Updates from the World of Cardiology:

Cardiometabolic Risk

Mechanistic approaches to management

Eveline Oestreicher Stock, MDAssistant ProfessorCardiovascular Prevention Center University of California, San Francisco

Paving the Road Ahead: New Clinical Guidelines

“Knowing is not enough, we must apply.Willing is not enough, we must do.”

Goethe

How would you design trustworthy guidelines?

• To advise clinicians?• To advise healthcare systems?• Insurers?

• “One size fits all?” • Concise• Clear• Evidence based• Flexible• Universal• Best advice for the greatest number of patients and advice to individuals

ACC/AHA enlisted 10 other stakeholder organizations, including NLA

Ensure best practices, consensus, and distribution of the recommendations

Merits and shortcomings to be discussed at a later meeting

Takeaway

• The American College of Cardiology (ACC) synthesized the guidelines into 10 key take-home messages

• ACC also has created a hub of related resources for clinicians and patients: https://www.acc.org/guidelines/hubs/blood-cholesterol

Why this matters?

• The latest cholesterol guidelines call for combining atherosclerotic cardiovascular disease (ASCVD) risk score with “risk enhancer” factors to personalize decision-making

• The new recommendations introduce some necessary complexity

Key messages• Outlines critical role of lifestyle intervention (message #1)

• Reminds clinicians on importance of clinician-patient risk discussion (message #6)

• Reinforces assessment of response and adherence to therapy (message #10)

• Other messages - specific, content-driven recommendations with review of supporting evidence

Key messages• Take-homes 2-5 (risk assessment not needed)• Identifies 4 main categories of risk:

• Clinical ASCVD• LDL-C ≥ 190 mg/dl• DM• Primary prevention with moderate ASCVD risk

• Acknowledges there is a range of ASCVD among patient in those categories

• Suggests evidence-based criteria for enhancing stratification: • ApoB, Lp(a) and coronary artery calcium scoring (CAC) – “hidden pearls”• Hope Guidelines will lead to greater utilization of these important risk

markers

Key messages

• Reinforce importance of treatment thresholds• Give clinicians (patients and payers) clear recommendations for when

there is strong enough evidence to intensify pharmacotherapy

• Many clinical questions remain• We need to continue to support rigorous clinical scientific

investigation Remind us of critical importance of healthy lifestyle• Emphasis on communication with our patients• Need for long term support for long term therapy

Mechanisms of Atherosclerosis: Mechanistic Targets

• Atherogenic lipoproteins : ApoB, Lp(a), TG rich lipoproteins (VLDL)

• Inflammation

• Reverse cholesterol transport (Efflux – HDL function)

Lipid Targets - ASCVD

Lipid Targets – LDL-C HypothesisM

ajor

vas

cula

r eve

nts a

void

ed p

er 1

000

5-year risk of major vascular event

Vasc

ular

dea

ths a

void

ed p

er 1

000

5-year risk of major vascular event

LDL cholesterol reduction (mmol/L) with statin treatment

LDL cholesterol reduction (mmol/L) with statin treatment

Lancet. 2012 Aug 11; 380(9841): 581–590.

Lipid targets : LDL-C lowering

• > 30 years of large scale clinical trials to confirm the role of LDL-cholesterol (LDL-C) reduction

• Lovastatin - commercially available in 1987• Landmark 1994 Scandinavian Simvastatin Survival Study (4S) - LDL-C

lowering reduces major ASCVD events• Statin drugs to date : “single most important advance in the

therapeutic armamentarium against CVD” • Despite statins aprox 60-70% of ASCVD events occur in statin treated

patients – “Residual CV risk”

Lipid Targets

Pharmacy 2018, 6(1), 10.

Lipid Targets – Ezetimibe

Lipid Targets – Ezetimibe

Rate reduction 17% (95% CI 6-26%)Log-rank p=0.0021

Major atherosclerotic events:• Non-fatal MI• Coronary death• Non-hemorrhagic stroke• Arterial revascularization

13.4% vs 11.3%

Lancet. 2011 Jun 25;377(9784):2181-92. doi: 10.1016/S0140-6736(11)60739-3. Epub 2011 Jun 12.

Conclusions• No reduction in mortality• Beneficial in reducing major atherosclerotic events• Safe in patients with renal impairment• NNT = 48 over median 4.9 years

Lipid Targets – Ezetimibe

Lipid Targets – Ezetimibe

Conclusions• No reduction in mortality• Further reduction in LDL (12.8 mg/dL) reduced the proportion of

major vascular events by 7.2%• NNT = 55 over median 6 years

Lipid Targets – Ezetimibe

Lipid Targets – PCSK9 inhibitor

N=27,564on statins

Evolocumab*13,784

Placebo13,780

Lipid Targets – PCSK9 inhibitor

*140 mg q2 weeks OR 420 mg every month per patient preference

• 62.5 years old• 81% previous MI• 19% nonhemorrhagic stroke• 13% peripheral artery disease• 80% hypertension• 36% Diabetes• 28% current smoker• LDL range 80-109 mg/dL, median 92 mg/dL

N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Conclusions• No reduction in mortality• Effective in preventing future myocardial infarction• 2 injections per month or 1 subcutaneous infusion per month• NNT = 63 over median 26 months

Lipid Targets – PCSK9 inhibitor

Lipid Targets – PCSK9 inhibitor

>40 years oldHospitalized

with ACS* 1-12 months prior

LDL >70 mg/dLon atorva or

rosuva

Lipid Targets – PCSK9 inhibitor

ACS*: acute coronary syndrome (myocardial infarction or unstable angina)

Alirocumab subcut injection q2 weeks

N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7.

• 58 years old• 82% previous MI• 64% hypertension

• 29% diabetes• 24% current smoker

Lipid Targets – PCSK9 inhibitor

Conclusions• No reduction in mortality• Effective in preventing future myocardial infarction, hospitalizations

due to unstable angina, and revascularization• Results similar to FOURIER trial• NNT = 64 over median 2.8 years

Lipid Targets – Ongoing ResearchPt characteristics UCSF (N=54) FOURIER ODYSSEY

Male 63% 75% 75%Caucasian 77% 85% 79%

Diabetes 22% 37% 29%HTN 51% 80% 66%Current tobacco smoker 2% 28% 24%Prior MI* 26% 81% 82%

*Not all patients at UCSF had an event prior to starting PCSK9 inhibitors, but most of FOURIER & ODYSSEY patients had an event prior to being enrolled

Lipid Targets – Ongoing Research

Figure 1. Percent change in LDL-C from baseline

Lipid Targets

Table 2. Scenario analysis of MACE prevented and corresponding costs

Variable

Evolocumab in FOURIER

Simulation of ezetimibe in

FOURIER

Simulation of evolocumab in

IMPROVE-IT

Ezetimibe in IMPROVE-IT

NNT – 1 year (95% CI) 104 110 95 124

Cost of annual therapy per patient $6,540 $88 $6,540 $88

Cost to prevent one major adverse cardiovascular event (95% CI) $678,981 $9,627 $620,218 $10,870

Lipid Targets

Am J Cardiol. 2019 Jan 23. pii: S0002-9149(19)30113-4. doi: 10.1016/j.amjcard.2019.01.021.

Future Directions – EPA

• Secondary prevention trial (70%) N = 4089 vs 4090

Results• Significant difference in cardiovascular death (p=0.03)• NNT = 21 over median 4.9 years• Potential / viable treatment option

Future Directions – EPA

Future Directions – Bempedoic acid

https://www.esperion.com/development/. Accessed March 8, 2019.

• Cholesterol biosynthesis inhibitor

• Inhibits adenosine triphosphate citrate lyase (ACL)—2 steps upstream from HMG-CoARBempedoic acid is converted to its active moiety by ACSVL1 (not present in skeletal muscle)

•• BPA and BPA+ezetimibe are in

phase III clinical trials, hoping to apply for NDA in 2019

Contribution of Atherogenic Lipoproteins: LDL-C lowering• Studies with ezetimibe and PCSK-9 inhibitors have confirmed - lower

LDL-C is associated with reduced ASCVD events, regardless of the agent used and proportional to the degree of LDL-C lowering

• Even with aggressive LDL-C reduction, vascular events continue to occur at an alarming rate, suggesting that there are additional important factors at play

• Reiteration of the value of comprehensive risk reduction in the care of our patients

Role of Inflammation in the Development of Atherosclerotic Plaque

Different stages of the inflammatory process involve specific mediators/ (orange boxes) –drugs targets (white boxes)

Graphic created by Dr. Thomas Dayspring (modified )

Residual risk of MACE remains following cholesterol reduction

05

10152025303540

Statin High-dosestatin

Ezetimibe PCSK9inhibitor

Control InterventionM

ACE

(%)

SSSS PROVE-IT IMPROVE-IT FOURIER

On-treatment inflammation is a determinants of residual risk

PROVE-IT IMPROVE-IT

Relationship of plasma levels of IL-6 to future risks of cardiovascular disease in 25 prospective epidemiologic cohorts

For each SD increase in log IL-6, there is a 25% increase in risk of future vascular events (95%CI 1.19-1.32).

Adapted from Eur Heart J 2014;35:578-89

Recent advances in the clinical anti-inflammatory approach to ASCVD care

• Can we affect ASCVD risk by targeting inflammation?

• How important are inflammatory markers and the recognition of inflammatory disease in risk stratification?

• What aspects of inflammation are better targets than others?

Canakinumab effect on inflammation and lipid levels

-70-60-50-40-30-20-10

010

Placebo 50 mg 150 mg 300 mg

Med

ian

chan

ge fro

m b

asel

ine

(%)

Canakinumab Dose (mg/ 3 months)

TriglyceridesLDL-C

IL-6

hs-CRP

After 12 months of therapy

Canakinumab effect on MACE in CANTOS

4.50

4.11

3.86 3.90

3.40

3.60

3.80

4.00

4.20

4.40

4.60

Placebo 50 mg 100 mg 300 mgRat

e pe

r 10

0 Pe

rson

-Yea

rs

Dose of Canakinumab

MACE (median follow-up of 3.7 years)

HR=0.85 P=0.021

P-value for trend=0.02

Canakinumab effect on cancer mortality in CANTOS

0.640.55

0.50

0.31

0.000.100.200.300.400.500.600.70

Placebo 50 mg 100 mg 300 mg

Rat

e pe

r 10

0 Pe

rson

-Yea

rs

Dose of Canakinumab

Cancer (median follow-up of 3.7 years)

P-value for trend<0.001

CANTOS summary

• Canakinumab reduced MACE in established ASCVD with residual high CRP

• Canakinumab increased fatal infections• Canakinumab showed hypothesis-generating evidence of a cancer benefit

• CANTOS provided proof-of-concept for the inflammation hypothesis

Low-dose methotrexate is an anti-inflammatory for arthritis

• Mechanism of action• Poorly understood but may involve increased adenosine

release• Prior FDA approval

• Arthritis• Adult Rheumatoid Arthritis• Juvenile Rheumatoid Arthritis• Psoriasis

Cardiovascular Inflammation Reduction Trial (CIRT)

Low-dose methotrexate administered orally every week

Stable CAD (post MI)with Type 2 Diabetes or

Metabolic Syndrome

15-20 mg

Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)

Placebo

N = 4,786417 Centers2013 - 2018

CIRT study population baseline characteristics

CIRT CANTOSAge (years) 66 61Female sex 19% 26%Diabetes 34% 40%Current smoking 11% 23%Statin use 86% 91%LDL-C (mg/dL) 68 82hs-CRP (mg/L) 1.5 4.2

Low-dose methotrexate effect on MACE in CIRT

3.43 3.46

0.000.501.001.502.002.503.003.504.00

Placebo Low-DoseMethotrexate

Rat

e pe

r 10

0 Pe

rson

-Yea

rs

MACE (median follow-up of 2.3 years)

HR=1.01 P=0.91

Low-dose methotrexate effect on inflammation and lipid levels

-70-60-50-40-30-20-10

010

Placebo Low-dose methotrexate

Med

ian

chan

ge fro

m b

asel

ine

(%)

After 8 months of therapy

TriglyceridesLDL-CIL-6hs-CRP

Notable low-dose methotrexate adverse reactions in CIRT

Incidence rate Placebo Methotrexate PLeukopenia 3.63 5.14 <0.001Infection 14.4 16.5 0.02GI disorders 6.23 7.79 0.006Mouth sores/oral pain 1.13 1.95 0.001ALT elevation 0.34 0.97 <0.001Any cancer 0.60 1.03 0.02Any adverse event 56.0 62.4 0.004

CIRT summary

• Low-dose methotrexate did not reduce MACE in established ASCVD with DM2

• Low-dose methotrexate did not reduce IL-1β, IL-6, or hs-CRP

• Low-dose methotrexate increased infection• CIRT provides evidence for a targeted anti-inflammatory approach to ASCVD

Novel targeted anti-inflammatory therapies for ASCVD

NLRP3 complex

Pro-IL-1β

Active IL-1β

ColchicineSelective NLRP3 inhibitors

The role of inflammation in risk stratification for ASCVD

• 2018 AHA/ACC Cholesterol Guidelines• Inflammatory disorders are ASCVD risk factors• Elevated hsCRP, rheumatoid arthritis, systemic lupus erythematosus,

psoriasis, HIV• Patients with chronic inflammation are more likely to require statin therapy

and/or higher-intensity• The accuracy of the ASCVD risk estimator has not been well validated for

inflammatory disorders

A new era beyond statins: lipid and inflammation management

• Risk for MACE persists in patient who are treated initially with statins

• Add-on therapies that target lipids and inflammation reduce risk

• Ezetimibe, PCSK9 inhibitors, canakinumab, and icosapent ethyl

• Additional therapies are being investigated in ASCVD outcomes trials

Disorders Affecting TG

Disorders Affecting LDLDisorders Affecting HDL

Future directions

• Is it possible to customize diets that target inflammation and lipid lowering?

• How does the microbiome contribute to the inflammasome?

• Should anti-inflammatory pharmacotherapy be another tool in our belt in the future?

The 2018 AHA Scientific Statement on Atherosclerotic Cardiovascular Disease in South Asians in the United States

• Important step in increasing awareness of the excess CVD risk in South Asians

• Identifies key risk factors that drive this risk• Provides specific recommendations for healthcare providers to

identify risk factor and modifications needed to reduce the excess ASCVD burden in South Asians

• “Ensuring its key messages are disseminated and implemented sufficiently to impact on ASCVD in our South Asian population falls on us as healthcare providers, scientists, and CV societies who care about this important and ever growing segment of the American population”

The AHA Scientific Statement on Atherosclerotic Cardiovascular Disease in South Asians in the United States

• People from South Asia—India, Pakistan, Bangladesh, Nepal, Bhutan, Maldives and Sri Lanka—have a four times greater risk of heart disease than the general population and have a much greater chance of having a heart attack before age 50.

• Heart attacks strike South Asian men and women at younger ages and the attacks are more deadly compared to any other ethnic group.

• Almost one in three in this group will die from heart disease before age 65.

• In India, cardiovascular disease remains the No. 1 cause of death. One study found that South Asians developed heart disease 10 years earlier than other groups.

• What is causing this heart disease phenomenon in South Asians?

• Why these heart attacks occur is only partially answered with traditional risk factor assessment. South Asians tend to be smokers, and the typical South Asian diet tends to be high in sugar, refined grains, and fatty foods.

The AHA Scientific Statement on Atherosclerotic Cardiovascular Disease in South Asians in the United States

• People from South Asia—India, Pakistan, Bangladesh, Nepal, Bhutan, Maldives and Sri Lanka— 4x risk of heart disease than the general population, and much greater risk of MI < age 50

• Heart attacks are more deadly compared to any other ethnic group•• Almost one in three in this group will die from heart disease before

age 65

It appears to come down to biology…

Higher rates of diabetes aHigher rates of nd of high blood pressurehigher body mass index and higher levels of cholesterol and combined hyperlipidemias

Let’s dive into a few of these.

• Biology/diabetes:

• This is the biggest risk factor difference. South Asians are twice as likely to develop diabetes and have abnormal sugar levels. Type 2 diabetes is a risk factor for coronary disease and a predictor for having heart issues and diabetics have a two- to three-fold increased risk of cardiovascular death as high blood sugar affects the blood vessels.

Cholesterol levels

• South Asians in the U.S. have higher levels of triglycerides (fats) and “bad” cholesterol (LDL-C), with lower levels of (HDL-C) or "good" cholesterol. That’s genetic.

Table 2Summary of lipoprotein abnormalities in South Asians

• CAD occurs with relatively lower levels of LDL-C among South Asians• At any given LDL-C level, South Asians tend to carry a higher total

atherogenic burden (i.e., higher levels of apo B and a higher LDL particle concentration)

• South Asians tend to suffer from atherogenic dyslipidemia (i.e., high triglyceride and low HDL-C levels) more frequently compared with other ethnic groups

• In South Asians, higher HDL-C levels may not be as protective against CAD as in other ethnic groups

• In South Asians, HDL particles tend to be smaller and dysfunctional• South Asians have a genetic tendency for elevated atherogenic Lp(a) levels

Apo B: Apolipoprotein B; CAD: Coronary artery disease; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; Lp(a): Lipoprotein(a).

Hypertension:

• High blood pressure is another risk factor for developing heart disease -- and 43 percent of men and 35 percent of women of South Asian descent are hypertensive in the U.S.

Inflammation

• Research has shown that those with higher levels of inflammatory molecules (homocysteine, high-sensitivity C reactive protein, etc.) are at a higher risk for heart disease. South Asians have higher levels of these inflammatory markers circulating in their blood, which indicates more overall inflammation in their bodies.

Diet:

• The typical South Asian diet has a high percentage of carbohydrates and saturated fats. Lentils, vegetables, rice, meats and breads are the mainstays, but a lot of South Asians are vegetarians due to religious or culture reasons. That means an absence of lean meats and an increase of fats and carbohydrates in their diets.

Is there a way to identify high-risk patients at particularly high risk?• Yes. A simple, quick computed tomography (CT) scan to look at the

blood vessels of the heart is a great way to identify patients at the highest risk.

• Several studies have shown that South Asians have higher amounts of calcium, blockages in the coronary arteries and they tend to be in multiple vessels.

• Several decades of research tell us that higher amounts of calcium in the blood vessels that supply our heart mean a higher likelihood of heart disease and heart attacks.

• South Asians older than 60 have the highest coronary artery calcium burden (scores greater than 100) of any ethnic group.

What do you do about those blockages?

• The good news? The PCI/stent outcomes in South Asians are similar to other races.

• But if it requires more than a stent? Bad news: if South Asians require coronary bypass surgery, they have poorer outcomes.

So what does all this mean, from a practical standpoint?• You have to take on the risks themselves. The AHA recommends

tailored interventions including education, promoting a healthy diet, exercise and talking with doctors about their risk factors.

• Compounded risks in the South Asian population + lack of specific testing: Criteria for metabolic syndrome and the subfractionation of HDL and other lipid- and inflammatory-based cardiovascular risk biomarkers are typically not checked during routine physical exams and they are often overlooked in a standard cardiovascular workup

• The cardiovascular risk in South Asians appears to begin early: Research has shown that even in infancy, children of South Asian heritage may have high levels of cholesterol and lipoproteins

Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association, Volume: 138, Issue: 1, Pages: e1-e34, DOI: (10.1161/CIR.0000000000000580)

Proportional mortality rates (PMRs) for cardiovascular and cerebrovascular diseases in Asian American subgroups

Detection of Subclinical CVD

• The use of computed tomography angiography to identify high-risk patients in the South Asian population is a young and growing field. Computed tomography angiography has been able to demonstrate variable ASCVD distribution patterns, higher amounts of stenosis, and smaller luminal diameters in South Asians. A study showed that South Asians in a US cohort had smaller normalized proximal left anterior descending artery luminal diameters compared with NHWs.47 Specifically, South Asians in this cohort also displayed more severe ASCVD on computed tomography angiography as determined by both increased mean percent stenosis and a higher number of patients with multiple diseased vessel segments.47 As demonstrated in multiple studies, South Asians were younger with a higher prevalence of DM and dyslipidemia compared with NHWs.

• Among other cohorts of 4 ethnicities (NHWs, Asians, Hispanics, and blacks), Asian Indians were investigated for coronary artery calcification (CAC) burden compared with the other racial/ethnic groups.48 Asian Indians, who represented ≈10% of the cohort, had an increased mean calcium score, and the Asian Indian race was a significant independent predictor of CAC severity, even when controlling for traditional ASCVD risk factors. Among those >60 years of age, the prevalence of high CAC burden (scores >100) in Asian Indians is greater than in all other ethnic groups.

South Asians and Cardiovascular Risk, Volume: 113, Issue: 25, Pages: e924-e929, DOI: (10.1161/CIRCULATIONAHA.105.583815)

Altered Inflammatory Biomarkers and Adipokines

Adipokines link insulin resistance to vascular disease

Can dysfunctional HDL explain high coronary artery disease risk in South Asians?

Obtained from Fogelman et al. Nat Med. 2004 Sep; 10(9):902–3.

Conversion of HDL from anti-inflammatory to proinflammatory

“Optimism is the faith that leads to achievement. Nothing can be done without hope and confidence.”Hellen Keller

Phenotypes of Dyslipidemia

• Mechanistic understanding leads to correct diagnosis

• Identification of secondary causes is important

• Treatment selection is based on phenotype

• Molecular and genetic identification informs development of new therapies

Basic Structure of Lipoproteins

Modified from Biochemistry 39: 9763, 2000

Features of Primary Lipoproteins

Lipoprotein Subclasses

Modified from Advances Protein Chemistry 45:303, 1994