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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
