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Approach to Dyslipidemia among

diabetic patients

Farzad Hadaegh, MD,

Professor of Internal Medicine & Endocrinology

Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences

Shahid Beheshti University of Medical Sciences Tehran, Nov 2017

11/28/2017 3 Ray KK, et al. Lancet. 2009;373:1765–72

Per 0.9% lower

HbA1c Per 4 mmHg

lower SBP

Per 1 mmol/L

lower LDL-C

5

0

–5

–10

–15

–20

CV

eve

nts

–12.5

–8.2

–2.9

11/28/2017 4 Cholesterol, 2012, doi:10.1155/2012/861924

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8

Residual risk: Due to increased

triglycerides, elevated Lp(a), other

untreated risk factors

Cannon et al NEJM 2015

Significant Residual Risk Remains Untreated

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Normal

Insulin

resistance

VLDL

VLDL triglycerides

VLDL apo B

HDL

HDL cholesterol

particle number

particle size

(small, dense)

LDL

LDL apo B

particle number

particle size

(small, dense) VLDL: very low-density lipoprotein; LDL: low-density lipoprotein HDL: high-density lipoprotein; Apo B: apolipoprotein B

Watts G. Diapedia 2014. Available at: http://www.diapedia.org/61040851150/rev/5. Last accessed September 2016

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LDL cholesterol (LDL-C) is the traditional measure of LDL, chosen for historical, not analytic or

clinical reasons.

Alternatively, LDL can be measured by particle number (LDL-P), or estimated by apolipoprotein B.

Due to differences in the amount of cholesterol contained in LDL, alternate LDL measures (LDL-C

vs. LDL-P) frequently disagree (discordance).1-7

1. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.

2. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.

3. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.

4. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.

5. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.

6. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.

7. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.

LDL Particle

Triglycerides

Cholesterol

LDL-P LDL-C

LDL Particle

Triglycerides

Cholesterol

LDL-P LDL-C

Cardiovascular risk tracks with LDL particle number

When alternate LDL measures (LDL-C vs LDL particle number) agree

(concordance) each measure is equally associated with CVD risk.

When alternate measures are discordant (e.g., diabetes, metabolic syndrome,

statin therapy), risk tracks with LDL-P, not LDL-C.

The majority of atherogenic lipoproteins in individuals with insulin resistance,

metabolic syndrome or T2D are smaller, cholesterol-depleted LDL particles.

These compositional changes in LDL particles may lead to a disagreement

between measures of LDL-C and LDL-P resulting in “discordance”

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Reduce LDL Particle

Production

(make less)

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LDL-P Target

Diet

Exercise

Weight Loss

Glycemic Control

Co-Morbidity

Management

(up to 30-50% 6 LDL-P)

Marine Omega-3

o DHA + EPA

(no 6 LDL-P)

o EPA Only

(4-15 % 6 LDL-P)

Improve LDL Particle

Clearance

(remove more)

Statins

(35-55% 6 LDL-P)

Gut agents

o Ezetimibe

(15-30% 6 LDL-P)

o Resins / Bile Acid

Sequestrates

(15-30% 6 LDL-P)

Statin + Gut

(50-70% 6 LDL-P)

Statin + Gut + Niacin

(> 60% 6 LDL-P)

PCSK9 inhibitors

Lipid and lipoprotein disorders: Current clinical solutions. Baltimore: International Guideline Center; 2012.

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• Aim: assess the effects on vascular mortality and morbidity of a substantial LDL-C reduction maintained for several years in a large cohort of diabetic individuals

• Methods : 5963 UK adults (aged 40–80 years) known to have DM, and an additional 14 573 with occlusive arterial disease (but no diagnosed DM), were randomly allocated to receive 40 mg simvastatin daily or matching placebo

Lancet 2003; 361: 2005-16 11/28/2017 11

11/28/2017 12 Lancet 2003; 361: 2005-16

11/28/2017 13 Lancet 2003; 361: 2005-16

• Allocation to 40 mg simvastatin daily reduced the rate of first major

vascular events by about a quarter in a wide range of diabetic patients

studied.

• Statin therapy should now be considered routinely for all diabetic

patients at sufficiently high risk of major vascular events, irrespective

of their initial cholesterol concentrations.

• n = 2838

• Age 40-75, no history of CVD

• T2DM plus one or more:

• Retinopathy

• Albuminuria

• Hypertension

• Smoking

• Intervention: Atorvastatin 10 mg vs. Placebo

• Outcome: ACS, revascularization, stroke

Colhoun HM, et al. Lancet 2004;364:685. 11/28/2017 14

Colhoun HM, et al. Lancet 2004;364:685. 11/28/2017 15

Aim of study:

Although statin therapy reduces the risk of occlusive vascular events in people with DM

There is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors.

Methods:

Data from 18686 individuals with diabetes (1466 type 1 and 17,220 type 2) in the context of a further 71,370 without diabetes in 14 randomised trials of statin therapy.

Estimates effects on clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol.

Lancet 2008, Jan 12;371(9607):117-25 11/28/2017 16

• Result in Diabetic patients:

All cause

mortality MI or

Coronary

Death

Coronary

Revasculari

sation

Stroke

Risk

Reduction

%9

RR= 0.87

P<0.0001

22%

RR=0.78

P<0.0001

25%

RR=0.75

P<0.0001

21%

RR=79

P=0.0002

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Lancet 2008, Jan 12;371(9607):117-25

After 5 years, 42 (95% CI 30–55) fewer people with diabetes had major

vascular events per 1000 allocated statin therapy.

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Lancet 2008, Jan 12;371(9607):117-25

Among diabetic patients the proportional effects of statin therapy were similar irrespective of whether there was a :

Prior history of vascular disease

Other baseline characteristics.

Conclusion: Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events.

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1501 patients with diabetes and CHD, primary end point: time to first major

cardiovascular event*

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal

or nonfatal stroke

TNT: Treating to New Target study

Shepherd J, et al. Diabetes Care 2006;29:1220–6

Cu

mu

lati

ve i

ncid

en

ce o

f m

ajo

r card

iovascu

lar

even

ts*

Relative risk reduction = 25%

0.15

HR = 0.75 (95% CI: 0.58, 0.97)

P = 0.026

Atorvastatin 10 mg

Atorvastatin 80 mg

0.20

0.10

0.05

0

0 1 2 3 4 5 6

Years

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The Risk Calculator.

The American College of Cardiology/American Heart Association

ASCVD risk calculator may be a useful tool to estimate 10-year ASCVD

(http://my .americanheart.org).

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Reduce LDL-C 18–55% & TG 7–30%

Raise HDL-C 5–15%

Major side effects

Myopathy

Increased liver enzymes

Contraindications

Absolute: liver disease

Relative: use with certain drugs

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Fibric acid derivatives, especially Gemfibrozil

Niacin

Cyclosporine

Azole antifungals

Macrolide antibiotics

HIV protease inhibitors

Nefazodone

Verapamil and diltiazem

Amiodarone

Grapefruit juice, >1 qt/d

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A meta-analysis of 13 randomized statin trials with 91,140 participants

showed an odds ratio of 1.09 (9%) for a new diagnosis of diabetes,

On average ,treatment of 255 patients with statins for 4 years resulted in 1

additional case of diabetes,

while simultaneously preventing 5.4 vascular events among those 255

patients

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Hypertriglyceridemia should be addressed with dietary and lifestyle changes

including abstinence from alcohol

Severe hypertriglyceridemia (>1,000 mg/dL) may warrant pharmacologic

therapy (fibric acid derivatives and/or fish oil) to reduce the risk of acute

pancreatitis.

Low levels of HDL cholesterol, often associated with elevated triglyceride

levels, are the most prevalent pattern of dyslipidemia in individuals with type

2 diabetes.

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Drug Dose

• Gemfibrozil 600 mg BID

• Fenofibrate 200 mg QD

• Clofibrate 1000 mg BID

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• Major actions

• Lower LDL-C 5–20% (with normal TG)

• May raise LDL-C (with high TG)

• Lower TG 20–50%

• Raise HDL-C 10–20%

• Side effects: dyspepsia, gallstones, myopathy

• Contraindications: Severe renal or hepatic disease

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Combination therapy (statin/fibrate) has not been shown to improve

atherosclerotic cardiovascular disease outcomes and is generally not

recommended. However, therapy with statin and fenofibrate may be

considered for men with both triglyceride level ≥204 mg/dL (2.3 mmol/L)

and HDL cholesterol level ≤ 34 mg/dL (0.9 mmol/L).

Combination therapy (statin/niacin) has not been shown to provide

additional cardiovascular benefit above statin therapy alone and may

increase the risk of stroke and is not generally recommended.

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Clinicians should attempt to find a dose or alternative statin that is

tolerable, if side effects occur.

There is evidence for benefit from even extremely low, less than daily,

statin doses .

The addition of Ezetimibe to moderate-intensity statin therapy has been

shown to provide additional cardiovascular benefit compared with

moderate-intensity statin therapy alone and may be considered for

patients :

with a Recent ACS with LDL –C >50 mg/dL or for those patients who

cannot tolerate high intensity statin therapy. A

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Individuals were 50 years of age who experienced an ACS within the

preceding 10 days and had an LDL –C level> 50 mg/dL.

In those with diabetes (27%), the combination of moderate intensity

simvastatin (40mg) and ezetimibe (10 mg) showed a significant reduction of

major adverse cardiovascular events with an absolute risk reduction of 5%

(40% vs. 45%) and RR reduction of 14% (RR 0.86 [95% CI 0.78–0.94])

over moderate-intensity simvastatin (40 mg) alone.

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Simvastatin† EZ/Simvastatin†

Male 34.9 33.3 Female 34.0 31.0 Age <65 years 30.8 29.9 Age ≥65 years 39.9 36.4

No diabetes 30.8 30.2 Diabetes 45.5 40.0

Prior LLT 43.4 40.7 No prior LLT 30.0 28.6

LDL-C >95 31.2 29.6 LDL-C ≤95 38.4 36.0

*p-interaction = 0.023, otherwise >0.05 †7-year event rates LLT: lipid-lowering therapy Ezetimibe/Simvastatin

better Simvastatin

better

*

0.7 1.0 1.3

Cannon et al NEJM 2015

The addition of the novel PCSK9 inhibitors, Evolocumab and

Alirocumab,

To maximally tolerated doses of statin therapy in participants who

were at high risk for ASCVD

Decrese the LDL cholesterol ranging from 36% to 59%.

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LAPLACE-2: LDL-C Assessment with PCSK9

Monoclonal Antibody Inhibition

Combined With Statin Therapy.

RUTHERFORD-2: Reduction of LDL-C With

PCSK9 Inhibition in Heterozygous Familial

Hypercholesterolemia Disorder Study.

GAUSS-2: Goal Achievement after Utilizing an

Anti-PCSK9 Antibody in Statin

Intolerant Subjects.

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Treatment of T2DM patients with evolocumab led to a:

reduction of ~60% in LDL-C vs placebo and ~39% vs ezetimibe1

reduction of ~55% in non-HDL-C vs placebo and ~34% vs ezetimibe1

Evolocumab has no measurable effect on glycaemic parameters in patients with or at high- or low-risk of diabetes2

1. Sattar N, et al. Lancet Diab Endocrin 2016;4:403–10 2. Sattar N, et al. Presented at EASD, 2015

Mean change in non-HDL-C concentration (%) from baseline to week 12

Evolocumab vs. placebo Evolocumab vs.ezetimibe

Mean change in LDL-C concentration (%) from baseline to week 12

Evolocumab vs. placebo Evolocumab vs. ezetimibe 0.0

-10.0

-20.0

-30.0

-40.0

-50.0

-60.0

-70.0

–33.8 –35.4

–54.9 –58.2 T2DM (n=413) No T2DM (n=2119)

0.0

–10.0

–20.0

–30.0

–40.0

–50.0

–60.0

–70.0

–39.3 –40.4

–60.2 –65.9

–80.0

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Evolocumab markedly reduces

atherogenic lipoproteins in patients

with type 2 diabetes, an effect that is

consistent across subgroups and

similar to that seen in patients

without type 2 diabetes

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N Engl J Med 2017; 376:1713-1722

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Global Cardiology Science and Practice 2015:20 11/28/2017 51

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Patients aged 40-75, without

ASCVD, with DM and

baseline LDLc 70-189 mg/dl

on statin for primary

prevention

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Patients with clinical

ASCVD with

comorbidities on statin

for secondary prevention

Patients with diabetes need to look beyond LDL C for better cardiovascular

risk factor stratification as they often have elevated triglycerides, non-HDL

cholesterol/LDL P

PCSK9 inhibitors reduce LDL cholesterol and have favorable safety profile

LDL-C reductions in those with diabetes were similar to those without

diabetes

PCSK9 inhibitors lower non HDL cholesterol , Lp(a) and may be an important

tool in reducing residual risk

All trials of PCKS9 inhibitors have been conducted on top of baseline statin

therapy

PCSK9 inhibitors do not yet have CV outcome data to support their use in

diabetes for primary prevention

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Thanks for

your patience,

dear colleagues!