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Diabetes and Lipids

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•Should we be checking LDL (or other lipid fractions)?

•What is the normal range?•Is there an upper limit to the range?•Is there a lower limit to the range?•What are the targets in people with diabetes? What should the targets be?

•Is the cholesterol hypothesis proven?•Hypothesis or fact?

With respect to (LDL) cholesterol….

Learning objectives:• Review the importance of statins to lower CV risk in

diabetes

• To review lipid guidelines (Canadian and American) as they

pertain to diabetes

• Is lower better (at least for diabetes)?

– To review results with Ezetemibe and PCSK9 inhibitors

• Are studies with these drugs going to impact guidelines?

• Does glycemic control matter wrt lipids/targets?

• To review where triglyceride management might fit in

• Is statin intolerance real? Does it matter?

• Do statins cause diabetes? Does it matter?

• Small interfering RNA

• Etc…..

Slide Source:

Lipids Onlinewww.lipidsonline.org

1.0

0.9

0.8

0.7

0.6

0.5

0

Proportion w

ithout

Majo

r CH

D E

vent

Years Since Randomization

0 1 2 3 4 5 6

Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620.

Diabetes by Hx, simvastatin

Diabetes by Hx, placebo

No diabetes by Hx, simvastatin

No diabetes by Hx, placebo

P=0.002

P=0.0001

Major Coronary Events in 4S Patients with Major Coronary Events in 4S Patients with

or without Diabetes by History (n=202)or without Diabetes by History (n=202)

placebo

Atorva 10

CARDS

TNT: Diabetes Subgroup

With DMThere is no question that treating diabetics

with statins lowers CV risk.

With DMThe resulting lower risk achieved still

exceeds non-diabetics

With DMThere does not seem to be a LDL below

which risk does not continue to drop

Learning objectives:

• Review the importance of statins to lower CV risk in

diabetes


pertain to diabetes








• Etc…..

Should every diabetic be treated with a statin?

USA guidelines: how do they compare?

• ≥40 yrs old or

• Macrovascular disease or

• Microvascular disease or

• DM >15 yrs duration and age >30 yrs or

• Warrant therapy based on (other) Canadian

Cardiovascular Society lipid guidelines

2013Who Should Receive Statins?

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

If on therapy, target

LDL ≤2.0 mmol/L

(77.2 mg/dL)

USA guidelines: how do they compare?

25

A New Perspective on LDL-C and Non-HDL-C goals

“The expert panel was unable to find RCT evidence

to support continued use of specific LDL-C and/or

non-HDL-C treatment targets”

Slide Source:


1.0

0.9

0.8

0.7

0.6

0.5

0

Proportion w

ithout

Majo

r CH

D E

vent

Years Since Randomization

0 1 2 3 4 5 6

Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620.

Diabetes by Hx, simvastatin

Diabetes by Hx, placebo

No diabetes by Hx, simvastatin

No diabetes by Hx, placebo

P=0.002

P=0.0001

Major Coronary Events in 4S Patients with Major Coronary Events in 4S Patients with

or without Diabetes by History (n=202)or without Diabetes by History (n=202)

CARDS

placebo

Atorva 10

NEJM 350;15 April 8 2004

TNT: Diabetes Subgroup

30





“… 4 major statin benefit groups were identified for

whom the ASCVD risk reduction clearly outweighs

the risk of adverse events….3) diabetes aged 40-75

years with LDL-C 70-189 mg/dl and without ASCVD”

31





“… 4 major statin benefit groups were identified for

whom the ASCVD risk reduction clearly outweighs

the risk of adverse events….3) diabetes aged 40-75

years with LDL-C 1.75 – 4.72 mmol/L and without

ASCVD”

• “The difficulty of giving up the treat to goal paradigm was deliberated extensively over a 3-year period”

• “Use of LDL-C targets may result in

– under-treatment with evidence based statin therapy

Mr. M. S., age 58, diabetic

TC: 4.0 mmol/L (155 mg/dl)

HDL: 1.1 mmol/L (42 mg/dl)

LDL: 2.4 (96 mg/dl)

Triglyceride: 2.2 mmol/L (200 mg/dl)

A1c: 6.9%

Are his lipids optimally controlled?

Should you add more statin?

Would more information help?

Meds include Metformin 1 gm bid, Ramipril10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg

Scenario 1

41



HDL: 1.24 mmol/L (49.6 mg/dl)

LDL: 1.7 mmol/L (68 mg/dl)


A1c: 6.9%

Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 20 mg.


Scenario 2

42

Mr. M. S., age 58, diabeticMeds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 20 mg. Had an MI 6 mos ago


Scenario 3


HDL: 1.24 mmol/L (49.6 mg/dl)



A1c: 6.9%

43



HDL: .9 mmol/L (35 mg/dl)



A1c: 6.9%

Meds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 80 mg. Had MI 6 mos ago


Scenario 4

44






A1c: 6.9%



Would you decrease the statin?

Scenario 4

45






A1c: 6.9%




Would LESS information help?

Scenario 4

46


TC: 2.4 mmol/L (96mg/dl)


LDL: 1.0 mmol/L (40mg/dl)


A1c: 6.9%


Scenario 4



Would LESS information help?

• “The difficulty of giving up the treat to goal paradigm was deliberated extensively over a 3-year period”

• “Use of LDL-C targets may result in

– under-treatment with evidence based statin therapy

Media, internet, print, etc



diabetes


pertain to diabetes








• Etc…..

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

A Multicenter, Double-Blind, Randomized Study to

Establish the Clinical Benefit and Safety of Vytorin

(Ezetimibe/Simvastatin Tablet) vs Simvastatin

Monotherapy in High-Risk Subjects Presenting

With Acute Coronary Syndrome

53

Patients stabilized post ACS ≤ 10 days:

LDL-C 1.3-3.2 mmol/L (1.3–2.6 mmol/L if prior lipid-lowering Rx)

Standard Medical & Interventional Therapy

Ezetimibe / Simvastatin

10 / 40 mg

Simvastatin

40 mg

Follow-up Visit Day 30, every 4 months

Duration: Minimum 2 ½-year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA,

coronary revascularization (≥ 30 days after randomization), or stroke

N=18,144

Uptitrated to

Simva 80 mg

if LDL-C > 2.05

(adapted per

FDA label 2011)

Study Design

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

90% power to detect

~9% difference

54

LDL-C and Lipid ChangesM

ean

LD

L-C

(m

mol/

L)

1.0

1.25

1.5

1.75

2.0

2.25

2.5

QE R 1 4 8 12 16 24 36 48 60 72 84 96

Time since randomization (months)Number at risk:

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 1.81 3.75 1.55 1.24 3.8 mg/dl

EZ/Simva 1.38 3.25 1.36 1.26 3.3 mg/dl

Δ in mmol/L -0.43 -0.50 -0.19 +0.2 -0.5mg/dl

55

LDL-C and Lipid ChangesM

ean

LD

L-C

(m

mol/

L)

1.0

1.25

1.5

1.75

2.0

2.25

2.5

QE R 1 4 8 12 16 24 36 48 60 72 84 96

Time since randomization (months)Number at risk:

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 70 145 1.55 1.24 3.8 mg/dl

EZ/Simva 53 126 1.36 1.26 3.3 mg/dl

Δ in mg/dl -17 -19 -0.19 +0.2 -0.5mg/dl

56

Simva — 22.2%

1704 events

EZ/Simva — 20.4%

1544 events

HR 0.90 CI (0.84, 0.97)

p=0.003

NNT= 56

CV Death, Non-fatal MI, or Non-fatal Stroke

7-year event rates

Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015

Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015Unpublished

Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. Supplementary Appendix.

Giugliano et al. Hotline sessions, ESC2015, London, UK, August 30thth 2015

Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. Supplementary Appendix.

LDL Receptor Function and Life Cycle

61 61

For illustration purposes only

The Role of PCSK9 in the Regulation of LDL Receptor Expression

62


Impact of PCSK9 inhibitors on LDL Receptor Expression

63 63


-8.5% (2.9)

-13.5%(3.2)

-8.6%(2.9)

-14.0%(4.2)

-7.4%(2.8)

-14.7%(3.8)

-69.7%(2.4)

-66.4%(2.9) -68.4%

(2.5)

-68.1%(4.2)

-69.2%(2.7)

-66.9%(3.0)

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

Pooled Results: % Change from Baseline in LDL-C at

Week 8/12 by Baseline LDL-C, non-HDL-C and Apo B

64

LS

me

an

(S

E)

% c

ha

ng

e in

LD

L-C

Le

ve

l

at

we

ek

8/1

2 L

OC

F

Baseline LDL-C

subgroup

Baseline non-HDL-C

subgroup

≤3.36 mmol/L <4.3 mmol/L ≥4.3 mmol/L>3.36 mmol/L

n=43 n=66 n=32 n=49 n=26n=38 n=77 n=27

Baseline Apo B

subgroup

<1.1 g/L ≥1.1 g/L

n=46 n=28n=59 n=44

Placebo

Alirocumab

150 mg Q2W

≤130 mg/dL <166 mg/dL ≥166 mg/dL>130 mg/dL <110 mg/dL ≥110 mg/dL

Cut-offs for LDL-C (3.36 mmol/L, 130 mg/dL) and non-HDL-C (4.3 mmol/L, 166 mg/dL) based on thresholds for starting therapy in patients at, respectively, moderate/moderately high cardiovascular (CV) risk in the most

recent US cholesterol management (ATP III) guidelines1 and intermediate CV risk in the 2012 Canadian dyslipidemia guidelines2. Cut-off for Apo B (1.1 g/L, 110 mg/dL) based on value derived by regression analysis

from consensus target LDL-C and non-HDL-C values3 and threshold for initiatiing therapy in intermediate-risk patients in the 2012 Canadian guidelines2. 1. Grundy et al. Circulation. 2004;110:227-239. 2. Anderson et al.

Can J Cardiol. 2013;29151-167. 3. Soran et al. Ann Clin Biochem 2011;48[Pt6]:566-571. Data pooled from mITT population of studies 1003 (NCT01266876), 11565 (NCT01288443), and 11566 (NCT01288469).

i.e., MACE

Adverse events were NOT more common if LDL was VERY lowUnpublished data



diabetes


pertain to diabetes








• Etc…..

1.42

1.81

2.58

2.07

2.58

3.37



diabetes


pertain to diabetes








• Etc…..

Does glycemic control affect

the function of lipids?

If it does, then should the degree of

glycemic control affect our

recommendations for treating the

lipids?

Slide Source:


LDL

LDL

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

Endothelium

Vessel Lumen

Monocyte

Modified LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

Inhibition of Adhesion Molecules

Intima

Foam Cell

HDL and “Anti-Atherosclerosis”

Slide Source:


LDL

LDL

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

Endothelium

Vessel Lumen

Monocyte

Modified LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

Inhibition of Adhesion Molecules

Intima

HDL InhibitOxidation

of LDL

HDL Inhibits Chemotaxis and inhibits Adhesion Molecule Expression

Foam Cell

HDL Promote Cholesterol Efflux

HDL and “Anti-Atherosclerosis”

91

Presented at ADA San Diego

2011

95

Mean A1c 7.6%

Glycated LDL and HDL

•Glycemic control may play a role in how atherogenic the lipoproteins may be

•Guidelines don’t specifically recommend it, but if you have someone with an A1c of 6.5% vs A1c of 8.5%, you might choose to be more aggressive treating the lipids of the latter.

•Some Type 1’s have HDL of 2 or more. If their A1c is 10%, do we care? Is the HDL doing anything? At what point are we assured?

Summary and conclusions• Statins lower CV risk in essentially all diabetics.

– The use of statins should be guided by perceived CV risk, as per guidelines (which guidelines???)

– Lifetime risk should also be considered

• Correct LDL first

• In people in whom you cannot decide, measuring an apoB, non-HDL might provide further information

Summary and conclusions: cont’d

• The addition of Ezetemibe to statin with subsequent lowering of LDL does lower risk more (at least in diabetics)

• Targets are changing (at least in the US) in view of IMPROVE-IT and FOURIER

• PCSK9 inhibitors …..

•Should we be checking LDL (or other lipid fractions)?

•What is the normal range?•Is there an upper limit to the range?•Is there a lower limit to the range?•What are the targets in people with diabetes? What should the targets be?

•Is the cholesterol hypothesis proven?•Hypothesis or fact?

With respect to (LDL) cholesterol….

Learning objectives:• Review the importance of statins to lower CV risk in

diabetes


pertain to diabetes








• Small interfering RNA

• Etc…..




LDL: 1.42mmol/L (55 mg/dl)


A1c: 6.9%




Should you add a fibrate?






A1c: 6.9%





Mr. M. S., age 58, diabeticMeds include Metformin 1 gm bid, Ramipril10 mg, Metoprolol 50 mg bid and Atorvastatin 10 mg








apoB: .94

Mr. M. S., age 58, diabeticMeds include Metformin 1 gm bid, Ramipril 10 mg, Metoprolol 50 mg bid and Atorvastatin 80 mg








apoB .79

BIP: Effects of baseline Triglycerides

on response to treatment

Circulation, 2000;102:21-27

Characteristic

Placebo

(n = 4900)

Fenofibrate

(n = 4895)

Male, % 63 63

No Prior CVD, % 78 78

Lipid parameters, mg/dl (mmol/L)

TC 194 195

LDL-C 119 (3.07) 119 (3.07)

HDL-C 42 (1.1) 42 (1.1)

TG 153 (1.73) 154 (1.74)

Dyslipidemic*, % 37 39

Baseline Characteristics

*TG >150 (1.7) and HDL <40 mg/dL (1.03) for men or <50 mg/dL (1.29) for women

The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Lipid Goals for Individuals at Risk for ASCVD

Lipid parameter Goal (mg/dL)

TC <200

LDL-C <130 (low risk)

<100 (moderate risk)

<100 (high risk)

<70 (very high risk)

<55 (extreme risk)

Non–HDL-C 30 above LDL-C goal; 25 above LDL-C goal (extreme risk individuals)

TG <150

Apo B <90 (individuals at high risk of ASCVD, including those with diabetes)

<80 (individuals at very high risk with established ASCVD or diabetes plus

≥1 additional risk factor)

<70 (individuals at extreme risk)

Abbreviations: apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

AACE/ACE 2017;epub ahead of print; Baigent C, et al. Lancet. 2010;376:1670-1681; Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):485-494; Brunzell JD, et al. Diabetes Care. 2008;31:811-822; Cannon CP, et al. N Engl J Med. 2015;372(25):2387-2397; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Ridker PM, J Am Coll Cardiol. 2005;45:1644-1648; Sever PS, et al. Lancet. 2003;361:1149-1158; Shepherd J, et al. Lancet. 2002;360:1623-1630; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):1307-1315.

Question: How are different drugs used to treat dyslipidemia? Statins, Fibrates

Statins

• R56. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of morbidity and mortality outcome trials (Grade A; BEL 1).

• R57. For clinical decision making, mild elevations in blood glucose levels and/or an increased risk of new-onset T2DM associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction (Grade A, BEL 1).

• R58. In individuals within high-risk and very high-risk categories, further lowering of LDL-C beyond established targets with statins results in additional ASCVD event reduction and may be considered (Grade A, BEL 1).

• R59. Very high-risk individuals with established coronary, carotid, and peripheral vascular disease, or diabetes, who also have at least 1 additional risk factor, should be treated with statins to target a reduced LDL-C treatment goal of <70 mg/dL (Grade A, BEL 1).

• R60. Extreme risk individuals should be treated with statins or with combination therapy to target an even lower LDL-C treatment goal of <55 mg/dL (Grade A, BEL 1).

Fibrates

• R61. Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dL) (Grade A; BEL 1).

• R62. Fibrates may improve ASCVD outcomes in primary and secondary prevention when TG concentrations are 200 mg/dL and HDL-C concentrations <40 mg/dL (Grade A; BEL 1).

•R55. In individuals at risk for ASCVD, aggressive lipid-modifying therapy is recommended to achieve appropriate LDL-C goals (Grade A, BEL 1).

Re

com

me

nd

ati

on

s a

sso

cia

ted

wit

h t

his

q

ue

stio

n:

Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497.

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;

TG, triglycerides.

Summary and conclusions: cont’d

• Most guidelines around the world are coming around to the same conclusion, i.e., that in the presence of atherogenic dyslipidemia, there is reasonable evidence that fibrates decrease CV risk

• (Gemfibrozil should not be used with a statin)

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