a therogenic d iabetic d yslipidemia ( add ) - time to relook & evaluate treatment options
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A therogenic D iabetic D yslipidemia ( ADD ) - Time to Relook & Evaluate Treatment Options. 14339_89. 3_85. K ey questions. How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD ) in INDIA? Why diabetics are more prone to dyslipidemia? - PowerPoint PPT PresentationTRANSCRIPT
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Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options
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• How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD) in INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Diabetes & Dyslipidemia becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in ADD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in ADD?
• How LipaglynTM is different?
• Trial & evidence of LipaglynTM efficacy & safety?
• What is the proposed place for Lipaglyn in treatment of DD?
Key questions
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*Number in the adult population (20 years of age).Wild S et al. Diabetes Care. 2004;27:1047-1053.
Research in 2004 forecast Indian diabetic population to reach ~80 Mn by 2030…
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Diabetic population in India: ICMR INDIAB study 2011
62.4 million people with diabetes 77.2 million people with pre-diabetes
RM Anjana et. al. Diabetologia (2011) 54:3022–3027DOI 10.1007/s00125-011-2291-5
…however, it has breached 60 Mn in 2011 itself
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Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.
Conclusion : Every 3 out of 4 diabetic suffers from dyslipidemia
Globally, dyslipidemia is a widespread condition in diabetics
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Only a minority (<18%) of patients with T2DM achieve ABC goals
The “ABCs” of optimal CV health in diabetes are:
Most T2DM patients fail to achieve these targets: In a study of 5426 diabetic patients
(who were on treatment) in USA
from 2008 to 2009, only 17.3%
could achieve all the 3 ABC targets
So novel therapeutic options are
required for optimal management
Vouri Sm etal. Manag Care Pharm. 2011;17(4):304-12
A
B
C
HbA1c < 7.0%
BP < 130/80 mm Hg
LDL-C < 100 mg/dL
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This suggests that there are >55 millions patients of diabetic dyslipidemia in India
RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
85.5%
Dyslipidemia
97.8 %
Dyslipidemia
85.5 %
Prevalence of Dyslipidemia (%) in Male T2 DM
Prevalence of Dyslipidemia (%) in Female T2DM
But in India, almost 9 out of 10 diabetics have dyslipidemia
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• Diet
• Dyslipidemic profile - seen in vegetarians*• Indian diets rich in carbohydrate and low in Omega-3 PUFA-
exacerbates hyper-triglyceridemia.*
• Physical Activity• Asian Indians-more physically inactive: May be due to fast economic
development in recent years**
• Genetic Factors • Abnormal variants of ApoC 3 and ApoE 3 genes common in India^• Indians have more abdominal adiposity*• Thrifty gene to blame too
*Misra & Vikram ,Nutrition. 2004 May;20(5):482-91 ** Talwar & Misra,J Assoc Physicians India 2002;50:1521^Misra et al, J Assoc Physicians India 2004;52:137-42
Lifestyle and genetic factors also contribute to higher incidence of dyslipidemia in Indians
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*Misra, Nutrition. 2004 May;20(5):482-91
• Shorter height*
• Lower body mass index*
• Excess body fat in relation to body mass index †
• Abdominal adiposity
• High waist-to-hip ratio ‡
• Normal waist circumference*§
• High intra-abdominal fat*
• Truncal adiposity
• Thick subscapular skinfold thickness*
• More abdominal subcutaneous fat*II
• Less lean body mass*¶
* As compared with whites or blacks.† High body fat per unit of body mass index.II As estimated by skinfold thickness measurements or imaging techniques.¶ Particularly in the lower extremities.
‡ This may be due to less lean mass at the hips resulting in a smaller hip circumference.§ Average value of waist circumference usually does not exceed the currently accepted cutoff values for abdominal obesity.
Besides, body composition of Asian Indians makes them more vulnerable
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Lipid Relative Serum Concentrations
TC Similar
LDL-C Similar (129 Vs 124 mg/dL)
sd-LDL-C Similar
TG Higher (174.5 Vs 146 mg/dL)
HDL-C Lower (40.5 Vs 46.4 mg/dL)
Lp(a) Higher (29.3 Vs 25.9 mg/dL)
Comparison of Indian vs. Western Dyslipidemia
20th Annual Convention of the American Association of Physicians of Indian OriginClinical Implications: Dyslipidemia in the Asian Indian Population June 29, 2002
Atherogenic Dyslipidemia
Indians living in the US - 54% of men and 68% of women had low HDL levels. Similarly, 43% of Indian males and 24% Indian females have high TG levels that exceed 150 mg/dL
Indian dyslipidemia is different from its Western counterpart in terms of lipid parameters
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↔ LDL-C (>100) &↑sd-LDL-C
↓HDL-C<40 for Males
<50 for Females
↑TG>150
The Triad of
ADD
Sarma ,IHJ, 2000, 52: 173-177Sarma, Am J Med, 1998, vol 105(1A), 48S-56S
ADD affects TG, LDL-C and HDL-C
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• How big is the challenge of Diabetic dyslipidemia (DD) in INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Dyslipidemia and Diabetes becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in DD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in DD?
• How Lipaglyn is different?
• Trial & evidence of Lipaglyn efficacy & safety?
• What is the proposed place for Lipaglynin treatment of DD?
Agenda
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Why diabetics are more prone to ADD?
↑HSL
Type II Diabetes is characterized by insulin resistance
IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,J Clin Invest. 2000;106:453–458.
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Why diabetics are more prone to ADD?
IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,J Clin Invest. 2000;106:453–458.
↑HSL
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Why diabetics are more prone to ADD?
↑HSL
IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,J Clin Invest. 2000;106:453–458.
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IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,J Clin Invest. 2000;106:453–458.
Why diabetics are more prone to ADD?
↑HSL
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• How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD) in
INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Diabetes and Dyslipidemia becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in ADD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in ADD?
• How LipaglynTM is different?
• Trial & evidence of Lipaglyn efficacy & safety?
• What is the proposed place for Lipaglyn in treatment of DD?
Agenda
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Diabetes is CHD equivalent: NCEP ATP III guidelines^
*Balkau B, et al. Lancet 1997; 350:1680. ^SM Grundy et al,Circulation. 2004;110:227-239
0
5
10
15
20
25
30
35
Control (non-diabetes)
Diabetes
Ratio 2.5 Ratio 2.2 Ratio 2.1
WhitehallStudy
Mor
talit
y ra
te(d
eath
s pe
r 1,
000
patie
nt-
year
s)
Paris ProspectiveStudy
Helsinki Policemen Study
N = 10087 N= 6908 N= 657
Mortality rate is doubled in individualswith diabetes*
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INTERHEART
9 Modifiable factors account for 90% of first-MI risk worldwide
Yusuf S et al, Lancet; 364:937-52
Dyslipidemia is the single most important CV risk factor for MI
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J Stamler et al, Diabetes Care February 1993:16:434-444
In dyslipidemia patients with diabetes, CV risk is heightened by 3-4 times as compared to dyslipidemia without diabetes
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*Total area under 3 hours response curve (mean of 2 tests) Olefsky JM et al. Am J Med. 1974;57:5551-560
TG levels
Insulin levels
150 mg/dl
150 pmol/L
300 mg/dl
325 pmol/L
Hypertriglyceridemia has a direct relation with insulin resistance
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Hypertriglyceridemia is an independent CV risk factor
For every increase in TG level of 89 mg/dL, CVD risk increases by
32% in men and 76% in women
Meta-analysis of 17 studies (> 55,000 patients)
Hokanson JE et al. J Cardiovasc Risk. 1996; 3: 213-219
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Hypertriglyceridemia in diabetes is an independent CV risk factor
Hypertriglyceridemia in T2DM patients increase CV risk
by 3 times compared to T2DM patients without high
TG.
Asian study of diabetic patients (followed up for 4.6 years)
Diabetes Metab Res Rev. 2005 Mar-Apr;21(2):183-8.
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*Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)
Meta-Analysis of 29 Studies
Duration of follow-up
• ≥10 years 5,902
• <10 years 4,256
Sex
• Male 7,728
• Female 1,984
Fasting status
• Fasting 7,484
• Non-fasting 2,674
Adjusted for HDL
• Yes 4,469
• No 5,689
Overall CHD Risk Ratio*
GROUPS CHD CASES
1.72 (1.56-1.90)
2
N = 2,62,525
3
CHD Risk Ratio* (95% CI)
Sarwar N, et al. Circulation. 2007;115:450-458.
Patients in highest tertile of serum TG had 72% higher risk of CVD than those in lowest tertile
1Increased Risk
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The Emerging Risk Factors CollaborationJAMA. 2009 November 11; 302(18): 1993–2000
N=302,430
Hazard Ratio for CHD is directly related to TG concentration
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Increased CV risk can be due to other serious consequences of hypertriglyceridemia
• Low levels of HDL-C
• The presence of sd-LDL-C particles
• The presence of atherogenic triglyceride-rich lipoprotein
remnants
• Insulin resistance
• Increases in coagulability and viscosity
• Pro-inflammatory status
Miller M. Eur Heart J. 1998 Jul;19 (Suppl H): H18-22
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• How big is the challenge of Diabetic dyslipidemia (DD) in INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Dyslipidemia and Diabetes becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in DD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in DD?
• How Lipaglyn is different?
• Trial & evidence of Lipaglyn efficacy & safety?
• What is the proposed place for Lipaglyn in treatment of DD?
Agenda
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At fasting TG<100 mg/dL, 85% population has predominant large
buoyant LDL particles while if fasting TG>250 mg/dL 85% of population has predominant sd-LDL-C particles.
sd-LDL is known to be more atherogenic, keeping TG at 200-250 mg/dL may not be optimal to reduce atherosclerosis
Austin et al, Circulation. 1990; 82:495-506
Pattern B: a predominance of small, dense LDL particles
Pattern A: large, more buoyant LDL particles predominate
Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-C
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TG Designate1984 NIH
Consensus Panel
1993 NCEP Guidelines
2001 NCEP Guidelines 2011 AHA
Statement<100
(optimal)Desirable <250 <200 <150
Global Guidelines (Goal for TG)
ESC
< 150 mg/dlAHA
ACC
ADA
Circulation. published online April 18, 2011
With the realization of importance of TG, the suggested target for TG has kept coming down
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Lets look how TG reduction benefits in outcome…
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BIP study 3090 CAD patients were randomized to
bezafibrate vs Placebo, primary end point was fatal, nonfatal MI/sudden death Follow up:6.2 yrs
VA-HIT:Primary Endpoint (non-fatal MI and CHD death)
Rubins HB et al, N Eng J Med, August 5, 1999 Vol. 341;410-418 BIP Study Group Circulation. 2000;102:21-27
2500 CHD patients randomized to gemfibrozil or placebo follow up; 5 yrs
CV benefits of PPAR alpha agonists
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Fenofibrate(200 mg)
N=4895
Endpoints
• Primary - Composite of CHD death or non-fatal MI at 5 year follow-up
• Secondary - Composite of total CV events, CV mortality, total mortality, stroke, coronary revascularization and all revascularization at 5 year follow-up
PlaceboN=4900
9795 patients, Age 50-75 years, type 2 diabetes diagnosed after age 35 years, no clear indication for cholesterol-lowering therapy at baseline (total cholesterol 116-251 mg/dL, plus either total cholesterol to HDL ratio ≥4.0 or triglyceride >88.6 mg/dL
Keech A et al, Lancet 2005; 366: 1849–61
Baseline Lipid levels:
• LDL-C 120 mg/dL (mean)
• TC 195 mg/dL (mean)
• HDL-C 43 mg/dL (mean)
• TG 155 mg/dL (median)
Let’s understand what the FIELD trials show about the benefits of PPAR- α therapy
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Lancet 2005; 366: 1849–61
Perception is that FIELD trial failed, but lets look critically at
high TG Population or Atherogenic Dyslipidemics..
Composite CHD death or nonfatal MI at 5 Years (% of treatment arm)
p=0.16
Series10%
2%
4%
6%5.2%
5.9%
Fenofibrate Placebo
N= 9795
PPAR-α agonist showed no clear benefit in primary endpoints
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FIELD: Sub-analysis :Total CV events in patients with Metabolic Syndrome
R Scott et al, Diabetes Care 32:493–498, 2009
P=0.01
↓23%
% p
ati
ents
develo
pin
g e
vents
↓27%
TG>204 mg/dl0
2
4
6
8
10
12
14
16
18
20Fenofibrate Placebo
N=2517
TG>204 mg/dl + ...0
2
4
6
8
10
12
14
16
18
20Fenofibrate Placebo
% p
ati
ents
develo
pin
g e
vents
P=0.005 N=2014
PPAR-α agonists reduce CV events in T2DM patients with high TG and low HDL (ADD)
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• 5518 patients with type 2 diabetes (HbA1c > 7.5%) who were being treated
• All patients were on open-label simvastatin. Median Age: 62.3 years. 36.5% patients had CVD.
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
Baseline:
• TG: 162 mg/dl
• TC: 175.2 mg
• LDL: 100.6 mg/dl
• HDL: 38.6 mg/dl
The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.
The mean follow-up was 4.7 years.
Fenofibrate 160 mg Placebo
Let’s also look at what ACCORD trials show about the benefits of PPAR-α therapy
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The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group
(hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32)
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
P=0.32
% p
ati
ents
develo
pin
g p
rim
ary
end P
oin
t
0
0.5
1
1.5
2
2.5
3
2.22.4
Fenofibrate
Placebo
However, ACCORD results did not show any significant CV benefits in overall population
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P=0.03
N=941
941 T2DM patients (already on simvastatin) were randomized to fenofibrate or placebo Mean Follow up: 4.7 yrs
*MI, stroke and deathTenenbaum and Fisman, Cardiovascular Diabetology 2012, 11:125
% p
ati
ents
develo
pin
g e
vents
Series10
2
4
6
8
10
12
14
16
18
20
Fenofibrate Placebo
↓31%
ACCORD: PPAR-α agonist significantly reduce CV events in T2DM patients with TG>204 and HDL<34 (ADD)
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FIELD Study
Limitation
•More patients in the placebo group (17%) than in the PPAR-alpha agonist group(8%) received the non-study lipid-lowering agents (predominantly statins) .
Learning
• If adjustment is done for statin therapy then PPAR-alpha agonist reduces CHD risk by 19% (p = 0.01)
•PPAR-α agonist significantly reduces CV events by 27% in patients with TG>204 & low HDL-C
•PPAR-α agonist therapy reduced CV events significantly by 31% in patients with high TG and Low HDL who were already on statin at the time of randomization and continued throughout the trial
Limitation & Learning from FIELD & ACCORD Trial
FIELD Study
ACCORD Study
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18 trials metaanalysis, > 45000 patientsJun M et al, Lancet 2010; 375: 1875–84
-40
-36
-32
-28
-24
-20
-16
-12
-8
-4
0
-10-13 -14
-12
-37
P=0.048
P<0.0001P=0.02
5
P=0.02
P<0.0001
Cha
nge
in r
elat
ive
Ris
k (%
)
Major CV events Coronary events Albuminuria Revascularization Retinopathy
By lowering TG, PPAR-α agonists can reduce the macro- & microvascular complications of T2DM
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N Engl J Med. 2010:363(7):692-4Diabetes Care 32:493–498, 2009
P<0.05
TG > 204 mg/dl and HDL < 34 mg/dl TG < 204 mg/dl and HDL > 34 mg/dl
N=4726
In a meta analysis of 5 landmark studies (n = 4726), PPAR-α agonists reduced CV events significantly by 35% in patients with high TG≥ 204 mg/dL and low HDL ≤ 34 mg/dL (Atherogenic Dyslipidemia)
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In different studies in last 30 years, TG reduction, with or without statin, has been proven to cause significant risk reduction in patients with high TG and low HDL-C (Atherogenic Dyslipidemia)
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Let’s look how good Glycemic Control helps…
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(Microvascular diseases included are photocoagulation, vitreous hemorrhage, renal failure)
UKPDS 80. NEJM 2008;359:1577-89
Optimal glycemic control leads to ~24% risk reduction for microvascular diseases
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Prospective, randomised, double-blind, placebo-controlled, study
5238 patients with type 2 diabetes (with macrovascular disease)
PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events)JA Dormandy et al,Lancet 2005; 366: 1279–89
End Point: Time to death, MI (except silent MI) and stroke
Follow up: 34.5 months
Baseline Values:TG – 160 mg/dL
Pioglitazone 15-45 mg(n=2605)
Placebo(n=2633)
Let’s understand what the PROactive trial about the benefits of glycemic control and CV outcomes through PPAR γ therapy
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JA Dormandy et al, Lancet 2005; 366: 1279–89
16% risk reduction
PPAR-γ agonist reduced CV end points (Death, MI, stroke) significantly (by 16%) in DM patients with baseline TG 160 mg/dL
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HR 0.8295% CI 0.72-0.94
P=0.005
Lincoff et al. JAMA 2007;298:1180-1188
Composite Events (Death, Nonfatal MI, Stroke)P
atie
nts
%
Pioglitazone Control
4.4%
5.7%
A meta analysis of 19 trials, 16,390 patients with T2DM suggested that PPAR-γ agonist agent reduces CV events by 18%
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We understood the importance of TG reduction and good Glycemic Control- now what next?
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Non-HDL-C Vs LDL-C for CV risk in healthy women
In a prospective study of healthy 15,632 women who were followed up for 10 years, strength of association between different lipid parameters (HDL-C, LDL-C, non-HDL-C) and CV risk were measured.
Paul Ridkar JAMA. 2005;294:326-333
Non-HDL-C was a stronger indicator of CV risk than LDL-C
Conclusion
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Non-HDL-C is a better indicator of residual risk than LDL-C
When triglycerides are > 200 mg/dL but < 500 mg/dL, a non–HDL-C calculation will provide better risk assessment than LDL-C alone
If insulin resistance is suspected, evaluate non–HDL-C to gain useful information regarding the patient’s total atherogenic lipoprotein burden.
Non–HDL-C targets are 30 mg/dL higher than estab lished LDL-C risk levels
Jellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)
AACE 2012 - Dyslipidemia Guidelines
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Non-HDL-C is better than ApoB for the CV risk prediction
A meta analysis was carried out including 25 trials of different types of lipid lowering therapies (12 on statin, 4 on fibrate, 5 on niacin, 2 on simvastatin–ezetimibe, 1 on ileal bypass surgery, and 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol, n=131,134)
Robinson J,,Am J Cardiol 2012;110: 1468–1476
Non-HDL-C decrease outperforms ApoB decrease for prediction of CHD and CVD risk.
Its decrease is a better predictor of CHD and CVD
Conclusion
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Importance of Non-HDL-C vis-à-vis LDL-C and ApoB for CV events in statin treated patients
A meta-analysis was carried out from 8 landmark statin trials (38,153 patients), to evaluate the relative strength of the associations of LDL-C, non–HDL-C, and ApoB with cardiovascular risk among patients treated with statin therapy.
8 studies: 4S, LIPID , AFCAPS, WOSCOPS, CARDS, IDEAL, TNT, SPARCL JUPITER
Boekholdt S, JAMA. 2012;307(12):1302-1309
Non-HDL-C was a better indicator of CV risk than ApoB (p=0.02)
and LDL –C (p=0.002)
(1 SD increase in non-HDL-C, ApoB and LDL-C increase CV risk by 16, 14 and 13%
respectively)
Conclusion
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•Non–HDL-C is as good as or better than LDL-C in the prediction of future cardiovascular events
JAMA. 2005;294:326-333
•When triglycerides are between 200- 500 mg/dl a non–HDL-C calculation provides better risk assessment than LDL-C alone AACE 2012 dyslipidemia guidelines (ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)
•Non-HDL outperforms Apo-B for prediction of CVD: A meta-analysis of 25 trials (n=131,134) on lipid lowering therapy
Am J Cardiol 2012;110: 1468–1476
•Among statin-treated patients, the strength of this association with CVD is greater for non–HDL-C than for LDL-C and ApoB
JAMA. 2012;307(12):1302-1309
To sum up - Non-HDL-C is a better indicator of residual risk than LDL-C
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Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Patient Category LDL-C target (mg/dL)
Non-HDL-C target (mg/dL)
CHD + DM <70 <100
CHD/CHD risk equivalent
<100 <130
No CHD, 2+ RF <130 <160
No CHD, <2 RF <160 <190
Non-HDL-C targets are related to LDL-C targets but differ by patient categories
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• How big is the challenge of Diabetic dyslipidemia (DD) in INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Dyslipidemia and Diabetes becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in ADD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in DD?
• How Lipaglyn is different?
• Trial & evidence of Lipaglyn efficacy & safety?
• What is the proposed place for Lipaglyn in treatment of DD?
Agenda
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•Lifestyle changes and Rx of secondary causes
•Pharmacologic therapy•Anti-diabetic therapy
•Lipid management - Statins- Fibrate- Niacin- Omega-3 fatty acids
•Combination therapy
Current Management of ADD
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Algorithm/treatment protocol
Diabetes Care 2012:35:1364-79
ADA/EASD guidelines for management of diabetes
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•Sulfonylurea/Meglitinides: they are known to lead to early Beta cell fatigue by excessive stimulation* + significant risk of hypoglycemia and weight gain
•Pioglitazone: Significant weight gain, osteoporosis **
• Insulin: Parenteral administration, significant risk of hypoglycemia
•GLP-1 analogues: Parenteral administration, severe GI disturbance in initial period
•DPP-IV inhibitors: Possible risk of pancreatic metaplasia and pancreatitis^, URTI
* J Clin Endocrinol Metab. 2005;90:501–506, **Diabetes Care 2011; 34(4): 916-922^ JAMA Intern Med 2013 Feb 25:1-6
Limitations of current treatment of uncontrolled hyperglycemia after metformin therapy in T2DM
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•Lifestyle changes and Rx of secondary causes
•Pharmacologic therapy•Anti diabetic therapy
•Lipid management - Statins- Fibrate- Niacin- Omega-3 fatty acids
•Combination therapy
Current Management of ADD
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*Acute CHD event, coronary revascularization, stroke.Colhoun HM et al. Lancet. 2004;364:685-696.
Baseline End of Study
TG 173 mg/dl 143 mg/dl
LDL 118.5 mg/dl 82 mg/dl
HDL 54 mg/dl 49 mg/dl
Managing Dyslipidemia in T2DM reduces CV eventsCARDS: Atorvastatin Significantly Reduces Major CV Events in DM patients*
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Baseline End of Study
TG 169 mg/dl 128 mg/dl
LDL 129 mg/dl 83 mg/dl
HDL 48 mg/dl 48 mg/dl
Server PS et al. Diabetes Care, 2005; 28:1151-1157
Managing Dyslipidemia in T2DM reduces CV eventsASCOT-LLA: Total CV Events reduced by 23% with Atorvastatin in Patients With HT+DM
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Residual CHD risk in major statin trials
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Statins alone are not sufficient in Diabetic Dyslipidemia
*Patients with diabetes. (HPS also enrolled 14,573 high-risk patients without diagnosed diabetes.)1.HPS Study Group, Lancet. 2003;361:2005-2016; 2. Colhoun HM, Lancet. 2004;364:685-696.
CARDS2: N = 2838HPS1: n = 5963*
22% RiskReduction 32% Risk
Reduction
Majo
r Vasc
ula
r Event
Rate
(%
)
78% Residual CVD Risk
68% Residual CVD Risk
Acu
te C
VD
Event
Rate
(%
)Placebo Atorvastatin
0
4
8
12
16
13.4
9.4
Placebo Simvastatin0
4
8
12
16
20
24
28 25.1
20.2
Residual CVD risk remains in patients with diabetes treated with statins
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PROS:
•Reduction in TG, LDL-C & raises HDL-C, used alone or in conjunction with statins
CONS:
•Increased risk of gall stones
•Abnormal Liver Function Tests (increased AST and ALT levels) in 7.5% patients
• Increased serum creatinine levels.
Ref - TRICOR Prescribing Information
Fibrates do not seem to be the optimal solution for managing residual risk either
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Jun M et al, (J Am Coll Cardlol 2012;60:2061-71)
Fibrate therapy significantly reduces eGFR by 2.67 ml/min (p=0.01) in CKD patients
Fibrates have adverse effect on renal function in CKD patients A meta analysis of 10 studies, 16,800 patients with CKD (eGFR < 60 ml/min)
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JAMA 2004;292:2585–2590
Statins combined with fibrate increases the incidence of statininduced myopathies, by 5.5-fold compared with statin use aloneMH Davidson et al, Am J Cardiol 2007;99[suppl]:3C–18C
In mixed dyslipidemia, Statin + Fibrate combination is not always safe
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0 1 2 3 4 Years of follow-up
0
5
10
15
20
Pati
ents
su
fferi
ng e
vents
(%
)
15.0% 14.5%
Placebo ERN/LRPT
Log rank P=0.29
Risk ratio 0.96 (95% CI 0.90 – 1.03)
European Heart Journal (2013) 34, 1279–1291
ERN/LRPT: Extended release niacin + Laropiprant 25673 CVD patients were randomized to ERN/LRPT or placebo (all on simvastatin)
HPS 2 THRIVE Study - No CV benefits with Niacin, ADRs like myopathy & skin reactions were increased (ADRs were 10 times higher in Asians than European patients)
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Omega 3 Fatty Acids
• Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
• At therapeutic doses (4 gm/day), reduce TGs by 30-40%
• Eructation (belching), dyspepsia, fishy smell in mouth and taste perversion are most common ADRs
• Their effects on CV events are disputed, some studies suggest that they reduce CV events, other studies report the opposite.
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Omega 3 Fatty acids have shown inconsistent effects on CV outcomes in different studies
J Am Coll Cardiol 2011;58:2047–67
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• How big is the challenge of Diabetic dyslipidemia (DD) in INDIA?
• Why diabetics are more prone to dyslipidemia?
• Why management of Dyslipidemia and Diabetes becomes important?
• What is the evidence to support benefits from TG reduction?
• What is the current management approach in DD?
• What are the current limitations of treating dyslipidemia in diabetics?
• What’s new in ADD?
• How Lipaglyn is different?
• Trial & evidence of Lipaglyn efficacy & safety?
• What is the proposed place for Lipaglyn in treatment of DD?
Agenda
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Diabetes. 2005 Aug;54(8):2460-70
The importance of controlling both glucose and lipid levels in Diabetic dyslipidemia gave rise dual agonists
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Combination therapy of PPARα & PPARγ agonists, results in reduction of TG & A1c levels without increasing body weight in T2DM patients
In a study, obese, T2DM patients were treated with placebo for 2 months and then rosiglitazone (8 mg/day) + Fenofibrate (160 mg/day)(RGZ/FEB) or rosiglitazone (8 mg/day) (RGZ) alone for 2 months.
RGZ/FEB was more effective and safe than RGZ alone
RGZ/FEB lowered fasting plasma FFA more effectively than RGZ alone (22 vs. 5%, P < 0.05), and
More effective than RGZ alone in lowering A1c (0.9 vs. 0.4%)and TGlevels (38 vs. 5%)
RGZ/FFB prevented the fluid retention usually associated with RGZ (1.6 vs. 5.6%, P < 0.05)
Boden G, et al. Diabetes 56:248–255,2007
Conclusion
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Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate
R/F: Rosiglitazone/FenofibrateR: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007
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To sum up….
• ADD is highly prevalent in the Indian diabetic population
• Control of hypertriglyceridemia is equally vital in reducing
the CV events as is optimal glycemic control
• Non-HDL-C is a better indicator of CV risk than ApoB and LDL
–C
• Many unmet needs exist in the current management of ADD
and a significant residual CV risk prevails despite the current
optimal therapy
• Combined action of PPARα & PPARγ agonists results in reduction of
TG & A1c levels without increasing body weight in T2DM patients
• A dual PPAR α/γ agonist is the need of the hour – to achieve
optimal glycemic and lipid targets with better safety in the
comprehensive management of ADD
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Thank You