Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. METHODS AND RESULTS: We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. CONCLUSIONS: After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.

Association of systemic lupus erythematosus with peripheral arterial disease: a meta-analysis of literature studies.

OBJECTIVE: SLE patients have an increased cardiovascular morbidity and mortality. Contrasting data are available about the association between peripheral arterial disease (PAD) and SLE. We aimed to perform a meta-analysis of studies evaluating the association between SLE and PAD. METHODS: Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases according to preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Eight studies reporting on 263 258 SLE patients and 768 487 controls showed that the prevalence of PAD was 15.8% (95% CI: 10.5%, 23.2%) in SLE patients and 3.9% (95% CI: 1.8%, 7.9%) in controls with a corresponding odds ratio of 4.1 (95% CI: 1.5, 11.6; P <0.001). In addition, five studies reporting on ankle-brachial index showed significantly lower values in 280 SLE patients as compared with 201 controls (mean difference: -0.018; 95% CI: -0.034, -0.001; P =0.033). Meta-regression models showed that age, hypertension and diabetes were inversely associated with the difference in the prevalence of PAD between SLE patients and non-SLE controls, whereas no effect for all the other clinical and demographic variables on the evaluated outcome was found. CONCLUSION: SLE patients exhibit an increased prevalence of PAD and lower ankle-brachial index values as compared with non-SLE controls. This should be considered when planning prevention, interventional and rehabilitation strategies for these chronic patients with functional disability and poor long-term outcomes.

Association of apolipoprotein levels with peripheral arterial disease: a meta-analysis of literature studies.

AIMS: Lower limb peripheral artery disease (PAD) is a leading cause of atherosclerotic cardiovascular disease (ASCVD). Discordant data are available on the association between apolipoprotein and PAD. We performed a meta-analyses on the association between apolipoprotein (apo)B, apoA-I, and apoB/apoA-I ratio with PAD. METHODS AND RESULTS: PubMed, Web of Science, Scopus databases were systematically searched. Studies providing data about apoB, apoA-I, apoB/apoA-I ratio in PAD subjects and non-PAD controls were included. Differences between PAD and non-PAD subjects were expressed as mean difference (MD) with pertinent 95% confidence intervals (95%CI). Twenty-two studies were included. Peripheral artery disease subjects showed higher apoB (MD: 12.5 mg/dL, 95%CI: 2.14, 22.87) and lower apoA-I levels (MD: -7.11 mg/dL, 95%CI: -11.94, -2.28) than non-PAD controls. Accordingly, ApoB/ApoA-I ratio resulted higher in PAD subjects than non-PAD controls (MD: 0.11, 95% CI: 0.00, 0.21). Non-HDL-C showed a direct association with the difference in apoB (z-value: 4.72, P < 0.001) and an inverse association with the difference of apoA-I (z-value: -2.43, P = 0.015) between PAD subjects and non-PAD controls. An increasing BMI was associated with an increasing difference in apoA-I values between PAD subjects and non-PAD controls (z-value: 1.98, P = 0.047). CONCLUSIONS: Our meta-analysis suggests that PAD subjects exhibit increased apoB and reduced apoA-I levels, accompanied by an increased apoB/apoA-I ratio as compared with non-PAD controls.

Efficacy and safety of lomitapide in familial chylomicronaemia syndrome.

BACKGROUND AND AIMS: Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS. METHODS: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS enrolled patients >18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. RESULTS: Eighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452-2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219-801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%-32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment. CONCLUSIONS: Lomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

Speckle tracking echocardiography in patients with systemic lupus erythematosus: A meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE), is characterized by a systemic involvement including myocardial dysfunction. Being standard echocardiography not able at fully detecting subclinical alterations, speckle tracking echocardiography (STE) has recently emerged as a quantitative ultrasound technique to accurately estimate myocardial function. METHODS: We conducted a systematic review with meta-analysis of studies reporting STE parameters in patients with SLE. RESULTS: A total of 9 studies were included in the analysis. Left ventricle global longitudinal strain (GLS) was significantly lower in SLE patients than in non-SLE controls (MD: -2.331, 95% CI: -3.083, -1.580, p < 0.001). In addition, we found significant differences between SLE patients and non-SLE controls in left ventricle GLS rate (MD: -0.115, 95% CI: -0.177 to 0.063, p < 0.001), left ventricle circumferential strain(MD: -1.841, 95% CI: -3.160 to 0.521, p = 0.006) and left ventricle radial strain(MD: -11.03, 95% CI: -13.819 to 8.241, p < 0.001). Right ventricle strain was significantly lower in SLE patients than in non-SLE controls (MD: -5.814, 95% CI: -7.347, -4.281, p < 0.001). Meta-regression models showed a lower difference in left ventricle GLS between SLE cases and controls for studies with a higher prevalence of female gender and higher prevalence of hypertension. CONCLUSIONS: SLE patients have lower STE parameters than controls, thus suggesting the presence of an impaired myocardial function involving both left and right ventricle.

Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background Bempedoic acid (BA) is a novel lipid-lowering drug. We performed a systematic review and meta-analysis on efficacy and safety of BA compared with standard treatment in patients with hypercholesterolemia. Methods and Results Studies were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Efficacy outcome was represented by percentage changes (mean difference [MD] with pertinent 95% CIs) in total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, and hs-CRP (high-sensitivity C-reactive protein) in BA patients and controls. Seven studies were included (2767 BA-treated patients and 1469 controls), showing a more significant reduction in low-density lipoprotein cholesterol (MD, -17.5%; 95% CI, -22.9% to -12.0%), total cholesterol (MD, -10.9%; 95% CI, -13.3% to -8.5%), non-high-density lipoprotein cholesterol (MD, -12.3%; 95% CI, -15.3% to -9.20%), apolipoprotein B (MD, -10.6%; 95% CI, -13.2% to -8.02%), and hs-CRP (MD, -13.2%; 95% CI, -16.7% to -9.79%) in BA-treated patients compared with controls. Results were confirmed when separately analyzing studies on patients with high cardiovascular risk, studies on statin-intolerant patients, and studies on patients with hypercholesterolemia on maximally tolerated lipid-lowering therapy. BA-treated subjects reported a higher rate of treatment discontinuation caused by adverse effects, of gout flare, and of increase in uric acid compared with controls. On the other hand, BA-treated patients showed a lower incidence of new-onset diabetes mellitus than controls. Conclusions BA is associated with a significant reduction in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP compared with standard treatment. Documented efficacy is accompanied by an acceptable safety profile.

Association of Vitamin D deficiency with peripheral arterial disease: a meta-analysis of literature studies.

CONTEXT: Vitamin D deficiency patients have an increased cardiovascular (CV) morbidity and mortality. Contrasting data are available about the association between peripheral arterial disease (PAD) and Vitamin D status. OBJECTIVE: To perform a meta-analysis of studies evaluating the association between Vitamin D status and PAD. DATA SOURCES: Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS: Ten studies with data on Vitamin D levels in 2,079 PAD patients and 18,233 non-PAD controls and 6 studies on the prevalence of PAD in 23,171 subjects with Vitamin D deficiency (<20 ng/ml), 48,311 subjects with Vitamin D insufficiency (20-30 ng/ml) and 27,910 with normal Vitamin D levels (>30 ng/ml) were included. Compared to controls, PAD patients showed significantly lower Vitamin D levels (MD: -2.24 ng/ml; 95%CI: -3.38, -1.10; p<0.001, I2=86.5%; p<0.001). Moreover, a higher prevalence of PAD was found both in subjects with Vitamin D insufficiency (OR: 1.098, 95%CI: 1.010-1.195, p=0.029, I2: 0%, p=0,600) and in subjects with Vitamin D deficiency (OR: 1.484, 95%CI: 1.348-1.635, p<0.001, I2: 7.65%, p=0,367) compared with controls with normal Vitamin D levels. Sensitivity analyses and the analysis of data on the cumulative risk of PAD according to Vitamin D levels derived from multivariate analysis consistently confirmed results. CONCLUSIONS: PAD patients have lower vitamin D levels than controls and both Vitamin D deficiency and Vitamin D insufficiency are significantly associated with PAD. Reduced Vitamin D levels might represent an independent risk factor for PAD and, in turn, for CV events.

The use of odds ratio in the large population-based studies: Warning to readers.

When researchers conduct large prospective studies, they provide results generating statistical analysis; therefore readers need considerable familiarity with descriptive and inferential statistics. If quantitative judgments are based on interpreting odds ratios as though they were relative risks, they are unlikely to be seriously in error. Because of the calculating method, the OR is often less precise than the RR in estimating the strength of an association, and this should definitely be kept in mind by anyone who reads and interprets the results of a large population based-study.