Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis.

BACKGROUND: Lipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk. METHODS: We performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs. RESULTS: We included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47). CONCLUSION: LLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations. PROSPERO REGISTRATION: CRD42021271658.

Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

Background Randomized clinical trials (RCTs) might not be representative of the real-world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid-lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid-lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non-Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta-analyzed the prevalence of included patients to obtain pooled estimates with a random-effects model. We included 42 RCTs (298 605 patients). Eighty-one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy-one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%-49%), 11% (3%-18%) for >75 years of age, and 51% (38%-63%) for multimorbidity. Conclusions The majority of lipid-lowering therapy trials excluded patients with common diseases, such as moderate-to-severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side-effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909.

Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.

A general synthesis of 1-aryl carbamoyl-2-alkyl-4-aryl substituted semicarbazides as nonbasic factor Xa inhibitors.

An efficient four-step synthesis of 1-aryl-carbamoyl-2-alkyl-4-aryl-semicarbazides starting from benzophenone hydrazone is described leading to moderately active neutral factor Xa inhibitors.