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Polypill for cardiovascular disease prevention: Systematic review and meta-analysis of randomized controlled trials.
Mohamed, MG, Osman, M, Kheiri, B, Saleem, M, Lacasse, A, Alkhouli, M
International journal of cardiology. 2022;:91-98
Abstract
BACKGROUND Cardiovascular disease is the leading cause of death worldwide. Although many pharmacological agents exist, drug compliance and therapeutic goal achievement continue to be suboptimal. This meta-analysis aims to study the effectiveness of polypills in controlling blood pressure, dyslipidemia and in reducing future cardiovascular events. METHODS We conducted a systematic search of electronic databases using pre-specified terms. Randomized clinical trials (RCT) comparing polypills (statin, antihypertensive agents, with or without aspirin) with the standard of care were included. Outcomes of interest were changes in [systolic blood pressure (SBP), diastolic blood pressure (DBP)] mmHg, [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C)] mg/dl, cardiovascular (CVD) mortality, and major adverse cardiovascular events (MACE). RESULTS A total of 18 RCTs with 26,483 participants were included. The population had 55% males, with a mean age of 61.8 ± 7 years, and a mean BMI of 26.7 ± 4.2 kg/m2. The mean follow-up was 15.0 ± 20 months. Compared with standard of care, polypill use was associated with a significant reduction of SBP (Mean Difference [MD] -6.39; [95%CI -9.21, -3.56] p < 0.001), DBP (MD -4.19, [95%CI -5.48, -2.89; p < 0.001], TC (MD -24.95, [95%CI -33.86, -16.04]; p < 0.001), and LDL-C (MD -27.92, [95%CI -35.39, -20.44]; p < 0.001). Polypill use was also associated with a significant reduction of CVD mortality (RR = 0.78; 95% CI (0.61, 0.99); P = 0.04) and MACE [RR = 0.76;95% CI (0.64, 0.91); P = 0.002]. CONCLUSION This meta-analysis showed that compared to standard of care, polypill use was associated with a significant reduction of SBP, DBP, TC, LDL-C, and a significant reduction in fatal and non-fatal cardiovascular events.
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An updated systematic review and meta-analysis of the effect of statins on asymmetric dimethylarginine.
Zinellu, A, Mangoni, AA
Nitric oxide : biology and chemistry. 2022;:26-37
Abstract
OBJECTIVES We conducted an updated systematic review and meta-analysis of the effect of statins on serum or plasma concentrations of the endogenous inhibitor of endothelial nitric oxide synthase, asymmetric NG,NG-dimethyl-l-arginine (ADMA). METHODS A systematic literature search was conducted in the electronic databases PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for analytical studies and GRADE, respectively. RESULTS In 23 studies, reporting 25 treatment arms in 845 participants (mean age 53 years, 57% males, treatment duration 4-48 weeks), statins significantly reduced ADMA concentrations (SMD = -0.39, 95% CI -0.62 to -0.16, p = 0.001; moderate certainty of evidence). The extreme heterogeneity observed was substantially reduced in study subgroups of specific class and individual statins, regional areas, and analytical methods for ADMA concentrations. There was no publication bias. In sensitivity analysis, the corresponding SMD values were not substantially modified when individual studies were sequentially removed. Significant associations were observed, in meta-regression, between the SMD and publication year (t = -3.25, p = 0.003), but not baseline cholesterol concentrations. CONCLUSION Statin treatment significantly lowers ADMA concentrations. This effect is independent of baseline cholesterol. Prospective studies are required to determine whether ADMA-lowering mediates, at least partly, the protective effects of statins against atherosclerotic cardiovascular disease. (PROSPERO registration number: CRD42021275123).
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High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.
Omote, K, Yokota, I, Nagai, T, Sakuma, I, Nakagawa, Y, Kamiya, K, Iwata, H, Miyauchi, K, Ozaki, Y, Hibi, K, et al
Journal of atherosclerosis and thrombosis. 2022;(1):50-68
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AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial.
Shirakawa, T, Fujisue, K, Nakamura, S, Yamamoto, N, Oshima, S, Matsumura, T, Tsunoda, R, Hirai, N, Koide, S, Tayama, S, et al
Journal of atherosclerosis and thrombosis. 2022;(2):229-241
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AIM: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. METHODS This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. RESULTS Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. CONCLUSIONS This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.
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Polycystic ovarian syndrome-current pharmacotherapy and clinical implications.
Rashid, R, Mir, SA, Kareem, O, Ali, T, Ara, R, Malik, A, Amin, F, Bader, GN
Taiwanese journal of obstetrics & gynecology. 2022;(1):40-50
Abstract
Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism. The treatment in PCOS is mainly symptomatic and involves lifestyle interventions and medications such as Metformin, Oral contraceptives and Antiandrogens. However, the management of PCOS is challenging and current interventions are not able to deal with outcomes of this syndrome. This review encompasses latest pharmacotherapeutic and non-pharmacotherapeutic interventions currently in use to tackle various symptomatic contentions in PCOS. Our focus has been mainly on novel therapeutic modalities for treatment/management of PCOS, like use of newer insulin sensitizers viz., Inositols, Glucagon-like peptide-1(GLP-1) agonists, Dipeptidyl pepdidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors. Also, evidence suggesting the use of vitamin D, statins, and Letrozole as emerging therapies in PCOS have been summarized in this review. Additionally, novel cosmetic techniques like electrolysis, laser and use of topically applied eflornithine to tackle the most distressing feature of facial hirsutism associated with PCOS, non-pharmacological therapy like acupuncture and the role of herbal medicine in PCOS management have also been discussed.
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Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.
Roy, G, Couture, P, Genest, J, Ruel, I, Baass, A, Bergeron, J, Brisson, D, Brunham, LR, Cermakova, L, Gaudet, D, et al
The Canadian journal of cardiology. 2022;(3):311-319
Abstract
BACKGROUND Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.
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Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy.
Furuhashi, M, Sakuma, I, Morimoto, T, Higashiura, Y, Sakai, A, Matsumoto, M, Sakuma, M, Shimabukuro, M, Nomiyama, T, Arasaki, O, et al
Journal of atherosclerosis and thrombosis. 2022;(1):24-37
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AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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[State of the Art: Statin Therapy].
Laufs, U, Weingärtner, O, Kassner, U, Schatz, U
Deutsche medizinische Wochenschrift (1946). 2022;(1-02):62-68
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This review summarizes the pharmacology and clinical use of HMG-CoA reductase inhibitors, statins. LDL-Cholesterol lowering with statins reduces atherosclerotic cardiovascular risk by approx. one quater per year of treatment. The efficacy and safety of statins are demonstrated by randomized trials irrespective of the patient's age. The synthetic statins, rosuvastatin and atorvastatin, are superior with regard to LDL-C lowering, half-life and drug-interactions compared to the older statins such as simvastatin. Modern lipid lowering therapy uses individualized statin-based combination therapies.
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Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.
Abe, M, Ozaki, Y, Takahashi, H, Ishii, M, Masunaga, N, Ismail, TF, Iimuro, S, Fujita, R, Iwata, H, Sakuma, I, et al
American heart journal. 2021;:89-100
Abstract
BACKGROUND It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.
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Reported muscle symptoms during statin treatment amongst Italian dyslipidaemic patients in the real-life setting: the PROSISA Study.
Casula, M, Gazzotti, M, Bonaiti, F, OImastroni, E, Arca, M, Averna, M, Zambon, A, Catapano, AL, ,
Journal of internal medicine. 2021;(1):116-128
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AIM: Statin-associated muscle symptoms (SAMS) are a major determinant of poor treatment adherence and/or discontinuation, but a definitive diagnosis of SAMS is challenging. The PROSISA study was an observational retrospective study aimed to assess the prevalence of reported SAMS in a cohort of dyslipidaemic patients. METHODS Demographic/anamnestic data, biochemical values and occurrence of SAMS were collected by 23 Italian Lipid Clinics. Adjusted logistic regression was performed to estimate odds ratio (OR) and 95% confidence intervals for association between probability of reporting SAMS and several factors. RESULTS Analyses were carried out on 16 717 statin-treated patients (mean ± SD, age 60.5 ± 12.0 years; 52.1% men). During statin therapy, 9.6% (N = 1599) of patients reported SAMS. Women and physically active subjects were more likely to report SAMS (OR 1.23 [1.10-1.37] and OR 1.35 [1.14-1.60], respectively), whist age ≥ 65 (OR 0.79 [0.70-0.89]), presence of type 2 diabetes mellitus (OR 0.62 [0.51-0.74]), use of concomitant nonstatin lipid-lowering drugs (OR 0.87 [0.76-0.99]), use of high-intensity statins (OR 0.79 [0.69-0.90]) and use of potential interacting drugs (OR 0.63 [0.48-0.84]) were associated with lower probability of reporting SAMS. Amongst patients reporting SAMS, 82.2% underwent dechallenge (treatment interruption) and/or rechallenge (change or restart of statin therapy), with reappearance of muscular symptoms in 38.4% (3.01% of the whole cohort). CONCLUSIONS The reported prevalence of SAMS was 9.6% of the whole PROSISA cohort, but only a third of patients still reported SAMS after dechallenge/rechallenge. These results emphasize the need for a better management of SAMS to implement a more accurate diagnosis and treatment re-evaluation.