Diabetic dyslipidemic patients

Insights In The Recent Guidelines of Management of Diabetic Dyslipidemic Patients

BY ASHRAF OKBA

PROF.OF INTERNAL MEDICINE AIN SHAMS UNIVERSITY

Cairo -Egypt

1- http://www.diabetesprevention.pitt.edu/index.php/for-the-public/diabetes-and-related-conditions/cardiovascular-disease/last access 25/5/2015

2-J Am Coll Cardiol. 2007 May 15;49(19):1918-23. Epub 2007 Apr 30.Noninvasive screening for coronary atherosclerosis and silent ischemia in asymptomatic type 2 diabetic patients: is it appropriate and cost-effective?Beller GA1.et al

Diabetes and CVD

Adults with diabetes are 2-4 times more

likely to develop CVD than people without

diabetes(1) Coronary artery disease (CAD) accounts for 65% to 80% of deaths in diabetic patients(2)

East West Study: Patients with Diabetesat Similar Risk to No Diabetes with MI

0

10

20

30

40

50

7-ye

ar in

cide

nce

rate

of

MI

(%)

No prior MIMI

p<0.001

p<0.001

No diabetes (n=1373) Diabetes (n=1059)

Adapted from Haffner SM et al. N Engl J Med 1998;339:229–234

What types of lesions cause MI ?

Falk E, et al. Circulation. 1995;92:657-671.

100

80

60

40

20

0

14%

18%

68%

All fourstudies

50%-70%<50% >70%

100

60

40

20

0Ambrose

1988Little1988

Nobuyoshi1991

Giroud1992

Coro

nary

sten

osis

(%)

Coronary stenosis severity prior to MI

80

4www.drsarma.in

Not the degree of stenosis

Years after DM Diagnosis

≤ 2 3-5 6-9 10-14 15+

15%

21%24%

29%

48%

Harris, S et al.; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load. CDA 2003.

Duration of T2DM and CVD

5

Duration of DM - CV Mortality

0

0.5

1

1.5

2

2.5

3

3.5

4

< 5 6 to 10 11 to 15 16 to 25 26 +

Duration of Diabetes (years)

p for trend <0.001

Cho, et al. J Am Coll Card 2002:40:954.

Rel

ativ

e R

isk

6

Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.

Women, Diabetes, and CHD• Diabetic women are at high risk for CHD• Diabetes eliminates relative cardioprotective

effect of being premenopausal– Risk of recurrent MI in diabetic women is

three times that of nondiabetic women• Age-adjusted mean time to recurrent MI or

fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women

Predisposition to thrombosis - Atherogenic Diabetic Dyslipidemia - Platelet hyper-aggregability - Elevated concentrations of pro-coagulants - Decreased concentration and activity of

antithrombotic factors Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of 2-antiplasmin

Imbalance Between Thrombosis and Fibrinolysis in Subjects with Diabetes

Sobel BE. Circulation 1996;93:1613-1615.

ADD, Atherogenic Diabetic Dyslipidemia

Large LDL Small Dense LDL

Apo B LDL-C

130 mg/dL

Fewer Particles &Less Risk/Particle

More Particles &More Risk/Particle

More Apo-B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dLNon–HDL-C148 mg/dL

TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dLNon–HDL-C180 mg/dL

Same LDL-C Levels, Different Cardiovascular Risk.

Lipid ProfileLipid Profile

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD Potential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.Lamarche B et al. Circulation. 1997;95:69-75.

Significance of Small, Dense LDL• Low cholesterol content of LDL particles

– particle number for given LDL-C level• Associated with levels of TG and LDL-C, and

levels of HDL2

• Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B)

• Possible mechanisms of atherogenicity– greater arterial uptake– uptake by macrophages– oxidation susceptibility

SMC=smooth muscle cell.Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.

Potential Mechanisms of Atherogenesis in Diabetes

• Abnormalities in apoprotein and lipoprotein particle distribution

• Glycosylation and advanced glycation of proteins in plasma and arterial wall

• “Glycoxidation” and oxidation

• Procoagulant state

• Insulin resistance and hyperinsulinemia

• Hormone-, growth-factor–, and cytokine-enhanced SMC proliferation and foam cell formation

DM = CAD - Because• CVD is responsible for 60 - 75% of mortality in T2DM

• CVD is 4 times more prevalent in diabetes; CADI is more

• CVD prevalence increases with age, so is T2DM

• CVD in DM is often severe, silent, poor prognosis and fatal

• Diabetes ↑ mortality, 50% pre adm / recurrent MI and ACS

• Diabetes erases the protection conferred to women

• At diagnosis of T2DM, most patients have evidence of CVD

• Abnormal Glucose tolerance is a strong CV Risk factor

14

Case Study• 49-year-old white man with a history of type 2 diabetes,

obesity and hypertension.• Non smoker

• weight fluctuating between 75 and 83 Kg.

• Most recent hemoglobin A1c of 7.4%.

• Hypertension was diagnosed 5 years ago 160/90 mmHg, treated with Enalapril, starting at 10 mg daily and increasing to 20 mg daily, yet his BP control has fluctuated.

Case Study

• The man comes into the office today for his usual follow-up visit for diabetes.

• Physical examination reveals an obese man with a BP of 154/86 mmHg and a pulse of 78 bpm.

• Total cholesterol : 180 mg/dl• LDL-c:101 mg/dl• HDL: 35 mg/dl• TG:220 mg/dl

Intensity of Statin Therapy

High-Intensity Statin Therapy Moderate-Intensity Stain Therapy

Low-Intensity Statin Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Atorvastatin (40†)–80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg‡ Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg

Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use of cholesterol lowering drug therapies. Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

ADA 2015 guidelines Recommendations for Statin Treatment in People with Diabetes

Age Risk factors Recommended statin dose*

Monitoring with lipid panel

<40 years

None NoneAnnually or as needed to monitor for adherence

CVD risk factor(s)** Moderate or high

Overt CVD*** High

40–75 yearsNone Moderate

As needed to monitor adherenceCVD risk factors High

Overt CVD High

>75 years

None Moderate

As needed to monitor adherenceCVD risk factors Moderate or high

Overt CVD High

* In addition to lifestyle therapy. ** CVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, and overweight and obesity. *** Overt CVD includes those with previous cardiovascular events or acute coronary syndromes.

ADA. 8. Cardiovascular Disease and Risk Management. Diabetes Care 2015;38(suppl 1):S52, Table 8.1

2013 ACC/AHA Cholesterol Treatment Guideline Recommendations

20

Focus on ASCVD Risk Reduction: 4 statin benefit groups*

21Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

Clinical ASCVD† LDL-C level ≥190 mg/dL

Diabetes, aged 40-75 years, with LDL-C 70-189

mg/dL

Estimated 10-year risk of ASCVD of ≥7.5%,‡ 40-75

years of age, and with LDL-C 70-189

mg/dL

* Moderate- or high-intensity statin therapy recommended for these 4 groups

† Clinical ASCVD defined as acute coronary syndromes, history of MI, stable or unstable angina, coronary or arterial revascularization, stroke, transient ischemic attacks, or peripheral artery disease‡ Estimated using Pooled Cohort Risk Assessment Equations

Primary Prevention

* Estimated using Pooled Cohort Risk Assessment Equations

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

Moderate-Intensity Statin

Patients with Diabetes and LDL-C 70-189 mg/dL

(age 40-75 years) without clinical ASCVD

High-Intensity Statin if ≥7.5% estimated 10-year ASCVD risk*

ADA 2016 Guidelines

27

Efficacy + SafetyCardio protection+

A Complex Equation and a Simple Solution

The CORALL StudyChange in LDL-C with Rosuvastatin and Atorvastatin in High-Risk Patients

–54–60

–50

–40

–30

–20

–10

–46–51

–41–46

–48

0

Rosuvastatin

Atorvastatin

6 weeks 10 mg 20 mg

12 weeks 20 mg 40 mg

18 weeks 40 mg 80 mg

n=130 n=132 n=130 n=132 n=130 n=132

****

Mean change

from baseline

(%)

*p<0.05vs ATV, **p<0.01 vs ATVWolffenbuttel BHR et al. J Int Med 2005; 257: 531–539

Effects of rosuvastatin versus atorvastatin on small dense low-density lipoprotein:

a meta-analysis of randomized trials.

28 prospective randomized controlled clinical trials of Rosuvastatin versus Atorvastatin therapy.

In total, the meta-analysis included data on 7802 patients randomized to therapy with rosuvastatin or atorvastatin.

Hisato Takagi • Masao Niwa • Yusuke Mizuno •Hirotaka Yamamoto • Shin-nosuke Goto •Takuya Umemoto Heart Vessels (2014) 29:287–299 DOI 10.1007/s00380-013-0358-6

Pooled analysis of the 28 trials:

Demonstrated a statistically significant reduction in final sdLDL levels with rosuvastatin relative to atorvastatin therapy ; P-value = 0.0001.

Results

33

Efficacy + SafetyCardio protection+

A Complex Equation and a Simple Solution

Cumulative Incidence of the Primary Endpoint According to Baseline IFG Status

Impaired Fasting Glucose Normal Fasting Glucose

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

0.10

Cum

ulati

ve In

cide

nce

Placebo

Rosuvastatin

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

0.10

Cum

ulati

ve In

cide

nce

Placebo

Rosuvastatin

Follow-Up (years) Follow-Up (years)

HR 0.69 (0.49-0.98), p=0.037

JUPITER – Impaired Fasting Glucose (IFG) Subgroup Data

Pradhan A et al. Circulation 2009; 120 (Suppl): S500; Abs 1425

HR 0.51 (0.40-0.67), p<0.0001

31% 49%

37

Efficacy + SafetyCardioprotection+

A Complex Equation and a Simple Solution

ALT >3 × ULN: Frequency by LDL-C reduction1,2

Persistent elevation is elevation to >3 x ULN on two successive occasions

1. Brewer H. Am J Cardiol 2003; 92(Suppl): 23K–29K2. Davidson M. Exp Opin Drug Saf 2004; 3: 547–557

Rosuvastatin Safety – Liver Effects

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Fluvastatin (20, 40, 80 mg)

Rosuvastatin (5, 10, 20, 40 mg)

Lovastatin (20, 40, 80 mg)

Atorvastatin (10, 20, 40, 80 mg)Simvastatin (40, 80 mg)

Occ

urre

nce

of A

LT >

3×U

LN (%

)

Rosuvastatin Safety – Muscle Effects CK >10 x ULN: Frequency by LDL-C Reduction1,2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Occ

urre

nce

of C

K >1

0 ×

ULN

(%)

Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (5, 10, 20, 40 mg)

Pravastatin (20, 40 mg)

Atorvastatin (10, 20, 40, 80 mg)Simvastatin (40, 80 mg)

1. Brewer H. Am J Cardiol 2003; 92(Suppl): 23K–29K2. Davidson M. Exp Opin Drug Saf 2004; 3: 547–557

Effects of Atorvastatin and Rosuvastatin on renal function: A meta-analysis

Author: G. Savarese et al. Publication: International Journal of Cardiology 167 (2013) 2482–2489

Design:

23 trials enrolling 29,147 participants were included in Randomized trials about A or R treatments reporting clinical end-points were included in the meta analysis.Influence of both treatments on GFR and new onset proteinuria was assessed

RENAL SAFETY

1. Diabetic Dyslipidemia increases risk of CVD

2. ACC/AHA 2013 :Diabetic patients (age 40-75 years) and LDL more than 70 mg/dl must receive Statins.

3. The 2015 ADA Standards of Care have been revised to recommend when to initiate and intensify statin therapy (high versus moderate) based on risk profile.

4. Rosuvastatin is effective in terms of lipids profiles including sdLDL-c and provides cardio protection with high

tolerability.

Take Home messages