Giovambattista DesideriUO Geriatria e Lungodegenza

Ospedale di AvezzanoUniversità degli Studi di L’Aquila

Nuove idee e moderne strategie per innovare la

prevenzione primaria cardiovascolare

DISCLOSURE INFORMATIONGiovambattista Desideri

negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in

campo sanitario:Consuente Servier, Menarini, Bayer, AlfaSigma, GrunenthalRelatore a meeting supportati da Servier, Menarini, Bayer,

AlfaSigma, Grunenthal

Nuove idee e moderne strategie per innovare la prevenzione primaria cardiovascolare

Iperuricemia

Aderenza

Ipertrigliceridemia

20% IperproducersXO overactivity (genetic, induced) or 

”overfeeding” (food, fructose, purines)

80% Underexcretors(physiologically, low GFR, 

Diuretics)

Uric Acid excretion/production balance

Frederick Akbar Mohamed (1879)

Nuove idee e moderne strategie per innovare la prevenzione primaria cardiovascolare

Iperuricemia

Aderenza

Ipertrigliceridemia

Ho PM et al. Arch Intern Med 2006; 166: 1842-7.

Impact of Medication Therapy Discontinuationon Mortality After Myocardial Infarction

Poor compliance: The hidden risk

factor

Poor compliance: The hidden risk

factor

Nuove idee e moderne strategie per innovare la prevenzione primaria cardiovascolare

Iperuricemia

Aderenza

Ipertrigliceridemia

More than 25 years ago, mild–moderately high concentrations of triglycerides were regarded as a cardiovascular risk factor, similar to high total and LDL cholesterol.

Both types of lipid fractions were treated by lipid specialists with the aim of preventing cardiovascular disease, and greatly increased concentrations of triglycerides were treated to prevent acute pancreatitis.

Once upon a time….

Once upon a time….

Circulation. 1979 Sep;60(3):473-85.

The scientific breakthroughs….

1

1 Goldstein JK, et al New York: McGraw-Hill, 2001; 2863–913.2 Steinberg D et al. Circulation 1997; 95: 1062–713 Endo A. J Lipid Res 1992; 33: 1569–82.

First, the identification of LDL receptor mutations as the cause of familial hypercholesterolemia by Brown and Goldstein1

Second, the LDL oxidation hypothesis promoted by Steinberg and colleagues that focused attention on LDL2

Third, the discovery of mevastatin as an inhibitor of HMG‐CoA reductase, that provided a very effective means of reducing LDL‐cholesterol concentrations3

Triglycerides and cardiovascular risk. The end of the story, the begin of the end or…?

The Lancet, Vol 344, November 19, 1994

the relative risk was 0.70 (95% CI 0.58-0.85, p=0.0003) with simvastatin.

HDL metabolism and reverse cholesterol transport

Elevated HDL cholesterol is associated with adverse cardiovascular outcomes

Allard –Ratick M et al. ESC congress 2018

5,965 individuals (mean age 63.3±12.4 years, 35% female, 23% African American)

Association of HDL-C and CV death/MI

Lincoff AM et al. N Engl J Med 2017;376:1933-42.

Causal risk factors? Bystanders?

Triglycerides and cardiovascular risk. The end of the story, the begin of the end or… the end of the begin?

Evidence from epidemiology

Biological plausibility

Genetics suggest causality

And….

Observational associations between raised concentrations of triglycerides, and cardiovascular disease and all‐cause mortality, in the Copenhagen City 

Heart Study and Copenhagen General Population Study combined

Nordestgaard BG et al .Lancet 2014; 384: 626–635

1.06 1.72

2.21 1.50

1.18 1.23 1.19

0.98 1.00

1.61 2.30

Age (in years)

Gender (male)

Previous ASCVDs

Antidiabetic drugs

Statins

Antihypertensive drugs

Anticoagulant drugs

Baseline HDL chol. (mg/dl)

Baseline Total chol. (mg/dl)

High TG

Very high TG

1.00 2.00 3.00 4.00 5.00

1.09

1.14

1.53

1.24

0.71

1.08

1.71

0.97

0.99

1.49

3.08

Age (in years)

Gender (male)

Previous ASCVDs

Antidiabetic drugs

Statins

Antihypertensive drugs

Anticoagulant drugs

Baseline HDL chol. (mg/dl)

Baseline Total chol. (mg/dl)

0.00 2.00 4.00 6.00

High TG

Very high TG

ASCVD Overall Death

Hypertrigliceridemia and  risk of major atherosclerotic cardiovasculare disease (ASCVD) and all‐cause mortality in clinical practice

Degli Esposti L et al. (submitted)

Proportional eff ects on major vascular events per mmol/L reduction in LDL cholesterol by baseline lipid profile in 

participants with diabetes

CTT collaborators Lancet 2008; 371: 117–25

Kaplan‐Meier estimate of the risk of death, MI or recurrent ACS in post‐MI patients receiving statins with normal or elevated 

TG levels in the PROVE‐IT study.

Miller M et al. J Am Coll Cardiol 2008;51(7):724e30.

Short‐term cumulative incidence of events according to tertile of triglycerides at initial random assignment in the atorvastatin 

group of the MIRACL trial.

Schwartz, G.G. et al. J Am Coll Cardiol. 2015; 65(21):2267–75.

Triglycerides and cardiovascular risk. The end of the story, the begin of the end or… the end of the begin?

Evidence from epidemiology

Biological plausibility

Genetics suggest causality

And….

Triglyceride‐Rich Lipoproteins Isolated by Selected‐Affinity Anti‐Apo B Immunosorption From Human Atherosclerotic Plaque

Rapp JH et al. Arterioscler Thromb.1994;14:1767-1774.

VLDL + IDL LDL

Plaq

ue

Seru

m

Suggested role of raised plasma triglycerides and remnant cholesterolin intimal low-grade inflammation and development of atherosclerosis

Nordestgaard BG et al .Lancet 2014; 384: 626–635

Triglycerides and cardiovascular risk. The end of the story, the begin of the end or… the end of the begin?

Evidence from epidemiology

Biological plausibility

Genetics suggest causality

And….

Apolipoprotein C3 regulates triglyceride-rich lipoprotein concentrations and can promote inflammation

Libby P. European Heart Journal (2015) 36, 774–776

Observational and causal (by use of genetics) associations of raised remnant cholesterol and triglycerides with risk of IHD and MI

Nordestgaard BG et al .Lancet 2014; 384: 626–635

Genetic Variants Affecting the Lipoprotein Lipase Pathway and the Risk of Coronary Artery Disease.

Stitziel N et al. N Engl J Med 2016;374:1134-44.

Inactivating Variants in ANGPTL4and Risk of Coronary Artery Disease

Dewey FE et al. n engl j med 374;12 nejm.org March 24, 2016

Association between variants in genes encoding possible triglyceride‐lowering drug targets, and extent of triglyceride reduction with corresponding reduced 

risk of ischaemic vascular disease

Nordestgaard BG et al .Lancet 2014; 384: 626–635

Triglycerides and cardiovascular risk. The end of the story, the begin of the end or… the end of the begin?

Evidence from epidemiology

Biological plausibility

Genetics suggest causality

And… so what to do with TG’s?

Major lipid modifying agents

Class Effect on LDL-C

Effect on HDL-C

Effect onTG Side effects

Statins 18–55% 5–15% 7–30%

Transient liver enzymes in some patients

Rare but potentially serious myopathy and rhabdomyolysis

Drug interactions with treatments metabolised by cytochrome P450

systemPotential add-on lipid-management therapies to address residual risk

Fibrates Variable 5–20% 25–50%Gastrointestinal complaints most

common Myopathy, increased serum creatinine

and cholelithiasis may occur

Niacin 20% up to 30% up to 35%

Flushing commonMay induce hyperglycaemia,

hyperuricaemia or liver toxicity

EPA/DHA ethyl esters

or no change

or no change 45%

No major safety concernsEructations, dyspepsia and disrupted ability to taste (dysgeusia) are most

common

Chapmam MJ et al.Heart Journal (2011) 32, 1345–1361

Fibrates, n-3 PUFA-EPA, Niacin – CV Outcome TrialsLarger Risk Reductions in Hypertriglyceridemia

Trial (drug) Entire cohortHR (95% CI)

Subgroup SubgroupHR (95% CI)

AIM-HIGH(niacin)

1.02 (0.87, 1.21) TG >198 mg/dLHDL-C <33 mg/dL

0.74 (0.50, 1.09)

HHS(gemfibrozil)

0.66 (0.47, 0.92) TG ≥184 mg/dLBMI >27.5 kg/m2

0.30 (0.15, 0.58)

BIP(bezafibrate)

0.91 (NS) TG ≥200 mg/dL 0.60 (NR)

VA-HIT(gemfibrozil)

0.78 (0.65, 0.93) TG ≥151 mg/dL 0.73 (0.58, 0.93)

FIELD (DM)(fenofibrate)

0.89 (0.75, 1.05) TG ≥204 mg/dLHDL-C <42 mg/dL

0.73 (0.58, 0.91)

ACCORD(fenofibrate±Statin)

0.92 (0.79, 1.08) TG ≥204 mg/dLHDL-C ≤34 mg/dL

0.69 (NR)

Maki et al. J Clin Lipidol. 2012;6:413.  Guyton et al. JACC 2013;62:1580. 

TG ≥204 mg/dl HDL-C ≤ 34 mg/dL TG <204 mg/dl HDL-C > 34 mg/dL

Maki et al. J Clin Lipidol. 2012;6:413

Treatment options for the management of hypertriglyceridemia: strategies based on the best‐available evidence.

Eff ects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open label,  

blinded endpoint analysis

Yokoyama M et al. Lancet 2007; 369: 1090–98

total study population primary prevention arm secondary prevention arm

Sayto Y et al. J Atheroscler Thromb 2012;19:194-204

Effects of EPA on the incidence of MCE for the high TG/low HDL-C group.

Sayto Y et al. Atherosclerosis 200 (2008) 135–140

Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors

Patients who did not achieve the goals for LDL-C and non-HDL-C: the JELIS study

REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Bhatt DL et al. Clinical Cardiology. 2017;40:138–148.

PUFA n-3

-25%

The proportions of patients experiencing adverse events and serious adverse events in REDUCE-IT were similar between the active and placebo treatment groups. Median follow-up time in REDUCE-IT was 4.9 years.

Bhatt DL et al. published on November 10, 2018, at NEJM.org.

Kaplan–Meier event curves for the primary efficacy composite end point of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary efficacy composite end point (CV

death, nonfatal MI, or nonfatal Stroke): REDUCE-IT study

Effects of n−3 Fa y Acid Supplementsin Diabetes Mellitus – ASCEND study

ASCEND New Eng J Med 2018

Triglyceride levels were not measured as, in earlier studies, these had not been found to be sufficiently stable in mailed blood samples, although later data refuted this.

What about triglycerides?

A Long‐Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs 

With Hypertriglyceridemia (STRENGTH)

The study is a randomized, double-blind, placebo-controlled(corn oil), parallel group design that will enroll approximately13,000 patients with hypertriglyceridemia and low HDL and high risk for CVD to be randomized 1:1 to either corn oil + statin or PUFA n-3 + statin, once daily, for approximately 3-5 years as determinedwhen the number of MACE outcomes is reached.Completation date 2019-10-31

Journal Author Drug Target OutcomeN Engl JMed, 2015

Gaudet D et al

Antisense Oligonucleotidevs.mRNA(ISIS 304801)ISIS Pharma

APOC3 TG Levels (H)

N Engl JMed,2017

Dewey FE et al

Human MonoclonalAntibody-EvinacumabRegeneron Pharma

ANGPTL3 TG levels (H,A)ATS disease (A)

N Engl JMed, 2017

Graham MJ et al

Antisense Oligonucleotidevs. mRNAIonis Pharma

ANGPTL3 TG Levels (H,A)ATS disease (A)LDL-C (A)Hepatic TG (A)INS-SENS (A)

H=Humans data, R=Animal data (rats)

Therapeutic approches targeting LPL system

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Dewey FE et al. N Engl J Med 2017;377:211-21.

Effects of Inhibition of ANGPTL3 with a Monoclonal Antibody on Triglyceride Levels in Human Volunteers

Dewey FE et al. N Engl J Med 2017;377:211-21.

Triglyceride and TG Rich Lipoproteins

HDL LDL

Apo AI Apo B

CholesterolTriglyceride

Non-HDL cholesterol

Total cholesterol

IDL VLDL

Apo B Apo B Apo B48

All atherogenic lipoproteins

TRL-C = Non-HDL-C – LDL-C

Triglyceride Rich Lipoproteins (TRL)

Chylomicron remnant

My point of view…

High plasma levels of triglycerides are associated with an increased risk of CVD and may contribute to “residual” CV risk

The evidence of triglycerides as a CV risk factors is supported by epidemiological, genetic studies of Mendelian randomization, and intervention studies and could be related to different mechanisms.

The reduction of triglycerides is associated with lesser CV events REDUCE‐IT