VI. Drug Therapy

DA VINCI study: Change in approach to cholesterol management will be needed to reduce the implementation gap between guidelines and clinical practice in Europe

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Prevalence of Low High-Density Lipoprotein Cholesterol in Patients With Documented Coronary Heart Disease or Risk Equivalent and Controlled Low-Density Lipoprotein Cholesterol

Background: There haven’t been well-designed studies conducted to know an optimal goal for low-density lipoprotein cholesterol (LDL-C) after acute myocardial infarction (AMI). Methods: Of 2,409 consecutive patients (62.7 ± 12.4 years, 74.1% men) with AMI who had baseline LDL-C levels ≥70mg/dL and received discharge statin prescriptions after successful percutaneous coronary intervention, 1,305 patients (61.0 ± 11.8 years, 77.0% men) who had LDL-C levels tested at 1 year (mean baseline LDL-C, 126.5 ± 33.5 mg/dL; mean LDL-C reduction at 1 year, 53.1 ± 29.3 mg/dL) were analyzed in this study. Patients were categorized into 2 groups according to the values of LDL-C at 1 year in two different ways using percent change from baseline (≥50% reduction, n=428 versus <50% reduction, n=877) and fixed levels (<70 mg/L, n=625 versus ≥70 mg/dL, n=680). The primary endpoint was the composite of major cardiac events (MCEs) including cardiac deaths, non-fatal myocardial infarctions and coronary revascularizations (angioplasty or bypass grafting) after hospital discharge. A median follow-up duration was 2.0 years (interquartile range, 1.9 to 2.1 years). Results: At 2 years, MCEs occurred in 139 patients (10.7%). Kaplan-Meier estimates of the MCEs rates at 2 years revealed that patients with ≥50% LDL-C reduction from baseline had fewer MCEs compared with <50% LDL-C reduction (8.2% versus 11.9%; Log rank P =0.026), while those with LDL-C levels <70 mg/dL at 1 year did not (<70 mg/L, 10.7% versus ≥70 mg/dL, 10.6%; Log rank P =0.998). In a multivariable Cox proportional hazard model, patients with ≥50% LDL-C reduction from baseline had a 39% reduction in the risk of MCEs compared with <50% LDL-C reduction (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41 to 0.90; P =0.012). But, compared with LDL-C levels ≥70 mg/dL at 1 year, patients with LDL-C levels <70 mg/dL didn’t have a significant reduction in the risk of MCEs (adjusted HR, 0.98; 95% CI, 0.69 to 1.37; P =0.975). Conclusions: Obtaining a ≥50% reduction in LDL-C was associated with a significant reduction in the risk of MCEs after AMI, whereas achieving a <70 mg/dL was not. Our study suggests that obtaining a ≥50% reduction from baseline could be an optimal goal for LDL-C after AMI, not achieving a <70 mg/dL.

The National Cholesterol Education Program Adult Treatment Panel III (ATP III) listed diabetes as a coronary heart disease (CHD) risk equivalent for setting therapeutic goals for LDL cholesterol (1). A goal for LDL cholesterol of 20%. For the majority of patients with diabetes, this LDL cholesterol goal would evoke the use of cholesterol-lowering drugs, particularly statins. Some investigators have questioned whether most or all patients with diabetes have a CHD risk equivalent and thus require cholesterol-lowering drugs (2). One approach to this issue is to examine epidemiological data relating to absolute risk for developing CHD in various populations of persons with diabetes. In the present issue of Diabetes Care , Howard et al. (3) reported the incidence of CHD in the Strong Heart Study, a cohort study of cardiovascular disease (CVD) in 13 American-Indian tribes/communities conducted in three study centers in southwestern Oklahoma, central Arizona, and North and South Dakota. The population of the Strong Heart Study has a high prevalence of type 2 diabetes and CVD associated with diabetes. The findings of this study showed wide variation in rates of CHD in patients with diabetes, depending in part on coexisting risk factors. Most individuals had 10-year risk >20%, the threshold for ATP III’s CHD risk equivalency, but only those with multiple risk factors had rates of CHD events equivalent to patients with established CHD. The authors conclude that it may be prudent to consider therapeutic goals for risk factors based on the entire risk factor profile, rather than just the presence of diabetes. Other studies likewise have found …

Results of the National Cholesterol Education (NCEP) Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II Survey and Implications for Treatment Under the Recent NCEP Writing Group Recommendations

Background Inclisiran has demonstrated effective and sustained reductions in low-density lipoprotein cholesterol (LDL-C) of approximately 50% in clinical trials,1 but data are limited on the degree of LDL-C lowering achieved in clinical practice. With twice-yearly dosing, many factors can affect real-world effectiveness of inclisiran, such as adherence to intended dosing, pretreatment LDL-C, background therapy, and LDL-C measurement timing relative to inclisiran administration. Purpose To evaluate adherence to dosing schedules of inclisiran in clinical practice and the degree of LDL-C lowering achieved in patients given at least 3 doses of inclisiran at recommended intervals and by key subgroups. Methods This study utilized data from a national, multi-institution Electronic Health Record (EHR) database from a single EHR vendor (Epic Cosmos) which includes 295 million unique individuals across 1,633 hospital systems. We identified patients prescribed inclisiran between December 22, 2021 through December 21, 2024. We analyzed patient-level characteristics, inclisiran dosing patterns, and adherence to dosing schedules. We identified those who were adherent to the dosing schedule in the first year, defined as receiving the first 3 doses of inclisiran within at least 30 days of the optimal dosing window, i.e., day 0, 90, and 270. Among this "adherent" group, we assessed LDL-C reductions from baseline (on or within 1 year prior to first dose) over the subsequent year two ways: 1) calculating maximal % reduction compared with baseline LDL-C using the lowest LDL-C level between days 90-450, and 2) based on time-adjusted LDL-C levels from day 90-450 (i.e., 180 days after dose 3). Results Among 16,531 inclisiran recipients (mean age 71.4 years, 54.4% women, 88.8% White, baseline LDL-C 122.2 mg/dL), 30.2% (n=4,997) only received a single dose, and 86.7% (n=10,004) patients received ≥2 doses on-schedule. The "adherent" group who received ≥3 doses on-schedule consisted of 4,664 (28.2% of study population) patients; from this group, we identified n=2,357 patients who had a baseline LDL-C measurement and at least one subsequent LDL-C measured between days 90-450. Overall, the mean % LDL-C using the nadir between days 90-450 was -38.7% (SD 87.8), corresponding to an average reduction of 59.3 mg/dL (SD 56.1). Using all values available, the time-adjusted average LDL-C reduction from days 90-450 was -33% (SD 91.3, Figure 1). Differential LDL-lowering effects were observed according to background LLT and baseline LDL-C (Figure 2). Conclusion In the largest reported analysis to-date of LDL-C changes in patients given inclisiran, those with an LDL-C level ≥155 mg/dL who received three doses on-schedule in the first year experienced LDL-C lowering similar to what was observed in clinical trials after accounting for baseline LDL-C. Those with lower starting LDL-C and on PCSK9i mAb therapy had attenuated LDL-C lowering likely due to changes in background therapy.

Identification and treatment of individuals at high risk of coronary heart disease

Background: Although current cholesterol performance measures define good quality as low density lipoprotein cholesterol (LDL-C) levels < 100mg/dl in cardiovascular disease (CVD) patients, they provide a snap shot at one time point and do not inform whether an appropriate action was taken to manage elevated LDL-C levels. We assessed frequency and predictors of this appropriate response (AR). Methods: We used administrative data to assess 22,902 CVD patients receiving care in a Veterans Affairs network of 7 hospitals and affiliated clinics. We determined the proportion of CVD patients at LDL-C goal <100 mg/dl, and the proportion of patients with uncontrolled LDL-C levels (>100 mg/dl) who had an AR [defined as the initiation or dosage increase of a lipid lowering medication (LLM), addition of a new LLM, receipt of maximum dosage or >1 LLM, or LDL-C reading <100 mg/dl] at 45 days follow-up. Logistic regression was performed to evaluate facility, provider and patient characteristics associated with AR. Results: LDL-C levels were at goal in 16,350 (71.4%) patients. An additional 2,110 (9.2%) had an AR at 45 days of follow-up. Controlling for clustering between facilities and patient's illness severity, history of diabetes (OR 1.18, 95% CI 1.03-1.35), hypertension (OR 1.21, 95% CI 1.02-1.44), patients showing good medication adherence (medication possession ratio > 0.8) [OR 2.29, 95% CI 1.99-2.64] were associated with AR. Older CVD patients (age >75 years) were less likely to receive AR (OR 0.60, 95% CI 0.52-0.70). Teaching vs. non-teaching facility (p=0.40), physician vs. non-physician provider (p=0.14), specialist vs. non-specialist primary care provider (p=0.12), and patient's race (p=0.12) were not predictors of AR. Conclusion: Among patients with CVD and LDL-C above guideline recommended levels, only one-third receive AR. Diabetic and hypertensive CVD patients are more likely to receive AR, whereas older Veterans with CVD receive AR less often likely reflecting providers' belief of lack of efficacy from treatment intensification in older CVD patients. Our findings are important for quality improvement and policy making initiatives as they provide more actionable information compared with isolated LDL-C goal attainment as a quality indicator.

BACKGROUND: Patients with lower extremity peripheral arterial disease (PAD) have high rates of cardiovascular events but are less likely to achieve ideal low density lipoprotein cholesterol (LDL-C) levels than coronary artery disease patients. We determined whether a telephone counseling intervention, designed to activate PAD patients to request more intensive LDL-C lowering therapy from their physician, can help PAD patients achieve lower LDL-C levels compared to two control groups. METHODS: Three hundred fifty-five participants with PAD and baseline LDL-C ≥ 70 mg/dl were randomized to one of three parallel arms: telephone counseling intervention, attention control condition, and usual care. The primary outcome was change in LDL-C level at twelve- month follow-up. The secondary outcome was the percent of PAD participants with an LDL-C < 100 mg/dl at 12 month follow-up. The intervention consisted of eight patient-centered telephone counseling calls that encouraged PAD participants to request more intensive lipid-lowering therapy from their physician. The attention control group consisted of eight telephone calls providing knowledge about PAD. The usual care group participated in baseline and follow-up testing only. RESULTS: At 12-month follow-up, the telephone counseling intervention was associated with lower LDL-C levels as compared to attention control (-18.4 mg/dl vs. -6.8 mg/dl, p= 0.010) but not as compared to usual care (-18.4 mg/dl vs. -11.1 mg/dl, p= 0.208). Both attention control and the usual care condition were less likely to achieve an LDL-C < 100 mg/dl, compared to the intervention (odds ratio = 0.34, 95% Confidence Interval (CI) = 0.17-0.69, p=0.003 and odds ratio = 0.42, 95% CI = 0.20-0.86, p=0.018, respectively). Participants in the intervention were more likely to start a new statin medication than the attention control arm (18.6% vs. 5.5%, p=0.008) and usual care arm (18.6% vs. 5.5%, P=0.005). CONCLUSION: Among patients with PAD, a telephone counseling intervention designed to activate patients to request more intensive LDL-C lowering therapy from their physician resulted in lower LDL-C levels and higher rates of initiating cholesterol-lowering drugs, compared to control groups. 1

Introduction: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Strategies that lower LDL-C levels reduce this risk. Hypothesis: We hypothesized that real-world PAD patients are overall undertreated with lipid lowering therapies (LLT) but that LLT use and achieved LDL-C are improved in high risk patients with ischemic events. Methods: Patients with PAD in the MarketScan database linked to PROGNOS lab data from January 1, 2014 through December 31, 2018 were examined. Outcomes included use of LLT, defined as high intensity (HI) (high intensity statin, any statin plus ezetimibe, or any use of a PCSK9 inhibitor), low intensity (LI) (any other lipid regimen), or no therapy, and follow up LDL-C level. Goal LDL-C was defined as <70 mg/dl. Results: Among 18,747 PAD patients, 25% were on HI LLT, 43% were on LI LLT, and 32% were on no therapy at baseline (Figure A). The median LDL-C was 91 mg/dl (IQR 70, 118), and 25% of patients were at goal (Figure B). After a median follow up of 18 months, use of HI LLT increased by 4%, the median LDL-C decreased by 5 mg/dl, and an additional 3% of patients were at goal LDL-C. Greater use of HI LLT was observed among patients with a MACE (55%) or MALE (41%) event during follow up compared with patients without an ischemic event (26%) during follow up (Figure C). Follow up LDL-C levels remained above goal for most patients (post-MACE: median LDL-C 77 mg/dl, 42% patients at goal; post-MALE: median LDL-C 80 mg/dl, 36% patients at goal). Conclusions: In PAD patients, use of LLT is suboptimal, and LDL-C levels remain elevated. After an ischemic event, LLT use is intensified, with greater use of HI LLT observed after MACE than MALE. Despite this, LLT remains underutilized, with >50% of patients not at goal LDL-C. Strategies to better implement proven therapies to reduce risk in this high risk population are needed.

The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001). In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.

ObjectiveData on the intensity of statin therapy for patients with acute myocardial infarction (MI) and very low baseline low-density lipoprotein (LDL) cholesterol level are lacking. We sought to assess the impact of statin intensity in patients with acute MI and LDL cholesterol <70 mg/dL.MethodsA total of 1,086 patients with acute MI and baseline LDL cholesterol <70 mg/dL from the Korea Acute Myocardial Infarction Registry-National Institute of Health database were divided into less intensive statin (expected LDL reduction <40%, n=302) and more intensive statin (expected LDL reduction ≥40%, n=784) groups. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, MI, revascularization occurring at least 30 days after admission, and stroke, at 12 months.ResultsAfter 1:2 propensity matching, differences were not observed between less intensive (n=302) and more intensive statin (n=604) groups in incidence of cardiac death (0.3% vs. 0.3%) and hemorrhagic stroke (0.3% vs. 0.5%, p=0.727) at 12 months. Compared with the less intensive statin group, the more intensive statin group showed lower target-vessel revascularization (4.6% vs. 1.8%, p=0.027) and MACCE (11.6% vs. 7.0%, p=0.021). Major bleeding was not different between less intensive and more intensive statin groups (1.0% vs. 2.6%, p=0.118).ConclusionMore intensive statin therapy was associated with significantly lower major adverse cardiovascular events in patients with acute MI and very low LDL cholesterol compared with less intensive statin therapy.

Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia. To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. This multicenter, open-label, titration-based extension study enrolled subjects who completed one of three multicenter, randomized, double-blind, placebo-controlled phase II studies with colesevelam. This study consisted of a 4-week washout/dietary stabilization period, a 50-week open-label treatment period, and a 2-week follow-up period. Ten clinical centers within the US. Males and females 18 years of age or older who had completed a previous short-term (4- or 6-week) phase II clinical study with colesevelam. At week 0 (following a 4-week washout of all lipid-lowering medication), subjects initiated treatment with colesevelam at a dosage of 1.5 g/day. Colesevelam was uptitrated to a maximum dosage of 3.75 g/day as necessary to achieve a 15-30% reduction from baseline in LDL-C level. At week 12, an HMG-CoA reductase inhibitor (statin) or niacin (nicotinic acid) could be added if colesevelam 3.75 g/day was not sufficient to result in a 15-30% reduction from baseline in LDL-C level. The primary efficacy measure was the change in LDL-C level from baseline to week 50 across all treatment regimens. Secondary efficacy parameters included the change and percent change in total cholesterol, HDL-C, and triglyceride levels from baseline to week 50. There were three cohorts analyzed: (i) colesevelam monotherapy (included all subjects who received colesevelam monotherapy, regardless of dose); (ii) all treatment regimens (included all subjects who received colesevelam monotherapy or colesevelam plus low-dose statin or niacin therapy); and (iii) combination therapy (included only subjects who received colesevelam plus low-dose statin therapy). Two additional cohorts were also evaluated: (iv) maximum-dose colesevelam monotherapy (included only subjects who received colesevelam 3.75 g/day monotherapy); and (v) all maximum-dose colesevelam treatment regimens (included all subjects who received colesevelam 3.75 g/day, either as monotherapy or in combination with low-dose statin or niacin therapy). In total, 272 subjects were screened, 260 enrolled, and 186 completed the study. In total, 255 subjects were included in the intent-to-treat population. The maximum dosage of colesevelam (3.75 g/day) was taken by 50% of subjects (n = 94/188) at week 50; only 38 subjects received low-dose statin or niacin by study end. At week 50, LDL-C levels were significantly (p < 0.001) reduced from baseline across all treatment regimens (by 29.6 mg/dL [from 185.8 to 156.2 mg/dL; 15.0%]). Colesevelam also significantly reduced total cholesterol levels and significantly increased HDL-C and triglyceride levels across all treatment regimens (p < 0.001 for all). Drug-related adverse events were reported by 36.2% of subjects across all treatment regimens (and by 47.4% of subjects who received colesevelam plus low-dose statin or niacin therapy). In this study, colesevelam was found to be safe and effective for the management of LDL-C levels in adults with primary hypercholesterolemia.

Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012