History Of Statin Intolerance Research Articles

Abstract 4136334: Treatment Satisfaction With an “Inclisiran First” Implementation Strategy Versus Usual Care in Patients With Atherosclerotic Cardiovascular Disease

Background: Despite the availability of effective lipid-lowering therapies (LLTs), most patients (pts) with ASCVD do not meet guideline-recommended LDL-C goals. In VICTORION-INITIATE (NCT04929249), an “inclisiran first” (IF) strategy of adding inclisiran immediately on failure to achieve LDL-C <70 mg/dL, despite maximally tolerated statin therapy, in pts with ASCVD led to significantly higher LDL-C goal attainment vs usual care (UC) at Day 330. Objective: To evaluate change from baseline to Day 330 in pt-reported treatment satisfaction with an IF implementation strategy vs UC in pts with ASCVD enrolled in VICTORION-INITIATE. Methods: VICTORION-INITIATE, a Phase 3b, open-label, prospective trial, was conducted at 45 representative clinical sites across 20 US states. Pts randomized 1:1 (stratified by insurance status) received inclisiran 284 mg (300 mg inclisiran sodium) at Days 0, 90, and 270 plus UC or UC alone (lipid management directed by treating physicians). We evaluated change from baseline to Day 330 in pt-reported satisfaction with IF vs UC using the validated 11-question Treatment Satisfaction Questionnaire for Medication (TSQM)-II comprising 4 domains (effectiveness, side effects, convenience, and global satisfaction) scored from 0–100. As a post-hoc analysis of a pre-specified exploratory endpoint, we analyzed the difference in least-squares (LS) mean change in TSQM-II domain scores for IF vs UC using ANCOVA with baseline scores as a covariate. Results: We randomized 450 patients: median age 67 years, 30.9% female, 25.8% with a history of statin intolerance. From baseline to Day 330, difference in LS mean change (95% confidence interval) in TSQM-II scores for IF (n=139) vs UC (n=105) was significant (p<0.001) for effectiveness (10.4 [5.4, 15.5]), convenience (10.5 [5.8, 15.2]), and global satisfaction (12.1 [7.2, 16.9]). Statistical comparison was not applicable for the side effects domain at Day 330 due to the small sample size (IF: n=6, UC: n=7). On Day 330, mean scores for IF exceeded UC for each TSQM-II question (Figure). Conclusions: An IF implementation strategy resulted in significantly greater change from baseline to Day 330 across multiple domains of pt-reported treatment satisfaction vs UC.

Low-density lipoprotein cholesterol goal attainment with "inclisiran first" versus usual care in patients with atherosclerotic cardiovascular disease

Abstract Background Rapid and sustained attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals is critical for patients with atherosclerotic cardiovascular disease (ASCVD). In VICTORION-INITIATE, inclisiran administered twice-yearly by a healthcare professional earlier in the treatment pathway allowed more patients with ASCVD to achieve and sustain LDL-C goals vs current usual care (UC). Purpose To evaluate cumulative LDL-C exposure in the overall population and LDL-C goal attainment and safety in subgroups of participants (type of ASCVD, timing of ASCVD event, and history of statin intolerance) who received an "inclisiran first" implementation strategy (IF; adding inclisiran immediately on failure to achieve LDL-C <70 mg/dL [1.8 mmol/L] with maximally tolerated statins) compared with UC. Methods VICTORION-INITIATE was a 330-day, prospective, pragmatically designed trial that randomised participants 1:1 (stratified by insurance status) to IF (open-label inclisiran 284 mg at Days 0, 90 and 270 plus UC) or UC alone (lipid management directed by treating physician’s discretion). The study took place at 45 sites across 20 states in the USA. Treating physicians had access to LDL-C measurements and were encouraged to intensify treatment per clinical practice guidelines. This prespecified subgroup analysis evaluated LDL-C goal attainment by timing of the most recent ASCVD event (<1 year/≥1 year prior to consent), ASCVD subtype (coronary heart disease [CHD], peripheral arterial disease [PAD], and cerebrovascular disease [CVD]) and statin intolerance status. Cumulative LDL-C exposure over time in the overall population and safety by subgroup were also evaluated. Results Of 450 patients randomised to IF or UC, 11.1% and 84.2% had an ASCVD event <1 year or ≥1 year prior to consent, respectively; 91.8%, 18.2% and 14.7% had a history of CHD, CVD or PAD, and 25.8% were statin intolerant. Cumulative exposure to LDL-C to Day 330 was lower in patients treated with IF vs UC (mean time-adjusted LDL-C: 42.4 mg/dL vs 90.7 mg/dL, Figure). Significantly more patients who received IF achieved LDL-C goals of <70 mg/dL and <55 mg/dL at Day 330 vs UC, irrespective of subgroup (Table). Across subgroups, the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between IF and UC (IF: 52.6−71.2%, UC: 46.2−66.0% and IF: 10.7−28.3%, UC: 11.4−22.2%, respectively). Conclusions Participants with ASCVD and LDL-C >70 mg/dL who received IF had lower cumulative LDL-C exposure over the study period than those treated with UC. IF resulted in rapid and sustained achievement of LDL-C goals regardless of ASCVD subtype, event timing and statin intolerance. The safety profile of IF was consistent across the subgroups analysed.

Evolocumab-Based LDL-C Management in High and Very High Cardiovascular Risk Patients in German Clinical Practice: The HEYMANS Study.

Low-density lipoprotein cholesterol (LDL-C) is among the most important modifiable risk factors for cardiovascular disease. In very high-risk patients, the European Society of Cardiology/European Atherosclerosis Society guidelines recommend attaining LDL-C < 55mg/dL. In the German cohort of the observational HEYMANS study, we aimed to describe the clinical characteristics and LDL-C control among patients initiating evolocumab. Data was collected between 09/2016 and 05/2021 for ≤ 6months before (retrospectively) and ≤ 30months after evolocumab initiation (prospectively). Patient characteristics, lipid-lowering therapy (LLT), lipid values, evolocumab use, and safety were collected. Of 380 enrolled patients, 93% received evolocumab in secondary prevention and 69% had a history of statin intolerance. At study baseline, 49% did not receive any statins and LDL-C was very high (145mg/dL). Use of evolocumab decreased LDL-C by a median of 53% within 3months and remained stable thereafter, despite mainly unchanged background LLT. Overall, 59% attained an LDL-C level < 55mg/dL (69% with, 49% without LLT). Persistence to evolocumab was 90.6% in months 1-12 and 93.5% in months 13-30. Adverse drug reactions were reported in 8% of patients. Data from the German HEYMANS cohort corroborate previous reports on evolocumab effectiveness and safety in clinical practice. Evolocumab initiation was associated with a rapid and sustained LDL-C reduction. Persistence with evolocumab was high. Our finding that patients receiving an evolocumab/LLT combination are more likely to attain the LDL-C goal than those receiving evolocumab alone corroborates previous data showing the importance of using highly intensive therapy. Graphical abstract available for this article. ClinicalTrials.gov Identifier NCT02770131 (registration date 27 April 2016).

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss. While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed. ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Pharmacist intervention in cardiovascular disease prevention: lipid modifying treatment optimisation in type 2 diabetes within hastings primary care network

Abstract Introduction Cardiovascular disease (CVD) leads to 1 in 4 premature deaths with higher likelihood in the most deprived population1. Consistent data demonstrated efficacy of statins in CVD prevention and mortality reduction through modifying lipid profile1,2. NICE:CG181 recommends high-intensity statin, namely atorvastatin 20mg daily in type 2 diabetes (T2DM) with high risk of developing CVD1, whilst the European Society of Cardiology suggests LDL-C target below 1.4mmol/L, the lower the better 2. In contrast, 30% of patients in Hastings Primary Care Network (PCN) are prescribed sub-optimal statin therapy3 with scope to promote medicine optimisation through modification of CVD risk factor in one of the England’s most deprived areas. Aim Lowering patient’s CVD risk through optimising statin therapy and improving practice’s compliance with NICE:CG181. Methods NHS Health Research Authority Decision tool was followed, ethics approval was not required. Statin prescribing data were obtained through OpenPrescribing database. This pilot study focused on the prescribing of simvastatin at one surgery within the PCN where patients were identified using the surgery medical information system with the inclusion clinical codes of: “T2DM”, “QRISK2&amp;gt;10%”, “latest LDL-C&amp;gt;1.4mmol/L” and “current simvastatin 10/20/40mg prescription”. Systematic review of patient medical records was followed, including medical history, latest lipid profile and liver function, allergies, history of statin intolerance, previous lipid therapy and frailty status determined using the electronic frailty index, Rockwood score and medical notes. Patients with heterozygous familial hypercholesterolaemia diagnosis, confirmed statin intolerance and moderately-to-severely frail were excluded. Patients were contacted to exercise shared decision-making. Once intervention agreed, prescription was initiated for prescriber authorisation. Blood test 3 months post-intervention monitored for liver function and lipid profile. Results Search in February 2022 identified 44 patients with 39 suitable for intervention after exclusion. Thirty-six contactable patients were all switched to high-intensity statin. Thirty-four were switched to atorvastatin 20 mg whilst two with prior atorvastatin intolerance were switched to rosuvastatin 10 mg. At baseline, 32 patients (88%) had cholesterol profile done within a year as per NICE:CG181. Three-month post-intervention blood tests were completed for 21, with 15 pending; 33% (7/21) had a reduction of LDL-C. In February 2022, 28.9% of the practice’s statin prescriptions were of low and medium intensity and was reduced to 25.6% post intervention. Discussion/Conclusion All contactable patients had statin therapy optimised after exercising shared decision-making with improvement of prescribing compliance to NICE:CG181 demonstrated in this practice. Findings were inconclusive whether the intensification of statin therapy demonstrated cholesterol lowering effect in this cohort. Study limitations due to small sample size, currency of baseline profile at time of intervention and patient compliance not measured. Raised LDL-C observed could have been influenced by lifestyle changes such as poor diet and lack of exercise1. The limitations of this study will be reviewed for future roll out across Hastings PCN. Further exploration of therapy compliance, lifestyle education and the barriers to regular blood test would facilitate such medicine optimisation intervention. In conclusion, patients prescribed with sub-optimal lipid therapy should be reviewed and managed through healthy lifestyle recommendations and aggressive pharmacological intervention.

†Safety and Efficacy of Bempedoic Acid in Patients with Renal Impairment

<h3>Lead Author's Financial Disclosures</h3> PPT has received honorarium for consultancy from Amarin, AstraZeneca, Kowa, Merck, Novo-Nordisk, and Resverlogix. <h3>Study Funding</h3> Esperion Therapeutics, Inc. <h3>Background/Synopsis</h3> Patients with renal impairment and elevated levels of low-density lipoprotein cholesterol (LDL-C) are at very high risk for cardiovascular disease. Statins are safe and effective in this population but are often underutilized and underdosed; additional non-statin therapies to lower LDL-C are needed. Bempedoic acid (BA) is an ATP citrate lyase inhibitor that lowers LDL-C. <h3>Objective/Purpose</h3> To evaluate the safety and efficacy of BA in patients with Stage 2 or Stage 3a+b renal impairment. <h3>Methods</h3> Data were pooled from four phase 3 studies in which patients were randomized 2:1 to BA or placebo (PBO) for 12 to 52 weeks. All studies permitted stable background lipid-lowering therapy: in 2 studies, patients received background moderate- to high-intensity statin, and in 2 studies, patients had a history of statin intolerance and received low-dose or no statin. Patients were grouped by baseline estimated glomerular filtration rate (eGFR [mL/min/1.73m2]) into the following renal function subgroups: Stage 1 (≥90), Stage 2 (60-89) or Stage 3a+b (30-59). <h3>Results</h3> A total of 3,619 (2,422 BA; 1,197 PBO) patients were included in the analysis. Baseline Stage 2 or Stage 3a+b renal impairment was present in 63% and 15% of patients in each treatment arm, respectively; 22% of the patients had Stage 1 renal function at baseline. LDL-C lowering of BA was similar across renal function subgroups with significant reductions at week 12 from baseline in each subgroup: Stage 1-20.8%, Stage 2 -18.8% and Stage 3a+b -21.1% (P < .0001 vs PBO for each; interaction P = .4442). Significant reductions in ApoB levels were also observed with BA treatment compared with PBO regardless of renal function (P < .0001). The overall pattern of adverse events was consistent across the renal function subgroups; any differences appeared to be driven by overall BA vs PBO differences rather than by renal function at baseline. Creatinine levels were generally consistent within each renal function subgroup in both arms with arm means varying by < 7% at each assessed time point through 52 weeks. <h3>Conclusions</h3> BA was generally well-tolerated among patients with Stage 2 or Stage 3a+b renal impairment and significantly lowered LDL-C regardless of renal function status.

Abstract 9794: Factors Associated with Enhanced Low-Density Lipoprotein Cholesterol Lowering with Bempedoic Acid Among Patients Enrolled in Phase 3 Studies

Bempedoic acid (BA) inhibits ATP-citrate lyase in the cholesterol synthesis pathway. In phase 3 studies, 12 weeks of BA lowered low-density lipoprotein cholesterol (LDL-C) levels compared with placebo by a mean of 17.8% among patients primarily receiving moderate- to high-intensity statin and by 24.5% among statin intolerant patients who were receiving low-dose or no statin. Cholesterol guidelines (Grundy et al. J Am Coll Cardiol . 2019;73:e285) categorize statins according to percent LDL-C lowering: high-intensity (≥ 50%), moderate-intensity (30-49%), and low-intensity (&lt; 30%). We examined LDL-C lowering with BA similarly using pooled data from 4 phase 3 studies in patients on background maximally tolerated statins; 3488 (2321 BA, 1167 PBO) patients were included in the analysis. From baseline to week 12, BA lowered LDL-C levels comparable to that of a moderate- or high-intensity statin (≥ 30%) in 28.9% of patients; this degree of LDL-C lowering was observed in 50.9% of the patients not receiving background statin therapy (Table). A multivariate analysis showed that the absence of baseline statin use was associated with increased rates of achieving at least a 30% reduction in LDL-C with BA treatment (odds ratio [95% CI], 2.49 [1.94, 3.19; P &lt; .0001). Further, being female, a history of diabetes, baseline ezetimibe use, and a higher baseline hsCRP level were also associated with at least a 30% reduction in LDL-C levels ( P &lt; .01 for each). These findings suggest that 1) a significant proportion of patients initiating BA treatment may achieve LDL-C lowering comparable to moderate- or high-intensity statin therapy, especially among patients who cannot tolerate a statin, and 2) patients with hypercholesterolemia who are at higher risk for a cardiovascular event, including women and patients with a history of statin intolerance, diabetes, or higher baseline hsCRP levels, may also achieve enhanced LDL-C lowering with bempedoic acid.

Abstract 13130: Efficacy and Safety of Bempedoic Acid by Sex: Pooled Analyses From Phase 3 Trials

Introduction: Bempedoic acid (BA), an ATP-citrate lyase inhibitor, lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. Objective: To report efficacy and safety of BA by sex in patients with elevated LDL-C. Methods: Data were pooled from 4 phase 3 randomized (2:1), double-blind studies investigating oral BA (180 mg once daily) vs placebo for 12 weeks to 52 weeks in adults receiving maximally tolerated statins who required additional LDL-C lowering, analyzed by sex. The primary efficacy endpoint was % change in LDL-C from baseline to week 12. Results were analyzed in cohorts with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (“ASCVD/HeFH on statins pool”, n=3009) or history of statin intolerance (“statin intolerant pool”, n=614). Safety assessments included treatment-emergent adverse events (TEAEs). Results: Of all participants, 34.3% were women. Significant LDL-C lowering from baseline with BA vs placebo was demonstrated in both pools and sexes ( P &lt; 0.001; Table 1 ), with greater lowering in women vs men in the ASCVD/HeFH on statins pool ( P = 0.04). Rates of TEAEs were similar across groups ( Table 2 ). Rates of common TEAEs were similar in both pools and sexes, except urinary tract infection (men: BA, 2.8%; placebo, 3.0%; women: BA, 8.0%; placebo, 10.3%) and pain in extremity (men: BA, 2.5%; placebo, 1.2%; women: BA, 4.2%; placebo, 2.9%), which occurred more frequently in women. Conclusion: BA lowered LDL-C significantly in both women and men, with greater effect in women vs men in both pools, and a safety profile generally comparable to placebo in both sexes.

A Retrospective Chart Review Evaluating Efficacy, Tolerability, and Cost of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Older Adults.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia. The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy. We conducted a retrospective chart review of patients ≥65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice. A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE. PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.

Statin Intolerance in Clinical Practice.

In our pilot study, we aimed to determine how many patients with the statin intolerance history referred to the specialized center for the diagnostics and treatment of lipoprotein metabolism disorders really suffer from a complete statin intolerance. The purpose of the study was to prove that complete statin intolerance is overestimated and overdiagnosed, and with the detailed knowledge of the issue and patient approach, it is possible to find an appropriate statin treatment for the most of patients. With the increasing number of statin users worldwide, the issue of statin intolerance has been a frequently discussed topic in recent years. There are many factors that play a role in the manifestation of statin intolerance (predisposing factors as age, sex, and some diseases), genetic factors leading to a different metabolism, drug-drug interactions, psychological reasons, and the negative influence of the mass media. However, it is estimated that true complete statin intolerance, defined by an intolerance of at least three statins at their usual lowest daily doses, occurs in approximately 3-6% of all statin users. In our pilot study, we conducted a retrospective analysis of 300 patients who were referred to the Center of Preventive Cardiology with a history of statin intolerance. During the follow-up treatment, 222 patients (74%) were able to use some statin (rosu-, atorva-, simva-, fluvastatin), and in 21% of the cases (63 patient), the target values according their CV risk level were even achieved. Only 78 patients (26%) were confirmed as being complete statin intolerant following a thorough therapeutic effort. The most tolerated statin was rosuvastatin.

Achieving Guideline-Driven High-Intensity Statin Dose in Cardiac Rehabilitation Patients With Coronary Artery Disease.

The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high-intensity statin therapy in patients aged ≤75 y with clinical coronary artery disease (CAD). The effectiveness of cardiac rehabilitation (CR) in lipid management and guideline adherence is unknown. The purpose of this study is to determine whether CR participation affects guideline-driven achievement for statin use. This multicenter retrospective study evaluated statin utilization in patients pre- and post-CR between January 1, 2014, and August 31, 2015. Records for patients with known CAD who completed 18 or more CR sessions were reviewed for statin-drug use and dose before and after CR and documented statin intolerance. Of the total 468 patients, 76% were male with mean age ± SD = 66.0 ± 10.8 y and range of 32 to 89 y. Patients aged ≤75 y (n = 375) showed a modest but statistically significant increase (P = .0006) in high-intensity statin use post-CR (56.3%-61.1%). Males demonstrated a significant increase in high-intensity statin use (P = .0005). Of the 146 patients aged ≤75 y not on high-intensity statins post-CR, only 21 had history of statin intolerance. Of the subjects aged >75 y (n = 93), 91% were already on high- or moderate-intensity statins with no significant change during CR. Patients aged ≤75 y following CR completion increased high-intensity statin use but only by 4.8% and 33% of subjects were inadequately treated. The updated 2013 treatment recommendations simplified statin use, yet substantial data continue to reveal that guideline achievement even post-CR remains limited.

Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study

Background and aimsPatients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering. MethodsThis phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C. ResultsThe study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; −23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (−23.6%), total cholesterol (−18.0%), apolipoprotein B (−19.3%), and high-sensitivity C-reactive protein (−31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups. ConclusionsBempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.

Pitavastatin versus pravastatin in adults with HIV-1 infection and dyslipidaemia (INTREPID): 12 week and 52 week results of a phase 4, multicentre, randomised, double-blind, superiority trial

People living with HIV-1 infection are at greater risk for cardiovascular disease than seronegative adults. Treatment of dyslipidaemia with statins has been challenging in people with HIV because of an increased potential for drug interactions due to competing cytochrome P450 metabolism between statins and commonly used antiretroviral agents. Neither pitavastatin nor pravastatin depend on cytochrome P450 for primary metabolism. We aimed to assess the safety and efficacy of pitavastatin versus pravastatin in adults with HIV and dyslipidaemia. In the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) randomised, double-blind, active-controlled, phase 4 trial (INTREPID, we recruited adults aged 18-70 years with controlled HIV (with CD4 counts >200 cells per μL and HIV-1 RNA <200 copies per mL) on antiretroviral therapy for at least 6 months and dyslipidaemia (LDL cholesterol 3·4-5·7 mmol/L and triglycerides ≤4·5 mmol/L) from 45 sites in the USA and Puerto Rico. Patients being treated with darunavir, or who had homozygous familial hypercholesterolaemia or any condition causing secondary dyslipidaemia, or a history of statin intolerance, diabetes, or coronary artery disease were not eligible. We randomly assigned patients (1:1) to pitavastatin 4 mg or pravastatin 40 mg with matching placebos once daily orally for 12 weeks, followed by a 40 week safety extension. Randomisation was stratified by viral hepatitis B or C coinfection and computer-generated. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was percentage change in fasting serum LDL cholesterol from baseline to week 12 and the primary efficacy analysis was done in the modified intention-to-treat population. The safety analysis included all patients who took at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT01301066. Between Feb 23, 2011, and March 29, 2013, we randomly assigned 252 patients to the pitavastatin (n=126) or pravastatin group (n=126). LDL cholesterol reduction was 31·1% with pitavastatin and 20·9% with pravastatin (least squares mean difference -9·8%, 95% CI -13·8 to -5·9; p<0·0001) at 12 weeks. At week 52, four patients (3%) in the pitavastatin group and six (5%) in the pravastatin group had virological failure, with no significant difference between treatments. Both treatments had neutral effects on glucose metabolism parameters. 85 patients treated with pitavastatin (68%) and 88 patients treated with pravastatin (70%) reported treatment-emergent adverse events, and these caused study discontinuation in six patients (5%) versus five patients (4%). No serious adverse event occurred in more than one participant and none were treatment-related according to investigator assessment. The most common treatment-emergent adverse events were diarrhoea in the pitavastatin group (n=12, 10%) and upper respiratory tract infection in the pravastatin group (n=14, 11%). 11 treatment-emergent serious adverse events were noted in seven patients (6%) in the pitavastatin group (atrial septal defect, chronic obstructive pulmonary disease, chest pain, diverticulitis, enterovesical fistula, gastroenteritis, viral gastroenteritis, herpes dermatitis, multiple fractures, respiratory failure, and transient ischaemic attack) and four events in three patients (2%) in the pravastatin group (cerebrovascular accident, arteriosclerosis coronary artery, myocardial infraction, and muscle haemorrhage). In the pravastatin treatment group, one additional patient discontinued due to an adverse event (prostate cancer that was diagnosed during the screening period, 42 days before first dose of study treatment, and therefore was not a treatment-emergent adverse event). The INTREPID results support guideline recommendations for pitavastatin as a preferred drug in the treatment of dyslipidaemia in people with HIV. Kowa Pharmaceuticals America and Eli Lilly and Company.

Phytosterol supplementation in patients with history of statin intolerance or refusal

Phytosterol supplementation in patients with history of statin intolerance or refusal

Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance

Once-daily, oral ETC-1002 reduces low-density lipoprotein cholesterol (LDL-C) and has beneficial effects on other cardiometabolic risk factors but has not been examined in statin intolerant patients. To study the efficacy and safety of ETC-1002 (a novel LDL-C-lowering agent) in patients with hypercholesterolemia and a history of statin intolerance. Patients intolerant to at least 1 statin were entered into this multicenter, double-blind, 8-week trial. Participants were required to have a history of muscle complaints that developed during statin treatment and resolved within 4 weeks of statin discontinuation. Patients (n = 56) were randomized in a 2:1 ratio to ETC-1002 60 mg daily or placebo. The ETC-1002 dose was increased at 2-week intervals to 120 mg, 180 mg, and 240 mg. The primary end point was the percentage change from baseline to week 8 in calculated LDL-C. ETC-1002 reduced LDL-C 28.7% more than placebo (95% confidence interval, -35.4 to -22.1; P < .0001). ETC-1002 significantly reduced non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein. Triglycerides and high-density lipoprotein cholesterol did not change with ETC-1002 treatment. Sixty-two percent of patients receiving ETC-1002 and none in the placebo group achieved the 2004 National Cholesterol Education Program Adult Treatment Panel III LDL-C goal (P < .0001). Muscle-related adverse events occurred with similar frequency in the placebo and ETC-1002 treatment groups, causing no discontinuations in ETC-1002-treated patients. ETC-1002 appears to be effective at reducing LDL-C and was well tolerated in patients with statin-associated muscle complaints. Longer and larger studies are required to confirm the absence of muscle side effects.

ETC-1002 Lowers LDL-Cholesterol and is Well Tolerated in Hypercholesterolemic Patients with Statin Intolerance†

Methods: 56 patients with a history of statin intolerance involving muscle pain or weakness stopped lipid-lowering agents and received single-blinded PBO for 2 weeks. Patients were excluded if musclerelated AEs were reported during the single-blinded period. Remaining patients were randomized to receive PBO (n=19) or ETC-1002 in daily doses increasing from 60 to 120 to 180 to 240 mg (n=37) every two weeks over 8 weeks of treatment. The primary endpoint was percent change in LDL-C from baseline to Week 8.

Intolerance to Statins: Mechanisms and Management

Statins are considered very effective in reducing cardiovascular morbidity and mortality in high-risk patients. However, although adherence to statins improves morbidity and mortality (1), it remains suboptimal (2). One of the most important causes of nonadherence is the so-called statin intolerance, mainly because of muscle-related symptoms. These symptoms most often consist of myalgia unaccompanied by significant creatine kinase (CK) elevations. Less often, myositis (elevated CK >10 times the upper limit of normal) or rhabdomyolysis (CK level >10,000 IU/L or accompanied by significant elevation in creatinine level) develops. In randomized controlled trials, the incidence of statin myopathy is ~1.5–5.0% (3). However, this low incidence may be misleading for several reasons. First, in most studies patients with a history of statin intolerance were excluded. Other studies had a single-blinded statin run-in phase, and patients experiencing muscle-related symptoms or CK elevations during this phase were excluded. Patients who tend to be at risk for developing muscle-related symptoms, such as women, elderly patients, and patients with significant comorbidity, who comprise a large proportion of statin-treated patients in real-life settings, are underrepresented in randomized controlled trials. Some studies have defined muscle-related effects by elevated CK levels only, disregarding myalgia. Last but not least, patients enrolled in studies might be motivated and so minimize reporting of mild myalgias, thus leading to underestimation of the magnitude of the problem. Data concerning real-life incidence of statin-related myopathy are scarce. In the Prediction of Muscular Risk in Observational Conditions (PRIMO) study (4), 7,924 patients receiving high-dosage statin therapy in an outpatient setting in France were asked about muscle-related symptoms. Overall, muscular symptoms were reported by 10.5% of the patients. A weakness of this study is that it lacked a comparison/control group not treated with statins. In a study of adults aged ≥40 years who participated in National Health and …