ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR? Podcast - - PowerPoint PPT Presentation

ELEVATED TRIGLYCERIDES:

RISK MARKER OR RISK FACTOR?

Podcast developed by

This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.

Discussants

Alan D. Bell, MD, CCFP, FCFP

Family Physician and Assistant Professor, Department of Family and Community Medicine, University of Toronto, Toronto, ON

Robert Hegele, MD, FRCPC, FACP, FAHA, FCAHS, FCCS

Jacob J. Wolfe Distinguished Medical Research Chair in Human Gene Function; Martha G. Blackburn Chair in Cardiovascular Research; Director, London Regional Genomics Centre; Scientist, Molecular Medicine, Robarts Research Institute; Distinguished University Professor, Departments of Medicine (Division of Endocrinology) and Biochemistry, Western University London, ON

Disclosures

Alan D. Bell

Relationships with financial interests: – Grants/ Research Support: Amgen,

Bristol Myers Squibb, Janssen, AstraZeneca, Novartis, Pfizer, Bayer, Lilly, Boehringer Ingelheim, HLS Therapeutics, Spectrum Therapeutics, Sanofi, Bausch Health

– Honoraria: As above – Consulting Fees: As above – Clinical Trial Participation: Amgen,

Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Lilly, Sanofi, Akcea

– Patents: None – CME Development: See Honoraria

Robert Hegele

Relationships with financial interests: – Grants/ Research Support: Acasti, Sanofi, Amgen, Aegerion, HSFO, CIHR, Regeneron, Akcea, Cerenis, The Medicines Co. – Honoraria: Amgen, Akcea, Sanofi, Canadian Medical & Surgical Knowledge Translation Research Group – Consulting Fees: Aegerion, Amgen, Sanofi, Akcea, Genzyme, Regeneron, Acasti – Clinical Trial Participation: N/A – Patents: N/A – CME Development: N/A

Discussion topics:

.

• 1. Management challenges for high-risk CV

patients in primary care.

• Residual risk
• Advanced treatment options – who gets what?

.

• 2. Are elevated TG associated with CV risk?

.

• 3. What is the impact of TG lowering on CV risk?

.

• 4. What is the effect of fish oil, Omega-3 FA and

IPE on TG levels and CV outcomes?

• REDUCE IT design and results

Relationship between LDL-C and CV event rate

Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

Substantial residual risk remains in many patients with high CV risk despite intense statin therapy

*Death, myocardial infarction, unstable angina requiring hospitalization, revascularization (>30 days), stroke †Coronary heart disease death, non-procedure-related MI, resuscitation after cardiac arrest, stroke

• 1. Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504. 2. Adapted from LaRosa JC et al.
• 2. N Engl J Med. 2005;352:1425-1435.

Many factors contribute to CV risk

LDL-C–related risk reduction Residual CV risk

Statins

TGs Oxidation Endothelial dysfunction Inflammation Membrane instability/cholesterol crystals Plaque instability CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; TG=triglyceride

• 7. Libby P. Eur Heart J. 2015;36:774-776. 8. Ganda OP et al. J Am Coll Cardiol. 2018;72:330-343. 9.

Ference BA et al. JAMA. 2019;321(4):364-373.

Elevated TGs Predict Residual Risk Despite Achieving LDL-C <1.80 mmol/L with a High-Dose Statin (Results From PROVE-IT TIMI 22)

5 10 15 20 25

TG ≥ 1.70 mmol/L TG < 1.70 mmol/L†

(n=603) Risk of Death, MI, or Recurrent ACS (≥30 Days Post-ACS, %)

20.3%

(n=2796)

13.5%

Higher TG levels are associated with a 41% increase in risks of coronary events*

‡P = .001

ACS=acute coronary syndrome; CI=confidence interval; HR=hazard ratio; LDL-C=low-density lipoprotein cholesterol; mg/dL=milligrams/deciliter; MI=myocardial infarction; mmol/L=millimoles/liter; TG=triglyceride; *Death, myocardial infarction, or recurrent acute coronary syndrome; †From adjusted HR of TGs <200 mg/dL (95% CI, 0.60 (0.45%-0.81%)).

• 13. Miller M et al. J Am Coll Cardiol. 2008;51(7):724-730.

How can we reduce residual risk in which high risk patients?

Strategy Who +ve Who -ve Reversible Risk Factors Everyone Unmotivated PCSK9i LDL-C above target Needle averse, cost Extended DAPT Low bleed risk High bleed risk Dual Pathway Antithrombotic Low bleed risk High bleed risk Systolic BP < 120 SPRINT criteria Frailty IPE Elevated TG (> 1.7 mmol/L), DM Pill averse

Discussion topics:

.

• 1. Management challenges for high-risk CV patients

in primary care.

• Residual risk
• Advanced treatment options – who gets what?

.

• 2. Are elevated TG associated with CV risk?

.

• 3. What is the impact of TG lowering on CV risk?

.

• 4. What is the effect of fish oil, Omega-3 FA and

IPE on TG levels and CV outcomes?

• REDUCE IT design and results

Triglyceride-rich particles

Chylomicron VLDL IDL LDL HDL

Triglyceride Cholesterol

Triglyceride: cholesterol content

TRL particles ApoB particles (non-HDL) ApoA

Secondary causes of hypertriglyceridemia

Calorie Excess Central adiposity Hypothyroidis m Alcohol

Insulin resistance/metabolic syndrome/prediabetes

Nephrotic syndrome Physical inactivity Diabetes mellitus Medications

Copenhagen Studies:

Observational association between raised TG, vascular risk and mortality

TG, triglyceride Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Non-fasting triglyceride (mmol/L)

Emerging Risk Factors Study:

• bservational association between raised

TG and vascular risk

TG, triglyceride. Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Non-fasting triglyceride (mmol/L)

1 2 3 4 5 6 7 1 2 3 4 5 6 7 5 4 3 2 1

Hazard ratio (95% CI)

Ischemic heart disease

N=302,430 (events=12,785)

Ischemic stroke

N=173,312 (events=2,534)

Adjustments for HDL-C and non-HDL-C attenuate TG association with CVD

CVD, cardiovascular disease; HDL, high-density lipoprotein; TG, triglyceride. Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Lancet. 2010;375:1634-9;

1 2 3

0.5 1 1.5 2 2.5 3

Hazard ratio (95% CI)

U s ual TG co ncentratio n (m m

• /L

)

1.0 2.0 3.0 Adjusted for age and sex Further adjusted for non-lipid risk factors Further adjusted for non–HDL-C and HDL-C

Do genetic variants that alter LDL-C, HDL-C, and TG Levels impact MI Risk?

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; TG, triglyceride. Musunuru K, Kathiresan S. Circ Res. 2016;118:579-85.

Do people with more LDL DL-raising alleles (1-SD  ) have highe her MI risk? Do people with more HDL DL-raising alleles (1-SD  ) have low

• wer

er MI risk? Do people with more TG-raising alleles (1-SD  ) have highe her MI risk? Change in MI risk

113% P=10-10 No effect P=0.63 54% P=10-8 YES NO YES

Observational and causal genetic associations of raised remnant cholesterol and TG with outcomes

MI, myocardial infarction; TG, triglyceride. Adapted from

• 1. Varbo A et al. J Am Coll Cardiol. 2013;61:427-436,
• 2. Jørgensen AB et al. Eur Heart J. 2013;34:1826-33, and
• 3. Thomsen M et al. Clin Chem. 2014;60:737-46.

Are triglycerides a causal risk factor?

Adapted from Libby P. et al. Eur Heart J. 2015;36:774-6.

Cardiovascular benefit

Cau Causal sal r risk sk fact ctor

• r?

Triglyceride-rich lipoproteins By Bystande stander? ? HDL-C

Discussion topics:

.

• 1. Management challenges for high-risk CV patients

in primary care.

• Residual risk
• Advanced treatment options – who gets what?

.

• 2. Are elevated TG associated with CV risk?

.

• 3. What is the impact of TG lowering on CV risk?

.

• 4. What is the effect of fish oil, Omega-3 FA and

IPE on TG levels and CV outcomes?

• REDUCE IT design and results

Have we been studying the right patients?

Adapted from Sacks FM et al. N Engl J Med. 2010;363:692-4

Subgroup with HIGH TG, Low HDL-C Subgroup without HIGH TG, Low HDL-C ACCORD ACCORD FIELD FIELD BIP BIP HHS HHS VA-HIT VA-HIT Summary Summary

0.125 0.25 0.5 1 Odds ratio (95% CI) 0.125 0.25 0.5 1 Odds ratio (95% CI)

Have we been studying the right patients?

Adapted from Sacks FM et al. N Engl J Med. 2010;363:692-4

Subgroup with HIGH TG, Low HDL-C ACCORD FIELD BIP HHS VA-HIT Summary

0.125 0.25 0.5 1 Odds ratio (95% CI)

Does triglyceride- lowering therapy confer CV benefit in individuals with elevated triglycerides?

Post hoc analysis suggests that individuals with elevated TG and low HDL-C benefit from fibrates

HDL-C, high-density lipoprotein cholesterol; TG, triglycerides. Manninen V et al. Circulation. 1992;85:37-45; Robins SJ et al. JAMA. 2001;285:1585-91; Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21-7; Scott R et al. Diabetes Care. 2009;32:493-8; ACCORD Study Group. N Engl J Med. 2010;362:1563-74.

Study Duration (y) 5.0 5.1 6.2 5.0 4.7 N (High TG) 4,081 (1,046) 2,531 (788) 3,090 (459) 9,795 (2,517) 5,518 (1,822) Baseline TG (mmol/L) 1.99 1.82 1.64 1.74 1.83

Post hoc analysis suggests that individuals with elevated TG and low HDL-C benefit from fibrates

HDL-C, high-density lipoprotein cholesterol; TG, triglycerides. Manninen V et al. Circulation. 1992;85:37-45; Robins SJ et al. JAMA. 2001;285:1585-91; Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21-7; Scott R et al. Diabetes Care. 2009;32:493-8; ACCORD Study Group. N Engl J Med. 2010;362:1563-74.

Study Duration (y) 5.0 5.1 6.2 5.0 4.7 N (High TG) 4,081 (1,046) 2,531 (788) 3,090 (459) 9,795 (2,517) 5,518 (1,822) Baseline TG (mmol/L) 1.99 1.82 1.64 1.74 1.83 Pooled Relative Risk Reduction by Baseline:

• HDL <1.04 mmol/L

16% (95% CI 9, 23%)

• TG ≥2.26 mmol/L

25% (95% CI 14, 45%)

• HDL and TG

29% (95% CI: 18-38%)

Why have CVOTs of TG-lowering drugs failed to reach primary endpoints?

CVOTs, cardiovascular outcome trials; TG, triglyceride. Bhatt DL et al. Clin Cardiol. 2017;40:138-148.

Some did not prospectively enroll people with elevated TG despite statin therapy

• ACCORD
• HPS2-THRIVE
• AIM-HIGH

Some evaluated people with TG <2.26 mmol/L (non-high TG) on low

• mega-3 doses
• ORIGIN
• OMEGA

Discussion topics:

.

• 1. Management challenges for high-risk CV patients

in primary care.

• Residual risk
• Advanced treatment options – who gets what?

.

• 2. Are elevated TG associated with CV risk?

.

• 3. What is the impact of TG lowering on CV risk?

.

• 4. What is the effect of fish oil, Omega-3 FA and

IPE on TG levels and CV outcomes?

• REDUCE IT design and results

ORIGIN n-3 FA

• 12,536

patients with dysglycemia and high vascular risk with

• 1 g/day n-3

FA or PBO

• No benefit

ORIGIN investigators. N Engl J Med 367;4, 2012

OMEGA

• 3851patients

with acute MI

• 1 g/day n-3

FA or PBO

• No benefit

Rauch B et al. Circulation 2010

STRENGTH (DHA + EPA)

• Following the recommendation from an

independent Data Monitoring Committee, AstraZeneca has decided to close the Phase III STRENGTH trial for Epanova (omega-3 carboxylic acids) due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidaemia (MDL) who are at increased risk of cardiovascular (CV) disease.

AstraZeneca corporate release. Jan 13, 2020

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Key Inclusion Criteria

• 1. Age ≥ 45 with established CVD

(Secondary Prevention Cohort)

OR Age ≥50 with diabetes with ≥1 additional risk

factor for CVD (Primary Prevention Cohort)

• 2. Fasting TG levels ≥1.69 mmol/L and <5.65 mmol/L*
• 3. LDL-C >1.03 mmol/L and ≤2.59 mmol/L and on stable statin therapy (± ezetimibe)

for ≥4 weeks prior to qualifying measurements for randomization

Note: TG and LDL levels converted from mg/dL to mmol/L to reflect Canadian practices. CVD = cardiovascular disease; TG = triglyceride; LDL = low density lipoprotein

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

REDUCE-IT: multicenter, randomized, double-blinded, event-driven, placebo- controlled trial

• 8,179 with documented atherosclerosis related to CVD split into two

cohorts of 70:30 in secondary prevention vs. primary prevention

• Primary Efficacy Endpoints (5 point MACE): Composite of CV death,

Myocardial Infarction, Stroke, Coronary Revascularization, Unstable Angina Requiring Hospitalization

• Secondary Efficacy Endpoint (3 point MACE): Composite of CV death,

MI, stroke

• Median follow up duration: 4.9 years (min 0.0, max 6.2 years)

Total Population n= 8,179 Placebo n = 4,090 Icosapent Ethyl 4 g/day (n = 4,089)

Follow Up Period Follow up period

R

End of Follow Up Visit End of Follow Up Visit

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Mean follow up duration = 4.9 years

Primary End Point: CV Death, MI, Stroke, Coronary Revascularization, Unstable Angina

Hazard Ratio, 0.75 (95% CI, 0.68–0.83) RRR = 24.8% ARR = 4.8% NNT = 21 (95% CI, 15–33) P=0.00000001

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Key Secondary Endpoint: CV Death, MI, and Stroke

Hazard Ratio, 0.74 (95% CI, 0.65–0.83) RRR = 26.5% ARR = 3.6% NNT = 28 (95% CI, 20–47) P=0.0000006

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Icosapent Ethyl 4g/day significantly reduced 5-MACE, 3-MACE, and individual composite endpoints

RRR

25% 26% 25% 31% 35% 20% 32% 28% 23%

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Subgroup Analysis Consistent with Main Result

(≥1.70 mmol/L) (<1.70 mmol/L) (≥ 2.26 mmol/L) (≤0.90 mmol/L) (≤1.73 mmol/L) (>2.17 mmol/L) (>1.73 to ≤ 2.17 )

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Icosapent Ethyl showed minimal side effect compared to placebo

Icosapent Ethyl (n = 4,089) Placebo (n = 4,090) P-value Diarrhea 367 (9.0%) 453 (11.1%) 0.002 Peripheral edema 267 (6.5%) 203 (5.0%) 0.002 Constipation 221 (5.4%) 149 (3.6%) <0.001 Atrial Fibrillation 215 (5.3%) 159 (3.9%) 0.003 Anemia 191 (4.7%) 236 (5.8%) 0.03 Pneumonia 263 (6.4%) 277 (6.8%) 0.56

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Standard of Care: Cardiovascular Preventative Strategies

RRR Lipid Lowering (1mmol/L)1 BP lowering (per 10 mmg Hg)2 Icosapent Ethyl3 MACE 22% 20% 25% Stroke 15% 27% 28% MI 24% 17% 31% CV Death 16% 15% 20%

MACE = major adverse coronary events, BP = blood pressure, ACEi = angiotensin converting enzyme inhibitors; EPA = eicopentanoic acid, RRR = relative risk reduction; MI = myocardial infarction

The REDUCE-IT trial demonstrated a MACE reduction of 25%, with an absolute risk reduction of 4.8%; NNT of 21 on top of standard of care

• 1. CTT collaboration et al. 2015. Lancet. 385: 1397-1405.
• 2. Ettehad, D. et al. 2016. Lancet. Mar 5; 387 (100222): 957-967
• 3. Bhatt, D. et al. 2019. NEJM .Jan 3; 380:11-22. 10.1056/NEJMoa1812792

On top of standard of care

Discussion

This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.

Follow MD-Listen on your favorite listening platform for more programs