key clinical lipidology publications: 2015-16 · key clinical lipidology publications: 2015-16...

Key Clinical Lipidology

Publications: 2015-16

Kevin C. Maki, PhD, CLS, FNLA, FTOS, FACN

MB Clinical Research and DePaul University

Glen Ellyn and Chicago, Illinois

AFFILIATION/FINANCIAL INTERESTS

(past 12 months)

ORGANIZATION

Grants/Research Support: DuPont, AstraZeneca, ACH

Foods, Matinas BioPharma,

Shaklee, Egg Nutrition Center,

National Dairy Council, National

Cattlemen’s Beef Association,

Sancilio & Co.

Scientific Advisory Board/Consultant: AstraZeneca, Pharmavite, Matinas

BioPharma, Sancilio & Co.,

National Dairy Council, Egg

Nutrition Center, National

Cattlemen’s Beef Association

Speakers Bureau: None

Stock Shareholder: None >$10,000

Other Not Applicable

Disclosures

Key Developments in

Clinical Lipidology in 2015-16

• Ezetimibe Outcomes StudyCannon CP, et al.

• PCSK9 Inhibitor StudiesRobinson JG, et al. and Sabatine MS, et al.

• Failure of Another CETP Inhibitor TrialNicholls SJ, et al.

• Statins and Diabetes RiskMansi I, et al.

• Saturated vs. Unsaturated Fats, Carbohydrates and CHDLi Y, et al.

• NLA Recommendations: Part 1 Full Report, Part 2Jacobson TA, et al.

• Drugs for Glycemic Control and Heart Disease RiskKernan WN, et al., Zinman B, et al. and LEADER press release

• Genetic Variants Influencing TG and Coronary RiskDewey FE, et al. and Myocardial Infarction Genetics and CARDIoGRAM

Exome Consortia Investigators

Cannon CP, et al. N Engl J Med. 2015;372:2387-97.

Improved Reduction of Outcomes: Vytorin

Efficacy International Trial (IMPROVE-IT)

Cannon CP, et al. Am Heart J. 2008;156:826-32.

Blazing MA, et al. Am Heart J. 2014;168:205-212.e1.


IMPROVE-IT: Study Design

On treatment LDL-C = 69.5 mg/dL On treatment LDL-C = 53.7 mg/dL

IMPROVE-IT: Kaplan-Meier Curves for

Primary Efficacy End Point


IMPROVE-IT: Primary and Secondary

Efficacy End Points


IMPROVE-IT and Statin Trials: Association

Between LDL-C Change and Clinical Benefit


IMPROVE-IT: Conclusions

• These results further support the efficacy of atherogenic cholesterol

lowering per se for reducing the risk for atherosclerotic

cardiovascular disease (ASCVD).

• The degree of ASCVD event reduction was consistent with the

predicted effects based on results from statin trials for the degree of

LDL-C reduction, even in the range of low LDL-C levels.


Proprotein Subtilisin Kexin Type 9 (PCSK9)

Inhibitors: ODYSSEY LONG TERM and OSLER

Robinson JG, et al. N Engl J Med. 2015;372:1489-99.

Sabatine MS, et al. N Engl J Med. 2015;372:1500-9.

ODYSSEY LONG TERM and OSLER: Study Designs



HeFH = heterozygous familial hypercholesterolemia; Q2W = every other week; R = randomization; SC = subcutaneous; W = week

ODYSSEY LONG TERM (Alirocumab) and OSLER

(Evolocumab): LDL-C Levels



ODYSSEY LONG-TERM (Alirocumab) and OSLER

(Evolocumab): Incidence of CV Events



Assessment of Clinical Effects of Cholesteryl Ester

Transfer Protein Inhibition with Evacetrapib in Patients

at High Risk for Vascular Outcomes (ACCELERATE)

• Designed to evaluate the efficacy and safety of evacetrapib, a

cholesteryl ester transfer protein (CETP) inhibitor in participants

with high-risk CVD

• Multi-center, randomized, double-blind, placebo-controlled trial of

12,095 patients conducted at 540 sites in 37 countries

• Primary outcome measure: time to first occurrence of any

component of the composite CV events of CV death, MI, stroke,

coronary revascularization, or hospitalization for unstable angina

• Trial terminated due to insufficient efficacy

• Lilly discontinued development of evacetrapib for the treatment of

high-risk CVD and concluded other studies in the program.

https://clinicaltrials.gov/ct2/show/NCT01687998

https://investor.lilly.com/releasedetail.cfm?releaseid=936130

Nicholls SJ, et al. Am Heart J. 2015;170:1061-9.


https://investor.lilly.com/releasedetail.cfm?releaseid=936130

Significance of Failure of ACCELERATE

• CETP inhibitors are the most effective high-density lipoprotein

(HDL)-raising agents developed to date; they roughly double HDL-

C concentration. They also reduce LDL-C. However, clinical

outcomes trials conducted to date have failed:

Torcetrapib increased blood pressure; net CV detriment (2006)

Dalcetrapib showed no clinically meaningful CV efficacy (2012)

Evacetrapib showed no clinically meaningful CV efficacy (2015)

• The Randomized Evaluation of the Effects of Anacetrapib Through

Lipid-modification (REVEAL) is an ongoing Phase 3 randomized

controlled trial examining the potential of anacetrapib to reduce

CVD. Data collection planned through 2017.

Page MM, et al. Expert Opin Pharmacother. 2015;Dec 28:1-7 [Epub ahead of print].

Barter PJ, Rye KA. Clin Ther. 2015;37:2716-31.

Hovingh GK, et al. Circulation. 2015;132:433-40.



Statins and Diabetes

Mansi I, et al. J Gen Intern Med. 2015;30:1599-610.

Statins and Diabetes:

Retrospective Study Cohort


CCI = Charlson Comorbidity Index

CVS = Cardiovascular

Statins and New-Onset Diabetes Mellitus and

Diabetes Complications


Outcome Statin

non-users

(N = 3351)

Statin

users

(N = 3351)

Odds ratio

(95% CI)

P-value

Diabetes Mellitus 19.4% 30.9% 1.87

(1.67, 2.01)

<0.0001

Diabetes Mellitus with

Complications

2.1% 5.0% 2.50

(1.88, 3.32)

<0.0001

Outcome High-

intensity

statins

(N = 1155)

Lower-

intensity

statins

(N = 2827)

Adjusted*

odds ratio

(95% CI)

P-value

Diabetes Mellitus 39.3% 29.7% 1.50

(1.30, 1.73)

<0.0001

Diabetes Mellitus with

Complications

8.2% 4.2% 1.97

(1.49, 2.61)

<0.0001

*Adjusted for propensity score

Statins and Diabetes: Conclusions

• Most prior studies of statin use and increased incidence of new-

onset diabetes have been conducted in higher risk populations.

This study demonstrated an increased risk for diabetes among

statin users vs. non-users among healthy U.S. adults, and also

reported an increased risk for diabetes complications.

• Generally, the increased risk for diabetes mellitus is more than

offset by the reduced risk for CVD associated with statin use,

however, this study was not designed to investigate the trade-offs

between risks and benefits.


A Prospective Cohort Study of Saturated Fats Compared with

Unsaturated Fats and Sources of Carbohydrates in Relation

to Risk of Coronary Heart Disease

• 84,628 women (Nurses’ Health Study, 1980-2010) and 42,908

men (Health Professionals Follow-up Study, 1986-2010)

• Subjects were free of diabetes, CVD, and cancer

• Diet assessed by semi-quantitative food frequency

questionnaire every 4 years

• Follow-up of 24-30 years

• 7,667 documented incident cases of CHD

Li Y, et al. J Am Coll Cardiol. 2015;66:1538-48.

Estimated Percent Changes in CHD Risk

Associated with Isocaloric Substitutions

of Dietary Components for SFAs

Li Y, et al. J Am Coll Cardiol. 2015; 66:1538-48.

5%

-15%

-25%

2%

-9%

Implications of Findings from Dietary

Component Substitution Analyses

• Results from these two large, prospective cohorts of U.S. men

and women suggest that consumption of unsaturated fats and/or

high-quality carbohydrates may be used to replace saturated fats

(and refined starches/added sugars) to reduce CHD risk.

• These findings support the recommendations of the Dietary

Guidelines for Americans to reduce intakes of saturated fats and

refined starches/added sugars and to replace these dietary

components with unsaturated fats and carbohydrates from whole

grains.

Li Y, et al. J Am Coll Cardiol. 2015;66:1538-48.

National Lipid Association (NLA)

Recommendations Part 1 – Full Report

Jacobson TA, et al. J Clin Lipidol. 2015;9:129-69.

NLA Part 2 Recommendations

Jacobson TA, et al. J Clin Lipidol. 2015;9:S1-S122.

Key Differences Between the ACC/AHA Guidelines

and the NLA Recommendations

• Methods of CVD risk assessment• Four statin benefit groups, primary prevention risk assessment based

largely on age and quantitative risk scoring (ACC/AHA)

• Risk categories + risk factor counting + supplemental methods

including quantitative risk scoring (NLA)

• Use of treatment goals for atherogenic cholesterol (NLA)

• Inclusion of non-high-density lipoprotein cholesterol (non-HDL-C) as

a treatment target

• Approach to dietary cholesterol• No recommendation from the ACC/AHA

• Limitation of dietary cholesterol recommended by the NLA Expert Panel

Stone NJ, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2889-934.

Goff DC Jr., et al. J Am Coll Cardiol. 2014;63(25 Pt B):2935-59.

Eckel RH, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2960-84.

Jacobson TA, et al. J Clin Lipidol. 2015;9:129-69.

ACC Expert Consensus Clinical

Pathway on Lipid Management

• Writing committee of clinical experts was assembled following the

LDL: Address the Risk Think Tank meeting in September 2015.

• Participants identified the need for expert consensus document on

incorporation of non-statin therapies into treatment strategies for

higher risk patients if the response to statins is deemed inadequate.

• A 9-person writing committee was selected, chaired by Donald

Lloyd-Jones, MD and included a majority of members without

relevant relationships with industry (RWI); authors with relevant RWI

were not permitted to draft or vote on content or recommendations

pertaining to their RWI.

• Peer reviewers were established and the respective executive

boards of the professional societies provided final review and

endorsement of the document.

Questions Addressed by the ACC

Expert Consensus Writing Committee

1) In whom should non-statin therapies be considered?

1) In what situations should non-statin therapies be considered, i.e.

when is the amount of LDL-C lowering (percent LDL-C reduction or

LDL-C range achieved on therapy) less than anticipated, less than

desired, or inadequate, and what should be done with patients who

are truly statin intolerant?

1) If non-statin therapies are to be added, which agents or therapies

should be considered and in what order?

Insulin Resistance Intervention

after Stroke (IRIS) Trial

Kernan WN, et al. N Engl J Med. 2016;Published online.

Pioglitazone Effects on CVD and Diabetes

Incidence in the IRIS Trial

0

1

2

3

4

5

6

7

8

9

Pioglitazone (N = 1939) Placebo (N = 1937)

Incid

ence o

f D

iabe

tes M

elli

tus (

%)

Hazard Ratio, 0.48 (95% CI 0.33-0.69)

P < 0.001 7.7%

CVD Events Type 2 Diabetes Mellitus

Kernan WN, et al. New Engl J Med. 2016;Published online.

3.8%

Cardiovascular Outcome Event Trial in Type 2

Diabetes Mellitus Patients (EMPA-REG OUTCOME)

Zinman B, et al. New Engl J Med. 2015;373:2117-28.

Empagliflozin Effects on Cardiovascular

Outcomes in the EMPA-REG OUTCOME Trial

Primary composite outcome was death from CV causes,

nonfatal myocardial infarction, or nonfatal stroke

Zinman B, et al. New Engl J Med. 2015;373:2117-28.

Marso SP, et al. Am Heart J. 2013;166:823-30.

http://globenewswire.com/news-release/2016/03/04/816952/0/en/Victoza-significantly-reduces-the-risk-of-major-adverse-

cardiovascular-events-in-the-LEADER-trial.html

Liraglutide Effect and Action in Diabetes: Evaluation

of Cardiovascular Outcome Results (LEADER) Trial

• Multicenter, international (32 countries), randomized,

double-blind placebo-controlled trial• 9,340 adults with type 2 diabetes at high risk of major adverse

CV events

• Liraglutide (1.2 and 1.8 mg) compared to placebo, both in

addition to standard of care; patients followed for 3.5-5 y

• Primary endpoint: composite outcome of the first occurrence

of CV death, non-fatal myocardial infarction or non-fatal stroke

• The study met its primary endpoint and demonstrated

a statistically significant reduction in CV risk• Detailed results to be presented at the American Diabetes

Association Scientific Sessions, June 2016

Dewey FE, et al. N Engl J Med. 2016;Published online.

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. New Engl J Med. 2016;Published online.

Genetic Variants Influencing TG Levels and

Risk of Coronary Artery Disease (CAD)

Loss-of-function Mutations in ANGPTL4 and CAD

• DNA sequencing in 72,868 patients with CAD and

120,770 controls without CAD (Consortia Investigators) Carriers of loss-of function mutations in ANGPTL4 had 35%

lower TG levels than non-carriers (p = 0.003)

Odds ratio for myocardial infarction in carriers vs. non-carriers

was 0.47 (p = 0.04)

• DNA sequencing in 10,552 patients with CAD and

29,223 controls without CAD (Dewey et al.) Carriers of the E40K loss-of-function mutation in ANGPTL4

had 13% lower TG and 7% higher HDL-C than non-carriers

Odds ratio for CAD in carriers vs. non-carriers of the E40K

variant was 0.81 (p = 0.002)

Dewey FE, et al. N Engl J Med. 2016;Published online.


Effects of Genetic Variants on TG levels

and Risk of CAD

ANGPTL4 = angiopoietin-like 4

APO = apolipoprotein

LPL = lipoprotein lipase


Summary/Take Home Messages

• 2015-16 saw some exciting advancements in the understanding of CVD and

lipid-altering therapies, and drugs for glycemic control, for reducing risk for CVD

Clinical trials with PCSK9 inhibitors and ezetimibe showed evidence that

further supports the view that lower is better for LDL-C.

There is increasing evidence to suggest that statins increase the risk for

developing new-onset diabetes mellitus.

CV outcomes benefits from raising HDL-C via CETP inhibition continues to

lack clinical trial support.

Unsaturated fats and high quality carbohydrates are recommended to

replace saturated fats to reduce risk for CHD in the 2015 Dietary Guidelines

for Americans. Data from large prospective cohort studies in men and

women support these recommendations.

Hypoglycemic drugs (pioglitazone, empagliflozin, liraglutide) were shown to

decrease CV events in outcomes trials.

Carriers of genetic variants resulting in reduced TG levels were shown to

have lower risk of CAD than non-carriers.

Thank You

QUESTIONS?

key clinical lipidology publications: 2015-16 · key clinical lipidology publications: 2015-16...

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