz und statinassoziierte Muskelschmerzen.

Statins are among the best studied drugs. Due to the extensive evidence regarding efficacy and safety, they are the cornerstone of lipid-lowering therapy. While the tolerability of statins in large blinded studies is at the placebo level, so-called statin intolerance (SI) is a frequent and complex problem in everyday clinical practice. Statin-associated muscular pain (SAMS) is most commonly reported. In many cases SI is associated with inadequate lowering of low-density lipoprotein (LDL) cholesterol (LDL-C), thereby increasing the cardiovascular risk. The diagnosis of SAMS is based on the exclusion of possible alternative causes of muscular symptoms and the exclusion of nocebo effects through a diagnostic strategy of discontinuation of statin treatment, observation and assessment of symptoms, followed by renewed administration of a different statin initially at a low dose with subsequent dose increase. A large proportion of patients with SI and SAMS can take statins permanently and without discomfort by this approach. If LDL­C lowering is insufficient, combination therapies are used. It is an important task of the prescribing physicians and all those involved in the treatment to increase the adherence to statins through appropriate communication. Numerous questions on SI remain open and are being addressed by an ongoing register.

[Treatment and LDL cholesterol adjustment in patients with high and very high cardiovascular risk in Germany compared with Europe - data from the SANTORINI registry]. / Behandlung und LDL-Cholesterin-Einstellung von Patienten mit hohem und sehr hohem kardiovaskulärem Risiko in Deutschland und im europäischen Vergleich ­ Daten des SANTORINI-Registers.

INTRODUCTION: Current 2019 ESC/EAS guidelines for the management of dyslipidemia recommend LDL cholesterol (LDL-C) goals according to the patients' cardiovascular (CV) risk. SANTORINI is the first large European observational study since the 2019 guidelines to assess whether lipid management in patients at high and very high CV risk has improved. METHODS: SANTORINI is a multinational, prospective, non-interventional, observational study in 9602 patients ≥ 18 years at high and very high CV risk requiring lipid-lowering therapy. Individual CV risk was assessed by the investigator. The primary study objective is to document, in a real-world setting, the effectiveness of current lipid management regarding LDL-C levels. RESULTS: For this analysis, complete recruitment data was available for 2086 patients in Germany and 6958 patients Europe. Investigators used the 2019 ESC/EAS guidelines as a basis for CV risk classification in > 50 % of the patients and classified 15.6 % (173/1112) of patients in Germany as high and 84.4 % (939/1112) as very high-risk (Europe: 20.7 % [743/3594] high, 79.3 % [2851/3594] very high CV risk). An independent re-calculation of the CV risk based on these guidelines classified 4.1 % (46/1112) of patients in Germany as high and 94.5 % (1051/1112) as very high-risk. Also in Europe, CV risk was underestimated in around 10 % of patients.At baseline, 59.5 % (1241/2086) patients in Germany and 52.6 % (3661/6958) patients in Europe received lipid-lowering monotherapy; 19.9 % (416/2086) and 25.2 % (1753/6958) of patients in Germany and Europe received combination therapy. 78.6 % (1640/2086) of patients in Germany missed the 2019 ESC/EAS guideline recommended LDL-C treatment goals (Europe: 71.1 % [4989/6958]). DISCUSSION: The 2019 ESC/EAS guideline recommendations are only implemented in a minority of patients. The study identifies opportunities for improvements in the prevention of CV diseases in Germany.