Soebagijo Adi S Endocrine & Metabolic Division – Dep. Of Internal Medicine

Faculty of Medicine Airlangga University Dr. Soetomo General Academic Hospital - Surabaya

Dyslipidemia in Diabetes, Applicability of Recent Guidelines to

Achieve Primary and Secondary Target

WS 3.2

Shamiri M, Ghanaim MMA,..Santoso A,.. et al Int J Gen Med 2018; 11: 313 - 22

Proportion of Dyslipidemia is High in Indonesia Especially High LDL-C (83%)

Dyslipidemia is very common in Diabetes

DDM = Diagnosed Diabetes Mellitus

UDDM = Undiagnosed diabetes Mellitus

IGT = Impaired Glucose Tolerance

NGT = Normal Glucose Tolerance

NDDM = Newly Diagnosed Diabetes Mellitus

Lipid profile of DM patients in productive aged urban Indonesia1

1. Mihardja L, et al. J Diabetes Invest 2014; 5: 507–512

2. Soebardi S, et al. Acta Med Indonesia 2009; 41: 186-190

2

• In Indonesia, Dyslipidemia in individuals with type 2 diabetes is very common, with a prevalence of 80–90%

• This phenomenon is associated with a significantly increased risk of coronary artery disease relative to

individuals without diabetes

More Severe Atherosclerosis in Diabetes: Atherosclerotic Diabetic Dyslipidemia (ADD)

Atherosclerotic plaques in the presence of diabetes generally have increased calcification, necrotic cores, receptors for advanced glycosylation endproducts (RAGE), and macrophage and T-cell infiltration. These features can potentially contribute to the more severe atherosclerosis and a higher incidence of acute adverse events.

Faxon DP, et al.Circulation.2004;109(21):2617-25

UKPDS: LDL-C is a very strong predictor of CHD risk in patients with diabetes

Relation of lipid risk factors* to CHD in 2693 patients with diabetes

Turner RC et al. BMJ. 1998;316:823-8.

0.0

0.5

1.0

1.5

2.0

2.5

<189

189-223

>223

Total cholesterol

P<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

<117

117-150

>150

LDL-C

P<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

<108

108-166

>166

Triglycerides

P<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

<37

37-44

>44

HDL-C

P<0.0001

Ha

za

rd r

ati

o

Lipid tertiles (mg/dL)

*Age- and sex-adjusted.

Cardiovascular Disease is The Most Common Cause of Death Among Patients With Diabetes

Geiss LS, et al. Mortality in non-insulin-dependent diabetes. In: Diabetes in America. 2nd ed. Bethesda, Md: National Institute

of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; 1995:233-257. NIH Publication No. 95-1468.

Unadjusted CVD and CHD event rates per 1,000 person-years for subjects with DM, by the number of risk factors at target levels A HbA1c target : 7% B BP target : 130/80 mmHg C LDL-C target : 100 mg/dL

Multifactorial Intervention (A, B, C)

Improves Cardiovascular Outcomes in T2DM

Pooling of ARIC, MESA, and JACKSON Heart Studies

With All 3 Risk Factors Controlled • 62% lower of CVD Events • 60% lower of CHD Events

Wong ND, et al. Diabetes Care. 2016;39:668-676

Intensive therapy†:

Microalbuminuria with ACEIs, ARBs, or combination

Hypertension

Hyperglycaemia

Dyslipidaemia

Secondary prevention of CVD

Conventional treatment was in accordance with national guidelines

STENO-2 Study Intensive MRF management significantly reduces risk of CV events

Adapted from Gaede P et al. N Eng J Med. 2003;348:383-393.

Pri

mar

y co

mp

osi

te e

nd

po

int*

(%

)

MRF: Multiple risk factor

Multiple risk-factor intervention study comparing conventional vs intensive treatment of risk factors in a high-risk population with type-2 diabetes

Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%). *Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease; †Behavior modification and pharmacologic therapy

0

Months of follow-up

N=160; follow-up = 7.8 years P=0.007

12 24 36 48 72 96 60 84

20% absolute risk reduction

0

10

20

30

40

50

60 Conventional therapy Intensive therapy†

Intensive therapy:

Dyslipidemia

Lipid-Lowering Therapy Accounted for>70% of CV Risk Reduction in Type 2 Diabetes

Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.

Multifactorial therapy in type 2 DM , to achieve :

BP <130/80, HbA1c < 6.5%, total cholesterol < 175 mg/dL

Steno 2-Study

The most of the CV benefit was attributable to the use of lipid-lowering therapy

Which are the primary target in managing dyslipidemia?

↓ Total-cholesterol ?

↓ LDL-cholesterol ?

↑ HDL-cholesterol ?

↓ Triglyceride ?

3 Requirement Have To Fulfill To Be a Primary Target Dyslipidemia:

1. Patogenesis 2. Epidemiologi 3. Studi Klinis Acak

LDL-C, HDL-C, maupun TG berperan dalam patogenesis

terbentuknya plak aterosklerosis

LDL-C, HDL-C, maupun TG berhubungan dengan

morbiditas dan mortalitas PJK di tingkat populasi

• LDL-C: Penurunan LDL-C Penurunan risiko kardiovaskular

• TG: Hanya menurunkan risiko kardiovaskular bagi pasien dengan LDL-C yang rendah

• HDL-C: Meningkatkan HDL-C tidak menurunkan risiko kardiovaskular

Barter P. Eur Heart J 2004; 69(suppl 6):A19-A22 1. Ballantyne CM. Am J Cardiol. 1998;82:3Q–12Q., 2. The FIELD study investigators. Lancet. 2005;366:1849-61

1. Assman G. Am J Cardiol. 2001;87(suppl):2B-7B 2. Gordon T et al. Am J Med . 1977;62:707-714

Lipid Modification Clinical Benefit

↓ LDL-C √√

↓ Triglycerides √

↑ HDL-C X

LDL-C is The Primary Target to Focus in Dyslipidemia

Primary target: LDL-C

Secondary target: non-HDL-C (TC – HDL-C)

Not a target: HDL-C

PERKENI,2015

Alur ACC/AHA

Lipid Management According To ACC AHA 2018

Top 10 Take Home Messages To Reduce Risk of ASCVD Through Lipid Management

Top 10 Take Home Messages To Reduce Risk of ASCVD Through Lipid Management

Top 10 Take Home Messages To Reduce Risk of ASCVD Through Lipid Management

Top 10 Take Home Messages To Reduce Risk of ASCVD Through Lipid Management

ACC/AHA 2018: Primary prevention

Ten-Year ASCVD Risk

ADA 2019: Recommendations for Statin and Combination Treatment in Adults With Diabetes

Lower LDL-C is Better:

AACE 2017 Guideline Highlights More Stringent LDL-C Target

Kheloussi S,et al.US Pharm. 2018;43(7)22-26.

ESC 2019: New LDL-C target across CV risk categories

1. Mach F, et al. European Heart Journal (2019) 00, 1-78

ESC 2019 : High intensity statin is recommended as 1st line therapy (Class IA)1

1. Mach F, et al. European Heart Journal (2019) 00, 1-78

ESC 2019: Recommendations for the treatment of dyslipidemia in diabetes mellitus

ESC 2019 : Recommendations for the treatment of dyslipidaemias in older people (aged >65 years) 1

1. Mach F, et al. European Heart Journal (2019) 00, 1-78

ESC 2019: Emphasize on statin safety

1. Mach F, et al. European Heart Journal (2019) 00, 1-78

Donald M. Lloyd-Jones DM, et al. JACC. 2016;68:92-125

Statin Selection

Third Generation Statin Highest-Potency Generation of Statins

Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353

Crestor®: Superior efficacy start from low dose 5 mg

Karlson BW, et al. European Heart Journal – Cardiovascular Pharmacotherapy (2016) 2, 212–217

-41%

-35%

-33%

Crestor 5mg Atorvastatin 10mg Simvastatin 20mg

LDL-

C r

edu

ctio

n f

rom

bas

elin

e (

%)

Relative efficacy of statin-based therapies in LDL-C reduction2

Crestor is 3rd generation statin, the most potent statin to reduce LDL-C3

2. Adapted from FDA drug safety communication. Available in https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm 3. Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353

Crestor® showed superior efficacy in improving overall lipid profile as compared to other statin

Greater Reduction of LDL-C Level with Rosuvastatin vs. Atorvastatin in Patients with Diabetes

*p<0.0001 vs ATV; †p≤0.001 RSV 10 mg vs ATV 10 mg, and RSV 20 mg vs ATV 20 mg; ‡p<0.05 vs ATV; ‡‡p<0.01 vs ATV

Adapted from: 1. Berne C, Siewert-Delle A. Cardiovasc Diabetol 2005; 4: 7

2. Betteridge DJ et al. Diabet Med 2007; 24: 541–549 3. Wolffenbuttel B et al. J Intern Med 2005; 257: 531–539

ATP III = Adult Treatment Panel III; LDL-C = low density lipoprotein -cholesterol.

Adapted from Ballantyne CM,et al. Am Heart J. 2006;151:975.e1-975.e9

Switching to Rosuvastatin Significantly Helps More Diabetes Patients Achieve LDL-C Goal (MERCURY II STUDY)

CRESTOR 20 mg monotherapy lowers LDL-C as effectively as atorvastatin 20 mg/10 mg ezetimibe Comparison of percent reduction in LDL-C from baseline from 5 different studies

1. Olsson AG, et al. Cardiovasc Durg Rev. 2001;20(4):303-28 2. Goldberg AC, et al. Mayo Clin Proc. 2004;79:620-629

3. Ballantyne CM, et al. Circulation. 2003;107(19);2409-15 4. Kosoglou T, et al. Curr Med Res Opin 2004;20(8)

5. Ballantyne CM, et al. Am J Cardiol 2007;99:673-680

JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death

Intensive LDL-C Reduction Related to Plaque Stabilization to reduced CV morbidity & Mortality

Placebo

Rosuvastatin (CRESTOR)

HR 0.56, 95% CI 0.46-0.69 P < 0.00001

- 44 %

0 1 2 3 4

0.0

2

0.0

4

0.0

6

0.0

8

Cu

mu

lati

ve In

cid

ence

Follow-up (years)

0.0

0

Ridker et al, N Engl J Med. 2008;359:2195-207 Only in a few months

Rosuvastatin is a Hydrophilic Statin and Not Metabolized by CYP3A4 Less Prone To Drug Interactions & Rhabdomyolysis

Ramosevac AC, et Al. Acta Pharm 2013

KDIGO 2013: Adjusment Dose Apply To All Statins, Including Atorvastatin

KDIGO, ISN 2013.

Intensive LDL-C-Lowering Treatment with Rosuvastatin Does Not Affect the Risk of Developing Renal Insufficiency or Renal Failure in Patients Who Do Not Have Advanced, Pre-existing Renal Disease

Stein EA, et al. Atherosclerosis 2012.

Summary

• Type 2 diabetes is associated with a marked increase in the risk of atherosclerotic cardiovascular disease.

• Treatment initiation (and initial statin dose) is now driven primarily by risk status rather than LDL cholesterol level

• LDL-C is the primary target of lipid-lowering therapy in patients with diabetes & newest dyslipidemia guideline recommend more aggressive LDL-C target to reduce CV risk

• High intensity statin is recommended as 1st line therapy to be added to lifestyle therapy

• Rosuvastatin is proven as the most potent statin among different patient profile including diabetes with excellent safety