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

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00 p

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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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