Dr. Vivek Baliga Consultant Internal Medicine Managing Partner, Baliga Diagnostics Atherogenic Diabetic Dyslipidemia Emerging concepts
Dr. Vivek BaligaConsultant Internal Medicine
Managing Partner, Baliga Diagnostics
Atherogenic Diabetic Dyslipidemia
Emerging concepts
Major contributors of CV risk due to dyslipidemia
High LDLHigh TGs and Low HDLHigh Non-HDL
Diabetes
Non HDL-C
• Non HDL-C = Total Cholesterol - HDL-C • Encompasses all cholesterol present in potentially
atherogenic lipoprotein particles
– VLDL-C– IDL-C– LDL-C– Lp(a)
Adv Stu Med 2007; 7(1):8-11
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Why Non HDL Cholesterol?
• For many years, achieving LDL-C targets was given prime importance in dyslipidemia management
• However, the risk of CAD remains high despite bringing down LDL levels.
• PROVE-IT TIMI 22 trial– Patients who achieved LDL levels below 67 mg/dL still
had a 22.7% event recurrence at 2 years.– Probably an underestimation
• Other factors surely play a role (DM, HTN, smoking etc.), but non-HDL cholesterol would also explain this ‘residual risk’
• LDL cholesterol contributes very little to estimating cardiovascular risk as compared to non-HDL cholesterol**
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**Sniderman AD et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as
markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–345.
Non HDL-C – is it a new metric??
• Helsinki Heart study (1986):-– Non HDL-C used as a lipid parameter.– 4081 men with non-HDL > 200 randomized to
Gemfibrozil and placebo.– Primary end points: fatal and non-fatal MI and
cardiac death– Results:
• Non HDL-C declined by 14% from baseline in treatment arm (fibrate).
• Incidence of coronary heart disease – 34% risk reduction in treatment arm compared to placebo (p<0.02).
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NCEP ATP III guidelines
• Lowering non HDL-C as a secondary goal when TG >=200 mg/dL.
• Target goal recommended for non HDL-C is 30 mg/dL above the LDL target for each NCEP risk category.
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Is Non-HDL-C a better marker than LDL?
• Better marker than LDL in both primary and secondary prevention• 68 study analysis
– Non-HDL – C is a better predictor amongst all cholesterol measure for both CAD and stroke.
• IDEAL trial– non-HDL – C and ApoB were best predictors of adverse
cardiovascular outcomes following ACS; LDL – C was not.• Amongst statin treated patients, non – HDL cholesterol is a better
marker of future cardiovascular events compared to LDL and apoB.• Non-HDL – C is easier to calculate, and does not require fasting
(unlike LDL)• Unfortunately still a neglected marker – NEPTUNE II survey
– 62% of patients reached LDL –C goal <100 mg/dL– Only 33% reached non-HDL – C goals
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Non HDL-C is a better indicator of residual risk than LDL-C
A meta-analysis 25 trials (n=131,134) on lipid lowering therapy suggested that
Non HDL-C modestly outperforms Apo-B for prediction of CVD
Am J Cardiol 2012;110: 1468–1476
Non HDL-C and CV risk
Meta-analysis of data obtained from 62,154 statin treated patients enrolled in 8 trials published between 1994 and 2008
Boekholdt SM et al. JAMA. 2012;307(12):1302-1309
Patient = XYZLDL-C = 110
Non-HDL = 126TG = (non HDL – LDL) x 5
TG = 80
Relative risk of CV event= 2%
Patient = ABCLDL-C = 96
Non-HDL = 138TG = (non HDL – LDL) x 5
TG = 210
Relative risk of CV event =32%
AACE 2013 – Diabetes Guidelines
AACE have once again re-iterated in 2013
Non HDL goal to be achieved with TG lowering therapy after achievement of
desirable LDL-C level
Non HDL-C targets are 30 mg/dL higher than established LDL-C risk levels ENDOCRINE PRACTICE 2013;19 (Suppl 2):1-48
ADA 2014 – 15th June 2014
• The Utility of Non-HDL Cholesterol Levels Compared to LDL Levels for Targets in Diabetes Individuals
• 798 diabetes patients, currently taking lipid-lowering medication
• Average A1c was 8.0±2.6%. • Mean lipid levels were
– Total cholesterol of 150.6 mg/dL – HDL-C of 49 mg/dL– TG of 148 mg/dL, – LDL-C of 72.6 mg/dL and – non-HDL-C 101 mg/dL
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ADA 2014 – 15th June 2014
• Furthermore, 42.5%of those who reached the LDL-C target, did not reach the non-HDL - C target, yet all of those who reached the non-HDL-C target also reached the LDL-C target.
• These results suggest that using the non-HDL-C may be a better target for CVD risk reduction than the LDL-C when the TG are elevated.
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TG above average (>150mg/dL)n=313
TG below average (<150 mg/dL)n=485
% of patients on LDL goal
61.7%
69.48%
% of patients on Non-HDL goal
35.5% 72.2%
% of patients on both goal
35.5% 67.4%
The most recent – NICE lipid management guidelines draft
• ‘Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile’
• This should include measurement of TC, HDL-C,
Non HDL-C, and Triglyceride concentrations.
• A fasting sample is not needed.
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LDL-C measurement is not required
Major contributors of CV risk due to dyslipidemia
High LDLHigh TGs and Low HDL
High Non-HDLDiabetes
The role of insulin resistance in diabetic dyslipidemia
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Mooradian AD (2009) Dyslipidemia in type 2 diabetes mellitus Nat Clin Pract Endocrinol Metab doi:10.1038/ncpendmet1066
Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.
Globally almost 7 out of 10 diabetics suffer from dyslipidemia
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
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 1,0
00 p
atie
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ears
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Paris ProspectiveStudy
Helsinki Policemen Study
N = 10087 N= 6908 N= 657
Mortality rate is doubled in individualswith diabetes*
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
Lancet. 2009;373:1765–1772
BENEFITS OF DUAL CONTROL OVER 5 YEARS
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
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
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%
So to control diabetic dyslipidemia effectively we need to address LDL, non-HDL
& glycemic parameters by additional measures apart from statins
Research in the 90s focused on PPARs for their role in metabolic disorders
Diabetes. 2005 Aug;54(8):2460-70
Dual PPAR α/γ agonists can control dyslipidemia and in addition they also help to maintain glycemic control
Why DUAL PPAR agonists?
Combined activation of PPAR α & γ is believed to induce
complementary and synergistic action on
– lipid metabolism
– insulin sensitivity
– inflammation control
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 TG levels (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
Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate
R/F: Rosiglitazone/FenofibrateR: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007
The synergistic beneficial actions of balanced PPAR/ dual agonists
P. Balakumar et al. / Pharmacological Research 56 (2007)
Saroglitazar is the world’s first approved dual PPAR-α/γ agonist
Previous concerns
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A balance must be achieved in both agonistic activities to reduce side effect profile
A milestone in Indian history……
LIPAGLYNTM
A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters
PRESS VI TRIAL
PRESS V TRIAL
Published clinical trials of Saroglitazar
Saroglitazar: PPAR- induced triglyceride lowering plus PPAR- induced glucose lowering
Level Fenofibrate (200 mg/day) 2
Saroglitazar1,*(4 mg/day)
Pioglitazone1 (45 mg/day)
HbA1c -- -0.3% -0.4%
Triglycerides -30.2% -45.0% -15.5%
HDL-C +4.5% +7.6%* +7.1%
LDL-C -11.9% -5.0% +4.8%
Non HDL-C -32.5%*
Apo B -32%*
1 PRESS V study, 2FIELD study (Lancet, 2005)* PRESS VI study DIABETES TECHNOLOGY & THERAPEUTICS; volume 16.
% Change from baseline
Safety of Saroglitazar:PRESS V & PRESS VI studies
• Saroglitazar was found to be safe: – Cardiac parameters (ECG & 2D Echo)– LFT– RFT– CPK– Edema, weight gain
2-years preclinical studies:- no carcinogenicity
Mr SN
• 43 yr old male with a +ve TMT and recent diagnosis of DM• CAG showed 2 vessel disease – PCI to distal RCA.• Bloods prior to PCI
– TC 221– HDL 28– LDL 129– TG 485– Non – HDL 193– VLDL 97– FBS – 164
• Commenced on usual therapy with 40mg Atorvastatin and Metformin
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Mr SN
• Lipaglyn 4mg daily commenced• 1 month later
• TC 180• HDL 42• LDL 100• TG -140• Non – HDL 138• VLDL 23• FBS 93
• Significant improvement• Metformin dose halved• Continues treatment – awaiting 3 month review.
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Mr JD 55yrs
• 7 yr h/o DM (A1c 7.2%), Stage II HTN, Obese.• Previous IHD and CABG.• Rx - Metformin, Glimipride, Aspirin, Statin, Beta blockers,
ARB. Previous side effects with fibrates.• Lipid Profile
o TC 230o HDL 44, LDL 126, VLDL 56o TG 280o Non HDL 182
Treatment
• Started on Lipaglyn 4mg daily• 3 months lipid profile
o TC 190o HDL 50, LDL 88, VLDL 36o TG 180o Non HDL 140
o Yet to achieve targets – treatment continues.
Mr S, 55yrs
• Type 2 DM, HTN, previous PCI (SVD)• Ex-smoker, clinically stable. BP 150/90• Beta blockers, statins, ARB, Aspirin+Clopidogrel.• No response to fibrates (years)• Lipids
o TC 180o HDL 40, LDL 90, VLDL 44o TG 220o Non-HDL 140
Treatment
• 3 months post treatment on 4mg Lipaglyn o TC 174o HDL 50, LDL 74, VLDL 38o TG 190o Non-HDL 124
To sum up
• CVD - growing epidemic in India with dyslipidemia being the most important risk factor and diabetes also contributes to increased CV risk
• Statin therapy alone still leaves a residual risk of 70-80%• High TG is an important factor contributing to residual risk
• Non HDL-C is a better indicator of residual risk than LDL-C
• Saroglitazar is a dual PPAR alpha/gamma agonist – effective in reducing High TG by 45%– Reduces Non HDL by 32%– Improves insulin sensitivity & glycemic parameters.• Statin plus saroglitazar is a comprehensive management of
Diabetic Dyslipidemia
The future? My thoughts
• Applicability in non-diabetic dyslipidemia – Indian population are inherently insulin resistant
• Studies on effect on endothelial progenitor cells – NO mediated vasodilatation and athero-protection ? pleiotropism
• Long term studies looking at dual PPAR agonists and CV events in type 2 diabetic patients
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Thank you for listening
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