Non-statin Drugs Research Articles

Redefining Statin Dosage Post-Gastric Bypass: Insights from a Population Pharmacokinetics-Pharmacodynamics Link Approach.

Roux-en-Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic-pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed-effect modeling approach. A parent-metabolite model with first-order absorption, 2-compartments for SV and 1-compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL-cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low-intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post-RYGB patients to maintain a comparable response to that of non-operated subjects. Moderate-intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non-statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post-RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non-statin drugs to attain equivalent responses and mitigate potential adverse events.

Effects of statins beyond lipid-lowering agents in ART-treated HIV infection.

Antiretroviral therapies (ART) have reduced human immunodeficiency virus (HIV) infection-associated morbidity and mortality improving the life of people with HIV (PWH). However, ART lead to residual HIV production, which in conjunction with microbial translocation and immune dysfunction contributes to chronic inflammation and immune activation. PWH on ART remain at an increased risk for cardiovascular diseases (CVDs) including myocardial infarction and stroke; which in part is explained by chronic inflammation and immune activation. Lifestyle factors and certain ART are associated with dyslipidemia characterized by an increase of low-density lipoprotein (LDL), which further contributes in the increased risk for CVDs. Lipid-lowering agents like statins are emerging as immune modulators in decreasing inflammation in a variety of conditions including HIV. The international randomized clinical trial REPRIEVE has shed light on the reduction of CVDs with statin therapy among PWH. Such reports indicate a more than expected benefit of statins beyond their lipid-lowering effects. Bempedoic acid, a first-in-class non-statin LDL-lowering drug with immune modulatory effects, may further aid PWH in combination with statins. Herein, we critically reviewed studies aimed at lipid-lowering and immune-modulating roles of statins that may benefit aging PWH.

ЛИПИДСНИЖАЮЩАЯ ТЕРАПИЯ: ОТ ИСТОКОВ В СЕГОДНЯШНИЙ ДЕНЬ

The article deals with the treatment of dyslipidemia with HMG-CoA reductase inhibitors as well as non-statin lipid lowering drugs. Several lipid-lowering drugs have emerged in recent decades: bile acid sequestrants, fibrates, nicotinic acid, ezetimibe, bempedoic acid, volanesoren, evinacumab, PCSK 9 inhibitors evolocumab and alirocumab, and inclisiran. Although statins remain the gold standard of treatment, PCSK9-targeted therapy will play an increasingly important role in the correction of dyslipidemia. The review utilized information on the topic from publications based on PubMed and Google Scholar databases, depth of coverage 5 years.

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis

BackgroundIt remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity.MethodsTwo-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data.ResultsGenetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.ConclusionThis study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

CSI clinical practice guidelines for dyslipidemia management: Executive summary

Dyslipidemias are the most important coronary artery disease (CAD) risk factor. Proper management of dyslipidemia is crucial to control the epidemic of premature CAD in India. Cardiological Society of India strived to develop consensus-based guidelines for better lipid management for CAD prevention and treatment. The executive summary provides a bird's eye-view of the ‘CSI: Clinical Practice Guidelines for Dyslipidemia Management’ published in this issue of the Indian Heart Journal. The summary is focused on the busy clinician and encourages evidence-based management of patients and high-risk individuals. The summary has serialized various aspects of lipid management including epidemiology and categorization of CAD risk. The focus is on management of specific dyslipidemias relevant to India-raised low density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol (non-HDL-C), apolipoproteins, triglycerides and lipoprotein(a). Drug therapies for lipid lowering (statins, non-statin drugs and other pharmaceutical agents) and lifestyle management (dietary interventions, physical activity and yoga) are summarized. Management of dyslipidemias in oft-neglected patient phenotypes-the elderly, young and children, and patients with comorbidities-stroke, peripheral arterial disease, kidney failure, posttransplant, HIV (Human immunodeficiency virus), Covid-19 and familial hypercholesterolemia is also presented. This consensus statement is based on major international guidelines (mainly European) and expert opinion of lipid management leaders from India with focus on the dictum: earlier the better, lower the better, longer the better and together the better. These consensus guidelines cannot replace the individual clinician judgement who remains the sole arbiter in management of the patient.

Insights into the current management of dyslipidemia from a clinical pharmacological perspective

The low-density lipoprotein cholesterol (LDL-C) is established as a causative agent of atherosclerotic cardiovascular disease (ASCVD) and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular events. Statins remain the cornerstone of drug therapy for dyslipidemia. Although moderate- to high- intensity statin therapy has demonstrated consistent benefits for secondary prevention of cardiovascular events, statin monotherapy is insufficient to achieve the guideline-recommended LDL-C levels for high- and very high-risk patients. Some patients cannot tolerate statins, especially when taking long-term high doses. Several non-statin drugs that have a complementary mechanism of action to statins are now available, including ezetimibe, monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9 mAb), and, more recently, inclisiran, bempedoic acid, and evinacumab. Considering the recommendations from guidelines by domestic and international cardiovascular associations, combining these drugs should be contemplated to attain treatment goals for patients. Key words: dyslipidemia, atherosclerotic cardiovascular disease, lipid-lowering drugs, familial hypercholesterolemia, hypertriglyceridaemia, nonstatin therapies.

Adverse drug reactions of non-statin antihyperlipidaemic drugs in China from 1989 to 2019: a national database analysis

ObjectiveThis study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database.DesignAn approach of Chinese national database analysis was employed to...

Effectiveness and safety of Inclisiran in hyperlipidemia treatment: An overview of systematic reviews.

This paper aimed to comprehensively evaluate the effectiveness and safety of Inclisiran in treating hyperlipidemia through an overview of systematic reviews (SRs). The Cochrane Library, EMBASE, PubMed, CNKI, WANGFANG database, VIP database, ClinicalTrials.gov, and ICRT were searched electronically to collect SRs and meta-analysis of Inclisiran in hyperlipidemia treatment from the establishment of the database till May 2022. Two researchers independently screened the relevant literature, then the assessment of multiple systematic reviews tool was made into assess the methodological quality of the included studies. Data extracted were used to perform the study through RevMan5.3 software. The grading of recommendations assessment, development, and evaluation tool was used to grade the quality of the evidence of the outcomes included in the SRs. Prospero ID: CRD 42022326845. A total of 10 relevant SRs were included, involving 7 randomized controlled trials. The assessment results of the assessment of multiple systematic reviews tool suggested that the quality of the SRs included needed to be improved. The reduced level of low-density lipoprotein cholesterol of the experimental group was lower than the control group, and the difference in the amount of effectiveness was statistically significant (MD = -50.13, 95%CI: -56.2 to -44.06, P < .00001). The grading of recommendations assessment, development, and evaluation results showed that out of 27 outcomes, 8 were high-quality, 3 were of medium quality, 6 were of low quality, and 10 were of the most inferior quality. 300mg Inclisiran with 2 injections a year has the best therapeutic effect, which can significantly reduce low-density lipoprotein cholesterol and total cholesterol, and increase high-density lipoprotein cholesterol levels in patients with hyperlipidemia. Inclisiran has a favorable safety profile, with no significant difference in the incidence of adverse reactions compared to a placebo. Most of the adverse effects were associated with the reaction on the injection site.

The Management of Hypercholesterolemia in Patients with Neuromuscular Disorder.

We describe and discuss the safety of statins and non-statin drugs in neuromuscular disorders (NMDs). We also propose a pragmatic model of care for the management of such cases. Patients with both NMD and hypercholesterolemia may be particularly disadvantaged owing to the toxic effects of cholesterol-lowering therapy and the inability to take medication. Specifically, the management of hypercholesterolemia in patients with NMD is complicated by the increased risk of statin-related myotoxicity and concerns that statins may aggravate or possibly induce the onset of a specific NMD. The most severe form of statin-related myotoxicity is immune-mediated necrotizing myopathy. Management of hypercholesterolemia in patients with NMDs include treating modifiable factors, consideration of toxicity risk of statin, use of non-statin lipid lowering agents, noting possible drug interactions, and careful monitoring.

Hypertriglyceridemia and Atherosclerotic Carotid Artery Stenosis.

Both fasting and non-fasting hypertriglyceridemia have emerged as residual risk factors for atherosclerotic disease. However, it is unclear whether hypertriglyceridemia increases the risks of the progression of carotid artery stenosis. Statins are well known to prevent carotid plaque progression and improve carotid plaque instability. In addition, statin therapy is also known to reduce cerebrovascular events in patients with carotid artery stenosis and to improve clinical outcomes in patients undergoing revascularization procedures. On the other hand, there have been no randomized controlled trials showing that the combination of non-statin lipid-lowering drugs with statins has additional beneficial effects over statin monotherapy to prevent cerebrovascular events and stenosis progression in patients with carotid artery stenosis. In this article, the authors demonstrate the mechanisms of atherosclerosis formation associated with hypertriglyceridemia and the potential role of lipid-lowering drugs on carotid artery stenosis. The authors also review the articles reporting the relationships between hypertriglyceridemia and carotid artery stenosis.

Underutilization of combination therapy in lipid lowering: a missed opportunity.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. LDL cholesterol (LDL-C) is the key driving force in the atherosclerotic process, and LDL-C lowering can change the trajectory of ASCVD and decrease cardiovascular (CV) events. In the light of new evidence, LDL-C goals have become more stringent in the ESC guidelines, especially for high-risk patients.1 Unfortunately, these goals are rarely reached in real life as shown in registries such as EUROASPIRE documenting a large implementation gap.2 The reasons for underimplementation are multiple, but underutilization of therapies is a major cause. Statins are the first line of treatment in lipid-lowering therapy (LLT) but may not get the patient to the guideline-recommended goals, and combination therapy may be necessary. The recent ESC guidelines recommend adding ezetimibe first, followed by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody inhibitors to the treatment regimen, since both agents have been documented to decrease CV events further on top of a statin.3 However, combination therapy with non-statin drugs is widely underutilized. A recent pan-European observational study (the DA VINCI study) reported that a majority of patients under both primary and secondary prevention were receiving moderate-intensity statin therapy. Only 28% were receiving high-intensity statins, 9% ezetimibe combination therapy, and 1% PCSK9 inhibitors.4 As a result, only a third of the patients achieved their LDL-C goal as recommended in the recent guidelines.

Bempedoic Acid's Use as an Adjunct in Lowering Low-Density Lipoprotein Cholesterol in Patients With Coronary Artery Disease: A Systematic Review.

Coronary artery disease (CAD) is one of the leading causes of death worldwide. Atherosclerosis begins in childhood as fatty streaks, progresses with age, and lifestyle influences the progression of atherosclerotic plaque. Over time, with significant narrowing of the blood vessels, blood flow into the coronary arteries is compromised, resulting in various symptoms of coronary heart disease. Many drugs are used in clinical practice to prevent atherosclerotic cardiovascular events in patients with CAD. This review aims to investigate the efficacy and safety of a non-statin novel lipid-lowering drug, bempedoic acid (BDA), an adenosine triphosphate (ATP) citrate lyase inhibitor, in lowering serum low-density lipoprotein cholesterol (LDL-C) levels among patients with CAD. BDA is a new drug that recently got approval for clinical use. Following its discovery, BDA has been researched in order to investigate its role in the treatment of hypercholesterolemia. A search for studies was conducted using databases such as PubMed, PMC, ScienceDirect, and Google Scholar up untilApril 30, 2022. This systematic review has followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 11 studies were finalized to explore the role of BDA alone or as an adjunct in lowering serum LDL-C levels in high-risk patients under maximally tolerated statins, statin-intolerant groups, or treatment with other lipid-lowering drugs. These studies are three randomized controlled trials (RCTs), one pre-proof RCT, two systematic reviews and meta-analyses, and five narrative review articles. This review included 8465 participants from recently conducted RCTs and systematic reviews. Another 14014 participants, enrolled for the Cholesterol Lowering via Bempedoic Acid, an Adenosine Triphosphate-Citrate Lyase-Inhibiting Regimen (CLEAR) Outcomes clinical trial, were also included. BDA in combination with ezetimibe showed good evidence of LDL-C lowering effect. Patients on maximally tolerated statin failing to achieve desired LDL-C when treated in combination with BDA showed a significant decrement in serum LDL-C levels, high sensitivity C-reactive protein (HsCRP), and triglyceride. BDA use showed no adverse side effects. The most common side effect seen in several trials was the rise in serum uric acid level. When treating patients with BDA, baseline uricacid levels should be obtained and regular monitoring of uricacid should be done. The CLEAR Outcomes trial, scheduled to be completed by December 2022, will provide further information on BDA. BDA appears to be a promising alternative to currently available secondary lipid-lowering agents.

Ezetimibe and diabetes mellitus:a new strategy for lowering cholesterol

Diabetes mellitus is a well-recognized risk factor for cardiovascular diseases, so an “aggressive” therapeutic approach is necessary for some high-risk patients. Low-density lipoprotein (LDL) cholesterol is the leading modifiable risk factor for the development of atherosclerotic cardiovascular diseases (ACVD). It is known that statins are the gold standard to control LDL cholesterol and reduce the risks associated with ACVD; however, many patients do not achieve their LDL cholesterol target or are unable to use this class of drugs due to associated side effects. Recent studies of non-statin cholesterol-lowering drugs (ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors) have demonstrated benefits in the treatment of ACVD, and new drugs (bempedoic acid, inclisiran) have shown promising results in preclinical and clinical studies. New evidence suggests that prescription of ezetimibe as an addition to statins provides an additional cardioprotective effect. This review aims to discuss the role of ezetimibe in the treatment of patients with diabetes mellitus and dyslipoproteinemia and to consider its efficacy and safety. The combined use of low- or moderate-intensity therapy with statins and ezetimibe involves two complementary mechanisms: a decrease in the intracellular concentration of cholesterol with increased uptake of LDL cholesterol by hepatocytes and a decrease in cholesterol absorption in the intestines. These mechanisms act synergistically and can provide the same overall effect as when using high-intensity statin therapy. The safety of combined therapy is equivalent to that of monotherapy with HMG-CoA reductase inhibitors in similar doses. This combination is generally better tolerated than high doses of HMG-CoA reductase inhibitors and has advantages in patients at risk of myopathy and statin-induced type 2 diabetes. Thus, despite some caveats, ezetimibe remains the drug of choice in the arsenal of pharmacological agents.

Unmet Need for Further LDL-C Lowering in India despite Statin Therapy: Lipid Association of India Recommendations for the Use of Bempedoic Acid.

Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice.

From statin revolution to gene silencing therapy: 50 years of evolution in the treatment of hypercholesterolemia

The last 50 years have experienced a rapid evolution in the development of lipid-lowering agents to reduce low-density lipoprotein cholesterol levels. This significant advance in medicine has not occurred without debate. Whether lowering blood cholesterol levels was beneficial has remained one of the most controversial issues during the past 50 years. The discovery of statins was the revolution that made it possible to delay and stop the progression of the atherosclerotic process resulting in improved health and longevity for millions of people. To date, statins remain the drugs of choice for the treatment of hypercholesterolemia. Despite their use, the risk of cardiovascular events persists. Therefore, the use of non-statin drugs, such as ezetimibe or PCSK9 inhibitors, in combination with statins has been shown to further reduce the risk of cardiovascular events. This review aims to summarize the advances in the field of lipid-lowering therapies over the past 50 years, focusing on advances in the development of drug therapies up to and including gene silencing or gene editing treatments that are expected in the near future.

Low levels of low-density lipoprotein cholesterol, intracerebral haemorrhage, and other safety issues: is there still a matter of debate?

Although some observational studies suggest a potential association of low levels of low-density lipoprotein cholesterol (LDL-C) with intracerebral haemorrhage (ICH), these analyses have issues of confounding where other factors (e.g. older age, frailty) that likely explain the findings, and the number of events was very low. More recent results from randomized clinical trials have not found an increased risk in ICH, most notably trials using PCSK9 inhibitors that achieve very low levels of LDL-C, but also in the long-term follow-up of the IMPROVE-IT trial. Also, other statin-associated safety issues, including new onset diabetes and the cancer risk should not be the reason of statin discontinuation, especially for the former, the benefits highly outweigh the risk (even 5×), and for the latter, there is no confirmed link suggesting any increased risk, in opposite, data exist suggesting benefits of statin therapy in cancer prevention. Furthermore, use of intensive lipid-lowering strategies with statins and non-statin drugs leads to decrease of ischaemic major adverse cardiac events, without safety concern, in a large population of patients with atherosclerotic cardiovascular disease (ASCVD). These data should promote the concept ‘the earlier, the lower, the longer, the better’ for the lipid management of patients with ASCVD. While few uncertainties remain in several populations that have been underrepresented in clinical trials (African American and Asian patients, low weight individuals), the most recent data with intensive LDL-C lowering with PCSK9 inhibitors are reassuring that the benefit outweighs any possible risk.

The pharmacology of cholesterol-lowering drugs: The pharmacology of cholesterol-lowering drugs

The causal role of low-density lipoprotein cholesterol LDL-C in atherosclerotic-related cardiovascular disease (ASCVD) has been undoubtedly established over the last decades, and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular (CV) events. A large number of observations has definitely proven that the protective effect is independent of the drug used to lower LDL-C, with a continuous linear reduction of CV risk with further LDL-C reductions. Although high-intensity statin therapy may significantly reduce CV event incidence, frequently statins are insufficient to achieve the large reductions recommended by current guidelines for high and very high risk patients. Several non-statin drugs, having mechanisms of action complementary to that of statins, are now available, and include ezetimibe, monoclonal antibodies targeting PCSK9, and, more recently, inclisiran, bempedoic acid, and evinacumab. Combining these drugs based on the recommendations by current and future guidelines should be considered for optimal risk reduction, although several gaps in clinical practice remain to be filled.

Serum Low-Density Lipoprotein Cholesterol and Cardiovascular Disease Risk Across Chronic Kidney Disease Stages (Data from 1.9 Million United States Veterans)

In the general population, elevated low-density lipoprotein (LDL) cholesterol levels are an important risk factor for cardiovascular disease (CVD) and mortality; however, the association of LDL with mortality risk and cardiovascular events are less clear in chronic kidney disease (CKD). We sought to examine the relationship of LDL with mortality and rates of atherosclerotic cardiovascular disease (ASCVD) and non-atherosclerotic cardiovascular-related (non-ASCVD) hospitalizations across CKD stages. Our analytical cohort consisted of 1,972,851 United States veterans with serum LDL data between 2004 and 2006. Associations of LDL with all-cause and cardiovascular mortality across CKD stages were evaluated using Cox proportional hazard models with adjustment for demographics, comorbid conditions, smoking status, prescription of statins and non-statin lipid-lowering drugs, body mass index, albumin, high-density lipoprotein, and triglycerides. Associations between LDL and ASCVD and non-ASCVD hospitalizations were estimated using negative binomial regression models across CKD stages. The cohort consisted of 5% female, 14% Black, 29% diabetic, 33% statin-users, and 44% current smokers, with a mean patient age of 64 ± 14 years. Patients with high LDL (≥160 mg/dL) had a higher risk of all-cause and cardiovascular mortality as well as ASCVD and non-ASCVD hospitalization rates across all CKD stages compared with the reference (LDL 70 to <100 mg/dL). The associations with all-cause and cardiovascular mortality and ASCVD hospitalization rate were attenuated at higher CKD stages. These trends were reversed with amplification of the association of high LDL with non-ASCVD hospitalization at higher CKD stages. In conclusion, associations of LDL with mortality and both ASCVD and non-ASCVD hospitalizations are modified according to kidney disease stage.

Comparison of the Four Major US Guidelines for Lipid Lowering Therapy for the Primary Prevention of ASCVD in Patients with Diabetes

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Four US organizations (AHA/ACC, ADA, NLA, and AACE/ACE) have guidelines on statin and other lipid-lowering medication use for the primary prevention of ASCVD in patients with diabetes mellitus (DM). While all four guidelines recommend moderate to high-intensity statin as first-line therapy, the NLA and AACE/ACE have LDL-C goals based on risk and advocate non-statin LDL cholesterol lowering drugs for patients who need additional LDL-C lowering. <h3>Objective/Purpose</h3> To compare the four major guidelines in a contemporary cohort of patients with DM in a large cardiology practice. <h3>Methods</h3> We identified 8,834 patients (age > 20) with DM and no history of ASCVD who had at least one office visit between December 2019 and November 2020. Patient clinical characteristics, laboratory data, and medications were extracted from their electronic health record (EHR). Patients were considered to have met the AHA/ACC and ADA guidelines if they were aged 40 to 75 and were on a moderate or high-intensity statin. Adherence to the NLA and AACE/ACE guidelines was assessed among the 7,212 patients with DM (81.6%) who had an LDL-C value recorded in the EHR. Patients were stratified into high (LDL-C goal < 100 mg/dL) and very high-risk (LDL-C goal < 70 mg/dL) groups based on additional risk factors. <h3>Results</h3> The mean age of the study patients was 67.8 +/- 12.1 years, 50.4% were female and 70.1% were white. Among the 7,212 patients with an LDL-C in the EHR, 90.2% were stratified as very high-risk by the NLA and 98.8% by the AACE/ACE guidelines. Of the very high-risk patients not at their LDL-C goal, 69.9% were not on a high intensity statin and 92.6% not on any intestinal blocking agent. <h3>Conclusions</h3> In a contemporary cohort of primary prevention patients with DM seen in a cardiology practice almost all are very high risk and almost 60% have not achieved their NLA or AACE/ACE guideline directed LDL-C goal. Although the AHA/ACC and ADA guidelines are less stringent, over 25% have not met these goals. The use of non-statin LDL-C lowering drugs was low. Strategies are needed to improve guideline directed lipid lowering therapy in these high-risk patients.

Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia.