Dyslipidemia in Diabetes, Applicability of Recent ... Soebagijo Adi - Dyslipedemia in Diabetes.pdfBP

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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

• 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.

189-223

Total cholesterol

P<0.0001

117-150

P<0.0001

108-166

Triglycerides

P<0.0001

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.

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

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

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

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

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

ESC 2019: Emphasize on statin safety

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

Crestor 5mg Atorvastatin 10mg Simvastatin 20mg

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

Follow-up (years)

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

Dyslipidemia in Diabetes, Applicability of Recent ... Soebagijo Adi - Dyslipedemia in Diabetes.pdfBP

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