The Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes

doi:10.1016/j.cjca.2017.12.007

Canadian Journal of Cardiology

Volume 34, Issue 5, May 2018, Pages 595-604

https://doi.org/10.1016/j.cjca.2017.12.007 Get rights and content

Abstract

Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the “atherogenic dyslipidemia complex (ADC),” consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia. In this review, we briefly discuss the pathophysiology of the typical dyslipidemia that occurs in insulin-resistant states including obesity, the metabolic syndrome, and type 2 diabetes. Lipid-modifying strategies including lifestyle modification, ezetimibe, statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors in treating ADC are discussed. With the advent of novel therapies involving antisense oligonucleotides and monoclonal antibodies, new targets can be specifically downregulated to potentially promote lipoprotein clearance or suppress production. We review novel approaches currently undergoing clinical testing and we speculate on their suitability for use in treating ADC for the prevention of atherosclerotic cardiovascular disease. In addition, future targets that might be considered for therapeutic development are discussed.

Résumé

Malgré l’efficacité des stratégies de réduction du taux de lipoprotéines de faible densité (LDL) dans le traitement de la dyslipidémie du diabétique, un important risque résiduel de maladie cardiovasculaire athéroscléreuse demeure. Ce risque résiduel pourrait être en partie expliqué par des anomalies lipidiques autres que la hausse du cholestérol LDL, collectivement appelées dyslipidémies athérogènes et comprenant l’hypertriglycéridémie, le taux élevé de petites particules LDL denses, la diminution du cholestérol à lipoprotéines de haute densité et de particules de lipoprotéines de haute densité, l’augmentation de lipoprotéines reliquats et l’hyperlipidémie postprandiale. Dans cette analyse, nous abordons brièvement la physiopathologie de la dyslipidémie type qui survient en cas d’insulinorésistance, observée en présence d’obésité, de syndrome métabolique et de diabète de type 2. Nous abordons les stratégies visant à corriger la lipidémie, comme la modification du mode de vie, l’ézétimibe, les statines, les fibrates, la niacine et les inhibiteurs de la protéine de transfert de l’ester de cholestéryle, pour traiter les dyslipidémies athérogènes. Avec la venue de nouveaux traitements comportant des oligonucléotides antisens et des anticorps monoclonaux, les nouvelles cibles peuvent être particulièrement abaissées pour potentiellement favoriser la clairance des lipoprotéines ou en supprimer la production. Nous étudions des méthodes novatrices impliquant des épreuves cliniques existantes et nous spéculons sur la possibilité de leur utilisation dans le traitement des dyslipidémies athérogènes pour prévenir la maladie cardiovasculaire athéroscléreuse. De plus, nous abordons de futures cibles qui pourraient être considérées dans la mise au point de traitements.

Section snippets

Pathophysiology of ADC

An in depth description of lipoprotein metabolism is beyond the scope of this review and has been reviewed elsewhere.⁴ We focus in this report on a few aspects of lipoprotein metabolism that have direct bearing on the development of ADC. Briefly, in the healthy state, dietary lipids are actively transported or diffuse into intestinal enterocytes where they are packaged into large, buoyant, triglyceride-rich lipoproteins (TRLs) called chylomicrons (CMs; Fig. 1,⁵ pathways A and B). CMs contain a

Lifestyle Measures and Lipid-Modifying Therapies for the Treatment of ADC

A retrospective study of diabetes and ASCVD risk of Ontario adults confirmed the well-established trend of increasing rates of acute myocardial infarction with age in diabetic as well as healthy populations.¹³ However, people with diabetes were classified as “high-risk of cardiovascular disease” 15 years earlier than those without, with women becoming high-risk at 54.3 years of age and men at 47.9 years. In contrast, those with diabetes and younger than 40 years of age are not at significantly

Lipid-Lowering Therapies That Primarily Target TGs and HDL and Their Effectiveness in Treatment of ADC

Fibrates (eg, gemfibrozil, fenofibrate, and bezafibrate) activate peroxisome proliferator-activated receptor alpha (PPAR-α) and modulate lipid profile through numerous metabolic effects. On the basis of their marked TG-lowering and mild HDL-raising properties, fibrates would appear to be ideally suited for the treatment of ADC, and yet clinical trials of fibrate therapy have revealed mixed and generally disappointing results.2, 27 One notable issue with most fibrate clinical trials is that

Novel Therapies for ADC and ASCVD Outcomes

In recent years, the development of antisense oligonucleotides (ASO) and targeted monoclonal antibody biologics have provided novel approaches for inhibiting new targets for treatment of dyslipidemia and reduction in ASCVD (Table 1). Decisions for development of specific ASO and monoclonal antibody-based therapies are often on the basis of identification of naturally occurring human genetic variants that are associated with decreased protein function, favourable lipid profiles, and lifetime

Conclusions

Lipid-modifying strategies are currently available for prevention of ASCVD in individuals with the typical dyslipidemia of insulin resistant states including obesity, metabolic syndrome, and T2D. Lifestyle modification is the cornerstone of therapy for these metabolic disorders but in most instances lifestyle changes alone are insufficient to correct the dyslipidemia in this population, nor have lifestyle measures been proven to reduce ASCVD event rates. Although ADC is not primarily

Funding Sources

This work was supported by an operating grant from the Canadian Institutes of Health Research. G.F. Lewis holds the Drucker Family Chair in Diabetes Research and the Sun Life Financial Chair in Diabetes. P. Stahel is the recipient of a Banting and Best Diabetes Centre Postdoctoral Fellowship and Diabetes Action Canada Postdoctoral Fellowship.

Disclosures

The authors have no conflicts of interest to disclose.

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In cardiovascular disease prevention, low-density lipoprotein cholesterol (LDL-C) values guide treatment for lowering cholesterol level. After 50 years of clinical laboratories using the Friedewald LDL-C equation, the Canadian Society of Clinical Chemists recently recommended adoption of the new and more accurate Sampson / U.S. National Institutes of Health (NIH) LDL-C equation. Here, we estimate the anticipated population-level impact of this equation change.
We compared lipid profiles from the Canadian Health Measures Survey (CHMS) year 2019 to those from the National Health and Nutrition Examination Survey (NHANES) years 2017 to 2020. Then, based on 10,828 participants in the latter, we calculated the impact of changing the LDL-C equation from the Friedewald to the Sampson.
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Although changing the LDL-C equation used from the Friedewald to the Sampson affects only a small proportion of the population, an estimated 123,000 Canadians who are taking cholesterol-lowering medications may need to intensify treatment to lower their cholesterol level, due to small absolute changes around guideline threshold values of LDL-C.
Dans la prévention des maladies cardiovasculaires, les valeurs de cholestérol à lipoprotéines de faible densité (cholestérol LDL) guident le traitement hypocholestérolémiant. Depuis 50 ans, la formule de Friedewald est utilisée par les biochimistes pour calculer le cholestérol LDL. Or, la Société canadienne des clinico-chimistes vient de recommander l’adoption d’une nouvelle équation plus précise pour évaluer le cholestérol LDL : l’équation Sampson (National Institutes of Health des États-Unis). Nous analysons ici les conséquences que pourrait avoir cette nouvelle méthode de calcul à l’échelle de la population.
Nous avons comparé les bilans lipidiques issus de l’Enquête canadienne sur les mesures de la santé (ECMS) de 2019 à ceux de la National Health and Nutrition Examination Survey (NHANES) de 2017 à 2020. En nous appuyant sur les données de 10 828 participants à cette dernière enquête, nous avons évalué l’effet qu’aurait l’utilisation de la méthode de Sampson sur la décision thérapeutique.
Les valeurs de cholestérol LDL obtenues avec les équations de Sampson et de Friedewald sont fortement corrélées (r = 0,99, P < 0,001), mais l’écart se creuse lorsque le taux de triglycérides est plus élevé ou que le taux de cholestérol LDL est plus faible. Nous avons évalué l’effet de cette divergence en appliquant les valeurs seuils de traitement du cholestérol LDL établies par les lignes directrices de 2021 sur la dyslipidémie de la Société cardiovasculaire du Canada. Parmi les patients prenant des médicaments pour abaisser leur taux de cholestérol, l'équation de Sampson reclasse 3,3 % plus de patients (intervalle de confiance à 95 % : 2,2 % à 4,9 %), soit environ 123 000 personnes, comme répondant au critère d’intensification du traitement.
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Effective, disease-modifying, clinical approaches to patients with mild-to-moderate hypertriglyceridaemia
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Citation Excerpt :
This belief has resulted in therapeutic inertia on the part of practicing clinicians, unless triglycerides are markedly elevated in the range known to increase risk for pancreatitis, generally considered to occur at fasting triglyceride concentrations of more than 10 mmol/L. Notwithstanding the current unresolved debate regarding putative atherogenicity of triglycerides and triglyceride-rich lipoprotein particles, and the absence of convincing evidence from randomised controlled trials supporting the effectiveness of targeting of hypertriglyceridaemia per se,7,8 we argue that individual components of the well described complex web of highly atherogenic atherosclerotic cardiovascular disease and diabetogenic risk factors that accompany the atherogenic dyslipidaemia complex,9,10 of which hypertriglyceridaemia is a central component, should be targeted to prevent diabetes and accelerated atherosclerosis. Although the correlation between hypertriglyceridaemia and insulin resistance, inflammation, hypertension, and a procoagulant state is neither absolutely linear nor necessarily consistent between individuals, the recurring patterns of convergence of these factors across clinical cohorts is unmistakable.
Plasma triglyceride concentration is easily, inexpensively, and accurately measured, and when elevated is a highly informative disease marker that identifies individuals who frequently have a host of underlying metabolic, inflammatory, and atherogenic risk factors. Although this concept aligns with much that has been discussed regarding the metabolic syndrome, individuals identified with mild-to-moderate hypertriglyceridaemia on a screening lipid profile are not necessarily recognised as having features of the metabolic syndrome and frequently do not receive definitive, meaningful, disease-modifying therapy. This treatment would include (1) lifestyle modification; (2) LDL-lowering therapies to aggressively treat elevated apolipoprotein B-containing particles; (3) antihypertensive therapies that have optimal therapeutic profiles for those individuals with metabolic syndrome; (4) icosapent ethyl for those individuals at high risk, particularly patients with established atherosclerotic cardiovascular disease who have residual hypertriglyceridaemia despite treatment with appropriate LDL-lowering therapies; (5) preferential use of cardiovascular protective diabetes therapies, in individuals with diabetes; and (6) antithrombotic therapies for secondary prevention of atherosclerotic cardiovascular disease in the context of high vascular disease risk and diabetes. Several emerging therapies, such as novel weight reducing, anti-inflammatory, lipid-modifying therapies, and therapies targeting the progression of non-alcoholic fatty liver disease, could also soon enter the clinical arena for patients with mild-to-moderate hypertriglyceridaemia and associated metabolic syndrome.
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Furthermore, studies suggested that hepatic de novo lipogenesis pathway may be up-regulated in obesity, and FA from the intra-hepatic FA pool may be directed towards VLDL-TG production and through a storage pathways rather than entering oxidative pathways [18]. Severe obesity is commonly associated with insulin resistance, which by itself is a CV risk marker associated with hypertriglyceridemia and disturbances in the lipid-lipoprotein profile [25]. Insulin is a key hormone in the regulation of lipid-lipoprotein metabolism.
Most patients with severe obesity will present some lipid-lipoprotein abnormalities. The atherogenic dyslipidemia associated with severe obesity is characterized by elevated fasting and postprandial triglyceride levels, low high-density lipoprotein cholesterol concentrations, and increased proportion of small and dense low-density lipoproteins. Bariatric surgery has been proven safe and successful in terms of long-term weight loss and improvement in obesity co-existing metabolic conditions including lipid-lipoprotein abnormalities. Nevertheless, bariatric surgery procedures are not all equivalent. We conducted a comprehensive critical analysis of the literature related to severe obesity, bariatric surgery and lipid-lipoprotein metabolism/profile. In this review, we described the metabolic impacts of different bariatric surgery procedures on the lipid-lipoprotein profile, and the mechanisms linking bariatric surgery and dyslipidemia remission based on recent epidemiological, clinical and preclinical studies. Further mechanistic studies are essential to assess the potential of bariatric/metabolic surgery in the management of lipid-lipoprotein abnormalities associated with severe obesity. Understanding the beneficial effects of various bariatric surgery procedures on the lipid-lipoprotein metabolism and profile may result in a wider acceptance of this strategy as a long-term metabolic treatment of lipid-lipoprotein abnormalities in severe obesity and help clinician to develop an individualized and optimal approach in the management of dyslipidemia associated with severe obesity.
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ReviewThe Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes

Abstract

Résumé

Section snippets

Pathophysiology of ADC

Lifestyle Measures and Lipid-Modifying Therapies for the Treatment of ADC

Lipid-Lowering Therapies That Primarily Target TGs and HDL and Their Effectiveness in Treatment of ADC

Novel Therapies for ADC and ASCVD Outcomes

Conclusions

Funding Sources

Disclosures

Lancet

Can J Cardiol

Public Health

J Nutr

Atherosclerosis

Lancet Diabetes Endocrinol

Lancet

Am J Cardiol

J Am Coll Cardiol

Lancet

J Clin Lipidol

J Clin Lipidol

J Clin Lipidol

J Allergy Clin Immunol

J Am Coll Cardiol

J Biol Chem

J Clin Lipidol

J Lipid Res

J Lipid Res

Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol

Diabetes

Management of dyslipidemia in people with type 2 diabetes mellitus

Rev Endocr Metab Disord

Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes

N Engl J Med

Pathophysiology of diabetic dyslipidaemia: where are we?

Diabetologia

Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial

PeerJ

The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking

Open Biol

Dyslipidemia of obesity and diabetes

New insights into the regulation of chylomicron production

Annu Rev Nutr

All low-density lipoprotein particles are not created equal

Arterioscler Thromb Vasc Biol

New insights into the regulation of HDL metabolism and reverse cholesterol transport

Circ Res

Lipids and lipoproteins in patients with type 2 diabetes

Diabetes Care

Lipoprotein heterogeneity and apolipoprotein B metabolism

Arterioscler Thromb Vasc Biol

A very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: a randomized trial

Diabetes Care

Effect of a multifactorial intervention on mortality in type 2 diabetes

N Engl J Med

The Diabetes Prevention Program (DPP)

Diabetes Care

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

N Engl J Med

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial

Lancet

Ezetimibe added to statin therapy after acute coronary syndromes

N Engl J Med

The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in incidence of coronary heart disease

JAMA

Evolocumab and clinical outcomes in patients with cardiovascular disease

N Engl J Med

Combination lipid therapy in type 2 diabetes

N Engl J Med

Review
The Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes