Concomitant Statin Therapy Research Articles

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels >190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C <70 mg/dL was attained by 39% and LDL-C <55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C <55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

Monoclonal Anti-PCSK9 Antibodies: Real-World Data.

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients.

Apremilast as a Potential Targeted Therapy for Metabolic Syndrome in Patients with Psoriasis: An Observational Analysis.

Psoriasis (PsO) is a chronic inflammatory dermatosis that often presents with erythematous, sharply demarcated lesions. Although psoriasis is primarily a dermatological disease, its immune-mediated pathogenesis produces systemic effects and is closely associated with various comorbid conditions such as cardiovascular disease (CVD), metabolic syndrome (MetS), and diabetes mellitus type II (DMII). Apremilast, an oral phosphodiesterase 4 (PDE-4) inhibitor, has shown promise in treating moderate-to-severe psoriasis and is associated with potential cardiometabolic benefits. In a 12-month prospective observational study involving 137 patients with moderate-to-severe psoriasis, we assessed changes in psoriasis clinimetric scores and metabolic profiles from baseline (T0) to 52 weeks (T1) to evaluate the efficacy of apremilast. After 52 weeks of apremilast treatment, we documented a statistically significant decrease in low-density lipoprotein (LDL) and total cholesterol, triglycerides, and glucose levels. Our findings even suggest a potential synergistic effect among patients treated with apremilast, alongside concomitant statin and/or insulin therapy. Although the results of our study must be validated on a larger scale, the use of apremilast in the treatment of psoriatic patients with cardio-metabolic comorbidities yields promising results.

1840. Implementation of a daptomycin dosing nomogram and assessment of clinical outcomes across a large health system

Abstract Background Daptomycin (DAP) is frequently used for a gram-positive infections with conflicting guidance on optimal dosing, especially dosing weight in obese patients. With newer commercially available vial sizes and limited supporting evidence pointing to an optimal dosing strategy and dosing weight (e.g., actual, ideal, adjusted), we seek to explore the impact of a standardized DAP nomogram (Figure 1) on both clinical and safety outcomes across a large health system. Figure 1.Standardized Daptomycin Dosing Nomogram Methods This retrospective cohort study evaluated patients receiving DAP across 7 campuses within AdventHealth between Sep 1, 2020 to Dec 31, 2020 (pre-implementation with standard mg/kg dosing) and Dec 1, 2021 to Jan 31, 2022 (post-implementation with nomogram dosing). Inclusion criteria: age ≥18, invasive infection (e.g., bone/joint, bacteremia, complicated cellulitis, endocarditis), hospital admission, and duration of DAP ≥72hr. Exclusion: DAP in ambulatory setting, duration of DAP < 72hr, and non-invasive infection, defined as uncomplicated cellulitis not requiring surgical intervention. Primary outcome was clinical success, defined as improvement in signs/symptoms at end of therapy or discharge and absence of repeat positive cultures. Secondary outcomes included mean length of therapy (LOT), adherence to nomogram-guided DAP dosing, and occurrence of adverse events. Results 100 patients were included in each group. Average age was 58 years and most were male (54%). Most common indication for DAP was bacteremia (46%) and S. aureus was isolated in 28% of all cultures. Thirty-four percent of patients in each group were on concomitant statin therapy and average BMI was similar between groups (31.4 kg/m2 vs. 31.9 kg.m2). Clinical success (Figure 2) occurred in 74% of patients in the post-implementation group compared to 70% in the pre-implementation group (p=0.529). Average LOT was similar (10.9 days vs. 9.15 days, p=0.191). Pharmacist adherence to the nomogram was high at 91%. Rates of adverse events were similar between groups, with CPK elevations > 200 units/L occurring in 12% of patients in the pre-implementation group compared to 14% of patients in the post-implementation group (p=0.674). Conclusion A standardized DAP nomogram led to a safe and effective process for treating invasive gram-positive infections. Disclosures All Authors: No reported disclosures.

Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18

BackgroundStatins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18.Patients and methodsABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD).ResultsIn the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed.ConclusionAccording to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.

Abstract P1-15-01: Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18

Abstract Background Statins are a common class of cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, it was suggested that statins may possess anti-cancer properties and interact with RANK ligand expression. Therefore, we aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. Methods ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor (HR) positive BC receiving a non-steroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post-hoc analysis, we investigated the potential effects of concomitant statin therapy on recurrence risk of BC, fracture risk and bone mineral density (BMD) using time-dependent Cox proportional hazards models. Sensitivity analyses accounting for immortal time and confounding bias were performed. Results In the analysis of the study population (n=3,420), statin therapy (n=824) was associated with worse disease-free survival (DFS) (HR 1.35, 95%; CI 1.04-1.75; p=0.023). Sensitivity analysis relativized these results (HR 1.22, 95% CI 0.94 - 1.59; p=0.14). While there was no significant effect of lipophilic statins (n=710) on recurrence risk (HR 1.30, 95% CI 0.99 - 1.72; p=0.062), patients on hydrophilic statins (n=87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; p=0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21 - 5.68; p=0.014). No association between statin use and fracture risk or osteoporosis was observed. Conclusion In this population of early-stage breast cancer patients from a prospective randomized study, an association of hydrophilic statins with increased recurrence risk was observed. According to this retrospective analysis hydrophilic statins may increase recurrence risk especially in patients treated with denosumab. Still, our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins. Therefore, no final conclusion is possible. This hypothesis generating result warrants further exploration. Citation Format: Christoph Minichsdorfer, Thorsten Fuereder, Michael Leutner, Christian F. Singer, Stephanie Kacerovsky-Strobl, Daniel Egle, Richard Greil, Marija Balic, Florian Fitzal, Georg Pfeiler, Sophie Frantal, Rupert A. Bartsch, Michael Gnant. Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-01.

State of platelet-plasma hemostasis in patients with hypertension and non-alcoholic fatty liver disease in condition of hypercholesterolemia

Abstract Non-alcoholic fatty liver disease (NAFLD) is a marker of metabolic and dyslipidemic disorders. Given the prevalence of atherogenic dyslipidemias and their proven effect on the development of thrombotic cardiovascular complications in patients with NAFLD, it is important to understand the role of hemostatic blood activity. Aim of the study To increase the effectiveness of early diagnosis of thrombophilic blood changes in patients with hypertension (HT) combined with non-alcoholic fatty liver disease by determining the state of plasma hemostasis in conditions of hypercholesterolemia and concomitant statin therapy. Materials and methods 152 patients were examined. Groups of patients: I – 46 patients with stage II GC, II – 54 patients with NAFLD without GC, group III – 52 patients with stage II GC with concomitant NAFLD. The analysis of spontaneous and induced platelet aggregation, indicators of coagulation, anticoagulant and fibrinolytic hemostasis. Results The degree of spontaneous aggregation was significantly higher in patients with hypercholesterolemia – by 32.4% (p<0.05). The level of fibrinogen was higher by 13.5% (p<0.05) due to hypercholesterolemia, at the same time there was a decrease in antithrombin (AT) III by 8.7% (p<0.05) in patients with high cholesterol. Patients with comorbid HT and NAFLD on statin therapy had a 16.5% (p<0.05) lower degree of spontaneous aggregation than patients who did not receive this treatment. In the NAFLD group, patients receiving statins had a significantly lower degree of arachidonic acid-induced aggregation against patients without lipid-lowering therapy (by 54.0%, p<0.001). However, the analysis of the general population of the examined revealed a decrease in the degree of collagen-induced aggregation by 38.7% (p<0.05) in a subgroup of patients receiving treatment. We observed a 23.4% (p<0.001) shortening of prothrombin time in the NAFLD group and a 16.0% (p<0.05) shortening in the combined course of HT and NAFLD. In the absence of statin therapy in the NAFLD group, there was a significant decrease in INR – by 9.7% (p<0.05) – compared with patients receiving lipid-lowering therapy. A decrease in thrombin time by 12.2% (p<0.05) was observed in the subgroup receiving statins among patients with NAFLD. In the general cohort, the use of statins increased the activity of AT III by 10.7% (p<0.01), but in the NAFLD group this difference was more significant – by 14.3% (p<0.001) AT III was more active in patients who received lipid-lowering therapy. Conclusion The results of the analysis showed that patients with hypercholesterolemia have procoagulant and prothrombogenic activity of blood. But statin treatment decrease platelet aggregation, blood coagulation potential and increased activity of anticoagulant hemostasis, which complements the mechanism of prophylactic effect of HMG CoA reductase inhibitor (statin). Funding Acknowledgement Type of funding sources: None.

Plasma Hemostasis in Patients with Essential Hypertension and Non-alcoholic Fatty Liver Disease Under Conditions of Hypercholesterolemia and Concomitant Statin Therapy

In the modern scientific world, it has been proven that non-alcoholic fatty liver disease (NAFLD) is a marker of the risk of cardiovascular (CV) events, and therefore, attention and control of risk factors for CV diseases is important. Considering the prevalence of atherogenic dyslipidemias and their proven effect on the development of thrombotic CV complications in patients with NAFLD, it is important to understand the role of hemostatic blood activity. The objective: To increase the efficiency of early diagnosis of thrombophilic changes in the blood in patients with essential hypertension (HT) combined with non-alcoholic fatty liver disease by determining the state of plasma hemostasis in conditions of hypercholesterolemia and concomitant statin therapy. Materials and methods. 152 patients were examined. Patient groups: I – 46 patients with stage II hypertension, II – 54 patients with NAFLD without hypertension, group III – 52 patients with stage II hypertension with concomitant NAFLD. Results. The growth of prothrombogenic activity of the blood among all groups of patients, however, with HT II stage, combined with NAFLD, the most significant effect was carried out precisely on the final stages of coagulation. An increase in the level of fibrinogen was observed in patients with grade II hypertension. by 29,3 % (p<0,01) and with a combination of HT and NAFLD by 39,7 % (p<0,001). The levels of soluble fibrin-monomeric complexes in all groups were significantly higher than the control values: in patients with hypertension. – 4,1 times (p<0,001), with NAFLD – 2,8 times (p<0,001), in the NAFLD group with hypertension – 4,5 times (p<0,001). Antithrombin III (AT III) was reduced by 12,3 % (p<0,01) relative to the control only in patients with hypertension. On the other hand, the fibrinolytic potential was reduced among all examined groups. Determination of the effect of lipid-lowering therapy revealed an acceleration of prothrombin time (PTT) by 19.2 % (p<0,01) in patients with NAFLD without statin treatment. In the general cohort, statin use increased the activity of AT III by 10,7 % (p<0,01), but in the NAFLD group, this difference was more significant – by 14,3 % (p<0,001). In patients with comorbid course of HT and NAFLD with cholesterolemia level <5 mmol/L, we observed an increase in PTT by 32,5 % (p<0,05), INR by 25,4 % (p<0,05) and thrombin time by 23,2 % (p<0,05) during statin therapy. On the other hand, in the subgroup with hypercholesterolemia, statins increased the activity of the anticoagulant link of hemostasis – the level of ATIII increased by 3,1 % (p<0,05). Conclusions. Depletion of the fibrinolytic potential against the background of activation of the coagulant hemostasis link is observed in patients with hypertension combined with NAFLD. In the case of concomitant hypercholesterolemia, the procoagulant activity of the blood increases, however, against the background of treatment with statins, there is a decrease in the coagulation potential of the blood and an increase in the activity of the anticoagulant link of hemostasis.

Dietary Geranylgeranyl Pyrophosphate Counteracts the Benefits of Statin Therapy in Experimental Pulmonary Hypertension.

The mevalonate pathway generates endogenous cholesterol and intermediates including geranylgeranyl pyrophosphate (GGPP). By reducing GGPP production, statins exert pleiotropic or cholesterol-independent effects. The potential regulation of GGPP homeostasis through dietary intake and the interaction with concomitant statin therapy is unknown. We developed a sensitive high-pressure liquid chromatography technique to quantify dietary GGPP and conducted proteomics, qualitative real-time polymerase chain reaction screening, and Western blot to determine signaling cascades, gene expression, protein-protein interaction, and protein membrane trafficking in wild-type and transgenic rats. GGPP contents were highly variable depending on food source that differentially regulated blood GGPP levels in rats. Diets containing intermediate and high GGPP reduced or abolished the effects of statins in rats with hypoxia- and monocrotaline-induced pulmonary hypertension: this was rescuable by methyl-allylthiosulfinate and methyl-allylthiosulfinate-rich garlic extracts. In human pulmonary artery smooth muscle cells treated with statins, hypoxia activated RhoA in an extracellular GGPP-dependent manner. Hypoxia-induced ROCK2 (Rho associated coiled-coil containing protein kinase 2)/Rab10 (Ras-related protein rab-10) signaling was prevented by statin and recovered by exogenous GGPP. The hypoxia-activated RhoA/ROCK2 pathway in rat and human pulmonary artery smooth muscle cells upregulated the expression of Ca2+-sensing receptor (CaSR) and HIMF (hypoxia-induced mitogenic factor), a mechanism attenuated by statin treatment and regained with exogenous GGPP. Rab10 knockdown almost abrogated hypoxia-promoted CaSR membrane trafficking, a process diminished by statin and resumed by exogenous GGPP. Hypoxia-induced pulmonary hypertension was reduced in rats with CaSR mutated at the binding motif of HIMF and the interaction between dietary GGPP and statin efficiency was abolished. In humans fed a high GGPP diet, blood GGPP levels were increased. This abolished statin-lowering effects on plasma GGPP, and also on hypoxia-enhanced RhoA activity of blood monocytes that was rescued by garlic extracts. There is important dietary regulation of GGPP levels that interferes with the effects of statin therapy in experimental pulmonary hypertension. These observations rely on a key and central role of RhoA-ROCK2 cascade activation and Rab10-faciliated CaSR membrane trafficking with subsequent overexpression and binding of HIMF to CaSR. These findings warrant clinical investigation for the treatment of pulmonary hypertension and perhaps other diseases by combining statin with garlic-derived methyl-allylthiosulfinate or garlic extracts and thus circumventing dietary GGPP variations.

The potential interaction of statins and clopidogrel in patients undergoing percutaneous coronary intervention

Clopidogrel is widely used for patients with acute coronary syndrome. It is a pro-drug that requires bioactivation by several cytochrome P450 (CYP) enzymes, mainly CYP3A4, CYP2C9, and CYP2C19 enzymes. Lipophilic statins such as atorvastatin are used concomitantly with clopidogrel due to their beneficial effects on morbidity and mortality in the arena of cardiovascular diseases. However, lipophilic statins are eliminated by CYP3A4 and undergo the same metabolic pathway of clopidogrel. Hence, statins may compete with clopidogrel for CYP3A4 enzyme resulting in diminishing the anti-platelet effect of clopidogrel. We aimed to study the impact of concomitant statin therapy on clopidogrel efficacy in patients undergoing percutaneous coronary intervention (PCI) evaluate the clinical relevance of potential clopidogrel and statins interaction and association between use of statins and risk of future adverse cardiac events. A cross-sectional retrospective cohort study was conducted on 50 patients attending Prince Sultan Cardiac Center for follow-up after PCI. All patients discharged on clopidogrel, aspirin, and atorvastatin were later divided into two groups according to the occurrence of MACEs. Statistical analysis was performed by Statistical Package for the Social Science (SPSS; V. 21.0). This study was on adult and geriatric males (72%)and female (28%). More than half of them exhibited major adverse cardiac events (MACEs), of which 48% exhibited it after 4 to 6 months from PCI indexing followed by 1 to 3 months (34%), and the least after 7 to 9 months. A significant association arises between gender and MACEs (P=0.042). Moreover, the average age was significantly higher in patients who experience MACEs compared to others (62.7 vs. 55.4, P=0.037). Regarding comorbidities, hypertension increased in patients with MACEs (73.1%) compared to those without MACEs (45.8%). The average duration of taking clopidogrel was significantly shorter in patients with MACEs compared to those who did not (3.42 vs. 5.54 months, P<0.001). According to the findings of this study, atorvastatin affects clopidogrel efficacy in patients undergoing PCI.

REDUCE-IT: outcomes by baseline statin type

Abstract Background REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with elevated triglycerides and increased cardiovascular (CV) risk to either icosapent ethyl (IPE), a pure, stable prescription form of eicosapentaenoic acid, 4g/day or placebo. IPE significantly reduced time to first occurrence of the primary composite endpoint of major adverse CV events (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) (HR 0.75, CI 0.68–0.83) and key secondary endpoint events (composite of CV death, nonfatal MI, or nonfatal stroke) (HR 0.74, CI 0.65–0.83) versus placebo (all p<0.0001). A modest reduction in placebo-corrected LDL-C was observed (−6.6%; p<0.0001). The mechanisms for the CV benefit of icosapent ethyl are not fully understood. Purpose Explore the impact of statin type and lipophilic/lipophobic category on outcomes, and on LDL-C, to further consider the possible relevance of LDL-C pathways to the observed CV benefit of icosapent ethyl. Methods Primary and key secondary endpoint analyses and LDL-C changes from baseline were explored by individual statin type (atorvastatin, simvastatin, rosuvastatin, or pravastatin) at baseline, and then by categorizing these statins into lipophilic (i.e., hydrophobic: atorvastatin, simvastatin) and lipophobic (i.e., hydrophilic: rosuvastatin, pravastatin) statin groups; 96.1% of patients fell within these individual statin groups. Results CV outcomes were similar across statin types (interaction p=0.61) and lipophilic/lipophobic categories (interaction p=0.51) (Figure). Statin type and category had a similar lack of meaningful impact on the modest placebo-corrected median LDL-C changes from baseline to one year, which ranged from −5.8 to −8.4% (all p≤0.0003). Conclusion No meaningful treatment differences in the primary or key secondary endpoints across statin type or lipophilic/lipophobic category were observed. A similar lack of treatment difference was observed in LDL-C changes from baseline to one year. Therefore, the LDL-C changes and CV risk reduction in REDUCE-IT appear independent of the type of concomitant statin therapy. These data provide clinicians with additional insight regarding concomitant statin therapy considerations when prescribing icosapent ethyl and suggest there are important mechanisms of action for the substantial CV risk reduction observed with icosapent ethyl that are distinct from the LDL receptor pathway. Funding Acknowledgement Type of funding source: Other. Main funding source(s): The study was funded by Amarin Pharma, Inc.

Preventing cancer therapy-related heart failure: the need for novel studies.

After enhancing the survivorship of cancers, the impact of cardiovascular diseases on mortality is increasing among cancer patients. However, anticancer therapies pose a higher cardiovascular risk to patients. As prevention against cancer therapy-induced cardiomyopathy has yet to be explored, the preventive ability of concomitant cardiovascular medications against incident heart failure was assessed. A retrospective, population-based study was run using anonymized integration of healthcare databases. All the Hungarian patients diagnosed with breast or colorectal carcinoma and undergoing chemotherapy or biological therapy were analysed. Participants were not treated with any anticancer therapy nor suffered from heart failure/dilated cardiomyopathy during the preceding observational period (≥6.5 years). The heart failure endpoint was established by I50 International Classification of Diseases codes upon discharge from hospital or issuance of an autopsy report. Among the 9575 patients who were enrolled, the cumulative incidence of heart failure over 4 years was 6.9%. The time until the first heart failure event in the propensity score-matched treated and untreated groups was compared using Cox proportional-hazards models. A significant association between lower heart failure risk and concomitant statin therapy was observed (hazard ratio: 0.748, P = 0.038); the preventive ability was more pronounced in the anthracycline/capecitabine/platinum-treated subgroup (hazard ratio: 0.660, P = 0.032). For angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy, a significantly lower heart failure risk was also observed (hazard ratio: 0.809, P = 0.032). Among beta blockers, nebivolol administered to anthracycline/capecitabine-treated patients was associated with a nonsignificant trend to lower heart failure risk (hazard ratio: 0.584, P = 0.069). Only concomitant statin and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapies were associated with significantly lower risk of anticancer therapy-related heart failure.

Musculoskeletal toxicities in patients receiving concomitant statin and daptomycin therapy.

This article evaluates the musculoskeletal safety of concomitant therapy with daptomycin and Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins). Often indicated for severe gram-positive infections, daptomycin is commonly administered with statins but there is limited guidance on the appropriate management of concomitant therapy with daptomycin and statins. A narrative review was conducted to review contemporary clinical evidence of the safety of concomitant therapy with daptomycin and statins. A total of 5 studies were identified comparing daptomycin monotherapy versus daptomycin and statin concomitant therapy for the primary outcome of creatine phosphokinase (CPK) elevations in a variety of patient populations with systemic, skin/soft tissue, and bone/joint infections. Of these studies, 4 also compared myalgia or myopathy as a secondary outcome. Case studies, the case-control study and 1 prospective registry comparing statin alone versus daptomycin and statin concomitant therapy were excluded. These studies showed that concomitant therapy with daptomycin and statin was not significantly associated with CPK elevation or higher event rate of myalgia or myopathy, compared to daptomycin monotherapy. Published cohort studies do not demonstrate a statistically significant difference in the rate of CPK elevations or musculoskeletal toxicities between patients receiving daptomycin monotherapy and daptomycin plus a statin. Patients receiving statins who start daptomycin therapy should continue statin but with weekly monitoring of CPK levels. Continuation of statins is especially important in high-risk patients receiving statins for secondary prevention for atherosclerotic cardiovascular diseases. If myalgia develops, it is reasonable to evaluate the degree of CPK elevation and reassess the need for statin use during daptomycin treatment.

Influence of Statins on Survival Outcome in Patients with Metastatic Castration Resistant Prostate Cancer Treated with Abiraterone Acetate.

ObjectiveEven though the exact mechanism is largely unknown until now, statins are supposed to improve survival outcomes in various malignancies. For prostate cancer however, statins are known to compete with dehydroepiandrosterone (DHEAS) for the transport into the cytosol both using the cell by the Solute Carrier Transporter and thus diminish the cellular uptake of DHEAS as a precursor of androgens. Abiraterone inhibits CYP17A1 and thus effectively decreases the production of all relevant androgens including DHEAS. In this study we examined whether statins still affect survival outcome in patients with metastatic castration resistant prostate cancer (mCRPC) when treated with Abiraterone.Patients and Methods108 men with mCRPC treated with Abiraterone from 02/2010 to 07/2015 with (n = 21) or without (n = 87) concomitant treatment with statins were investigated. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier-estimates and univariate Cox-regression analysis. The influence on best clinical benefit under Abiraterone treatment was analyzed with bivariate and multivariate logistic regression analysis.ResultsPSA-decline ≥ 50% was not significantly different in both groups (57 vs. 53%; p = 0.73). The median PFS (9 vs. 10 months; p = 0.97) and OS (14 vs. 18 months; p = 0.77) did not differ significantly between those men treated with and without concomitant statin therapy, respectively. Accordingly, there was no improvement for best clinical benefit in patients using statins (odds ratio: 1.2 (CI: 0.4–4.2); p = 0.76).ConclusionUse of statins as concomitant medication did not improve survival outcomes or best clinical benefit in men with mCRPC treated with Abiraterone.

Statin Use Mitigate the Benefit of Omega-3 Fatty Acids Supplementation-A Meta-Regression of Randomized Trials.

During last 2 decades, multiple studies have evaluated omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation for cardiovascular prevention. The benefit found in previous studies was not demonstrated in more contemporary trials. We aimed to investigate effect of study characteristics, particularly concomitant statin therapy on results of randomized controlled trials. We systematically searched electronic databases for randomized controlled trials evaluating ω-3 PUFA supplementation and reporting clinical outcomes. A meta-analysis was performed using a random effect model, followed by a meta-regression of dose, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio, and duration of treatment and use of lipid-lowering/statin therapy in control group. Twenty-three studies with 77,776 patients (38,910 PUFA; 38,866 controls) were included. PUFA had no effect on total mortality [risk ratio (RR) = 0.96; 95% confidence interval (CI), 0.92-1.01] and myocardial infarction (RR = 0.87; 95% CI, 0.73-1.02), but marginally reduced cardiovascular mortality (RR = 0.93; 95% CI, 0.87-0.98). Lower control group statin use (b = 0.222, P = 0.027) and higher DHA/EPA (b = -0.105, P = 0.033) ratio was associated with higher reduction in total mortality. Duration and dose had no effect. None of the variables except duration had significant effect on reduction in cardiovascular mortality by PUFA supplementation. There was evidence of publication bias. Statin use may mitigate, and higher DHA/EPA ratio is associated with the beneficial effect of PUFA supplementation.

MY APPROACH to evaluation of the ambulatory patient with suspected hypertension

(1) Staging of BP. I routinely use ambulatory or home monitoring to stage BP, because the office BP often overor underestimates out-of-office BP. I generally initiate antihypertensive therapy if the average awake BP is Z135/ 85 mmHg or the average sleeping BP is Z125/75 mmHg. Most private insurance plans will reimburse ambulatory monitoring, but Medicare will not except for suspected white-coat hypertension, the criteria for which are so rigorous as to make this impractical for older Medicare beneficiaries who would benefit most. For home BP, the key is to calibrate the patient's monitor in the office against careful manual readings. Home BP monitors are graded by the British Hypertension Society on the dabl Education Trust website (http://www.dableducational.org/). I instruct patients to take a set of three readings every morning before taking their pills and again every evening for 4 days in a row, and then provide me with all of the readings. I discard the first day's readings and the first reading of each set as being artificially high and average the rest, if the mean is Z135/85 mmHg, I diagnose and treat hypertension. (2) Global CV risk. I use the new 2013 ACC/AHA Pooled Cohort calculator to estimate 10-year cardiovascular risk to decide about starting concomitant statin therapy, which is indicated in 475% of my hypertensive patients. I also

A population-based analysis of the risk of drug interaction between clarithromycin and statins for hospitalisation or death.

BackgroundClarithromycin, known as a potent inhibitor of the cytochrome P450 isoenzyme CYP3A, may increase the plasma concentration of statins metabolized by this pathway; therefore, increase the risk of interaction with statins in reference to pharmacokinetic studies. This study aimed to characterize whether the concomitant use of a statin with clarithromycin is associated with serious outcomes among adult persons.MethodsHealth claims data of adult persons in the Regional Sickness Fund of Burgenland, Austria, who filled a prescription for clarithromycin between July 1, 2009 and June 30, 2012 were reviewed retrospectively. We assumed that the risk of hospitalisation increases acutely with the indication for taking an antibiotic, whereas statin use can be considered a chronic exposure with a low constant effect on hospitalisation. When defining the population as persons taking clarithromycin and the use of statins as the exposure we could achieve a comparable effect in both groups from the acute condition on hospitalisation. Therefore, we defined exposed patients as those who had overlapping treatment with a statin and unexposed controls as those who had filled a prescription for clarithromycin without concomitant statin therapy. Outcome was defined as a composite of hospital admission or death within 30 days after starting clarithromycin. We used generalised linear regression to model an association between outcome and exposure to statins.ResultsAmong 28,484 prescriptions of clarithromycin, 2317 persons were co-exposed to statins. Co-administration of CYP3A4 metabolized statins and clarithromycin was associated with a 2.11 fold increased risk of death or hospitalisation (95 % confidence interval [CI]: 1.79–2.48). This effect was explained by age, evidence of cardiovascular disease, diabetes mellitus and utilization of other antibiotics (multivariable adjusted risk ratio: 1.02, 95 % CI: 0.85–1.22). The sensitivity analyses did not change the significance of effect.ConclusionsThe risk for hospitalisation or death in persons receiving clarithromycin increases with age and cardiovascular disease but is not causally associated with statin-clarithromycine co-administration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-015-0134-y) contains supplementary material, which is available to authorized users.

PCSK9 inhibitors and cardiovascular disease: heralding a new therapeutic era.

Purpose of reviewThe first monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been approved for clinical use. This timely review highlights recent developments.Recent findingsLow-density lipoprotein cholesterol (LDL-C) is the primary driver of atherosclerosis and the key target for intervention. Yet despite best treatment including statins, attaining sufficient LDL-C lowering can be problematic for high cardiovascular risk patients. The development of PCSK9 inhibitors, driven by novel genetic and mechanistic insights, offers an answer. Removal of circulating PCSK9 increases LDL receptor availability, and thus markedly decreases plasma LDL-C levels (by ∼50–60%), and is additive to the lipid lowering effects of statins and ezetimibe. PCSK9 inhibition also reduces (by 25–30%) plasma levels of lipoprotein(a), a causal factor in atherosclerotic vascular disease, suggestive of partial catabolism of lipoprotein(a) by LDL receptors. The ODYSSEY and PROFICIO (Programme to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations) clinical trial programmes involving a wide range of high-risk patients, including statin intolerant patients, have confirmed the consistency of the LDL response, even with concomitant high-intensity statin or nonstatin therapy. Extensive evidence to date attests to a favourable safety and tolerability profile for these innovative agents.SummaryThe new pharmacotherapeutic era of PCSK9 inhibition is upon us, promising major reduction in cardiovascular events across a wide spectrum of high-risk patients.

Effects of phenotypic and genotypic factors on the lipid responses to niacin in Chinese patients with dyslipidemia.

The acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes DGAT1 and DGAT2 catalyze the final step in triglycerides biosynthesis. This study examined the relationships of baseline phenotypes and the common polymorphisms in DGAT1 and DGAT2 with the lipid responses to niacin.Lipid responses in Chinese patients with dyslipidemia treated with the extended release (ER) niacin/laropiprant combination 1000/20 mg for 4 weeks and then 2000/40 mg for 8 weeks (n = 121, the primary study) or with ER niacin 1500 mg for at least 4 weeks (n = 68, the replication study) were analyzed according to genotypes of DGAT1 rs7003945 T>C and DGAT2 rs3060 T>C polymorphisms.Treatment with ER niacin improved all lipid parameters in both studies. Absolute and percentage changes in lipids were related to their baseline levels, particularly for low-density lipoprotein cholesterol (LDL-C). The DGAT2 rs3060 T>C polymorphism was associated with lower baseline LDL-C, apoB, high-density lipoprotein cholesterol (HDL-C), and apoAI in patients on statin therapy in the primary study. Subjects with the DGAT2 rs3060 T>C variant had less reduction in LDL-C in the primary study and smaller changes in triglyceride and HDL-C in the replication study but these associations became non-significant after adjusting for baseline lipid values. The DGAT1 rs7003945 T>C polymorphism was not related to lipid baseline values or changes in either study. Concomitant statin therapy and lower body weight were also associated with greater reduction in LDL-C.Baseline lipid levels were the main determinants of lipid responses especially for LDL-C. The DGAT2 rs3060 polymorphism might influence the lipid responses depending on baseline phenotype, but this association did not persist after adjustment for the baseline lipid levels.

Elevated plasma-free cortisol concentrations and ratios are associated with increased mortality even in the presence of statin therapy in patients with severe sepsis.

Dissociation between plasma-free cortisol and total cortisol profiles exists in critical illness. Data on plasma-free cortisol are based on either calculated values or immunoassay-based measurements. Both have significant limitations. Statins have been advocated as a therapy in sepsis. Whether they impact on plasma cortisol through inhibition of cholesterol synthesis is unclear. In patients enrolled into a randomized trial of statins in sepsis (n = 250), we examined the association of mass spectrometry measured plasma-free cortisol, plasma-free cortisol/plasma total cortisol ratios, and outcome and the impact of concomitant statin therapy on cortisol profiles in 80 steroid naïve patients. Two hundred twenty serial measurements of plasma-free cortisol, plasma total cortisol, and interleukin-6 were collected from 80 patients (43 placebo and 37 statins). Data from 10 volunteers were used as controls. Data are presented as median and interquartile range. Compared with controls, in severe sepsis, baseline plasma total cortisol was elevated two-fold (463 nmol/L [284-742 nmol/L] vs 245 nmol/L [200-299 nmol/L], p < 0.001), plasma-free cortisol 20-fold (75 nmol/L [20-151 nmol/L] vs 5 nmol/L [5-7 nmol/L], p < 0.001), and plasma-free cortisol/plasma total cortisol ratio six-fold (0.15 vs 0.02, p = 0.058). Baseline interleukin-6 was elevated at 121 pg/mL (65-611 pg/mL). In severe sepsis, there were no differences in plasma total cortisol (p = 0.66), plasma-free cortisol (p = 0.77), and interleukin-6 (p = 0.29) between statins and placebo groups. Plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol were positively correlated with interleukin-6 (p = 0.0001, p < 0.0004, and p < 0.001, respectively) and day 90 mortality (p = 0.03, p = 0.03, and p = 0.058, respectively). Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay (p = 0.04). Baseline plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol ratios were higher in nonsurvivors as compared with survivors (174 nmol/L [77-329 nmol/L] vs 57 nmol/L [17-122 nmol/L], p = 0.016; 890 nmol/L [333-1,430 nmol/L] vs 408 nmol/L [269-681 nmol/L], p = 0.035; and 0.19 [0.13-0.29] vs 0.14 [0.07-0.20]; p = 0.054, respectively). In severe sepsis, plasma-free cortisol increase is 10-fold greater than that of plasma total cortisol. Both are similarly associated with inflammatory response and mortality. Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay. Statin therapy does not influence the plasma cortisol profiles in patients with severe sepsis.