A

therogenic

D

iabetic

D

yslipidemia (

ADD

)

- Time to Relook & Evaluate Treatment Options

Key questions

• 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 Lipaglyn TM is different?

• Trial & evidence of Lipaglyn TM efficacy & safety?

• What is the proposed place for Lipaglyn in treatment of DD?

Research in 2004 forecast Indian diabetic population to reach ~80 Mn by 2030…

*Number in the adult population ( 20 years of age).

Wild S et al. Diabetes Care. 2004;27:1047-1053.

…however, it has breached 60 Mn in 2011 itself 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 –3027 DOI 10.1007/s00125-011-2291-5

Globally, dyslipidemia is a widespread condition in diabetics Conclusion : Every 3 out of 4 diabetic suffers from dyslipidemia

Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.

Only a minority (<18%) of patients with T2DM achieve ABC goals

The “ABCs” of optimal CV health in diabetes are: A HbA1c < 7.0% B BP < 130/80 mm Hg C LDL-C < 100 mg/dL 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

Vouri Sm etal. Manag Care Pharm.

2011;17(4):304-12

But in India, almost 9 out of 10 diabetics have dyslipidemia

This suggests that there are >55 millions patients of diabetic dyslipidemia in India

Prevalence of Dyslipidemia (%) in Male T2 DM Prevalence of Dyslipidemia (%) in Female T2DM

85.5%

85.5 % Dyslipidemia 97.8 % Dyslipidemia

RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10 –12

Lifestyle and genetic factors also contribute to higher incidence of dyslipidemia in Indians

•

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

Besides, body composition of Asian Indians makes them more vulnerable

• • • • • • 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.

*Misra, Nutrition. 2004 May;20(5):482-91

‡ 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.

Indian dyslipidemia is different from its Western counterpart in terms of lipid parameters

Comparison of Indian vs. Western Dyslipidemia

Lipid Relative Serum Concentrations

TC LDL-C sd-LDL-C TG HDL-C Lp(a) Similar Similar (129 Vs 124 mg/dL) Similar Higher (174.5 Vs 146 mg/dL) Lower (40.5 Vs 46.4 mg/dL) Higher (29.3 Vs 25.9 mg/dL)

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

20th Annual Convention of the American Association of Physicians of Indian OriginClinical Implications: Dyslipidemia in the Asian Indian Population June 29, 2002

ADD affects TG, LDL-C and HDL-C ↑TG>150 The Triad of ADD ↓HDL-C <40 for Males <50 for Females

Sarma ,IHJ, 2000, 52: 173-177 Sarma, Am J Med, 1998, vol 105(1A), 48S-56S

↔ LDL-C (>100) & ↑sd-LDL-C

Agenda

• 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 i n treatment of DD?

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.

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.

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.

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.

Agenda

• 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 Lipaglyn TM is different?

• Trial & evidence of Lipaglyn efficacy & safety?

• What is the proposed place for Lipaglyn in treatment of DD?

Mortality rate is doubled in individuals with diabetes*

35 30 25 20 15 10 Ratio 2.5

Ratio 2.2

Ratio 2.1

5 0 Whitehall Study N = 10087 Paris Prospective Study N= 6908 Helsinki Policemen Study N= 657

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

Control (non-diabetes) Diabetes

Dyslipidemia is the single most important CV risk factor for MI

INTERHEART 9 Modifiable factors account for 90% of first-MI risk worldwide Yusuf S et al, Lancet; 364:937-52

In dyslipidemia patients with diabetes, CV risk is heightened by 3-4 times as compared to dyslipidemia without diabetes

J Stamler et al, Diabetes Care February 1993:16:434-444

Hypertriglyceridemia has a direct relation with insulin resistance TG levels Insulin levels

150 mg/dl 150 pmol/L 300 mg/dl 325 pmol/L

*Total area under 3 hours response curve (mean of 2 tests) Olefsky JM et al. Am J Med. 1974;57:5551-560

Hypertriglyceridemia is an independent CV risk factor Meta-analysis of 17 studies

(> 55,000 patients)

For every increase in TG level of 89 mg/dL, CVD risk increases by 32% in men and 76% in women

Hokanson JE et al. J Cardiovasc Risk. 1996; 3: 213-219

Hypertriglyceridemia in diabetes is an independent CV risk factor

Asian study of diabetic patients (followed up for 4.6 years)

Hypertriglyceridemia in T2DM patients increase CV risk by 3 times compared to T2DM patients without high TG.

Diabetes Metab Res Rev. 2005 Mar-Apr;21(2):183-8.

Patients in highest tertile of serum TG had 72% higher risk of CVD than those in lowest tertile

Meta-Analysis of 29 Studies

GROUPS CHD CASES CHD Risk Ratio* (95% CI) Duration of follow-up

• • ≥10 years <10 years

Sex

• • Male Female 5,902 4,256 7,728 1,984

Fasting status

• • Fasting Non-fasting 7,484 2,674

Adjusted for HDL

• Yes • No

Overall CHD Risk Ratio*

4,469 5,689 1 2 Increased Risk

Sarwar N, et al. Circulation. 2007;115:450-458. *

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) N = 2,62,525

1.72 (1.56-1.90)

3

Hazard Ratio for CHD is directly related to TG concentration

N=302,430

The Emerging Risk Factors Collaboration JAMA. 2009 November 11; 302(18): 1993 –2000

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

Agenda

• 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?

Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-C

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

Pattern B

: a predominance of small, dense LDL particles

Pattern A

: large, more buoyant LDL particles predominate

Austin et al, Circulation. 1990; 82:495-506

With the realization of importance of TG, the suggested target for TG has kept coming down TG Designate

Desirable

1984 NIH Consensus Panel

<250

1993 NCEP Guidelines

<200

2001 NCEP Guidelines

<150

2011 AHA Statement <100 (optimal) Global Guidelines (Goal for TG)

ESC AHA ACC ADA < 150 mg/dl

Circulation. published online April 18, 2011

Lets look how TG reduction benefits in outcome…

CV benefits of PPAR alpha agonists VA-HIT:

Primary Endpoint (non-fatal MI and CHD death) 2500 CHD patients randomized to gemfibrozil or placebo follow up; 5 yrs

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

Rubins HB et al, N Eng J Med, August 5, 1999 Vol. 341;410-418 BIP Study Group Circulation. 2000;102:21-27

Let’s understand what the FIELD trials show about the benefits of PPAR α therapy

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

Fenofibrate

(200 mg) N=4895

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) Placebo

N=4900

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

Keech A et al, Lancet

2005; 366: 1849 –61

PPAR α agonist showed no clear benefit in primary endpoints Composite CHD death or nonfatal MI at 5 Years

(% of treatment arm) 6% 5,2% 5,9% p=0.16

N= 9795 4% 2% Perception is that FIELD trial failed, but lets look critically at high TG Population or Atherogenic Dyslipidemics.. 0% Fenofibrate

Lancet 2005; 366: 1849 –61

Placebo

PPAR α agonists reduce CV events in T2DM patients with high TG and low HDL (ADD)

FIELD: Sub-analysis :Total CV events in patients with Metabolic Syndrome 20 18 16 14 12 10 8 6 4 2 0 Fenofibrate Placebo

↓23%

TG>204 mg/dl P=0.01

N=2517 20 18 16 14 12 10 8 6 4 2 0 Fenofibrate

↓27%

Placebo TG>204 mg/dl + Low HDL P=0.005

N=2014

R Scott et al, Diabetes Care 32:493 –498, 2009

Let’s also look at what ACCORD trials show about the benefits of PPAR α therapy

• • 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. Fenofibrate 160 mg • • • •

Baseline:

TG: 162 mg/dl TC: 175.2 mg LDL: 100.6 mg/dl HDL: 38.6 mg/dl Placebo 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.

ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

However, ACCORD results did not show any significant CV benefits in overall population

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)

3 2,5 2 1,5 1 0,5 0 2,2 P=0.32

2,4 Fenofibrate Placebo

ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

ACCORD: PPAR α agonist significantly reduce CV events in T2DM patients with TG>204 and HDL<34 (ADD)

20 18 16 14 12 10 8 6 4 2 0

↓31%

Fenofibrate Placebo 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 death Tenenbaum and Fisman, Cardiovascular Diabetology 2012, 11:125

Limitation & Learning from FIELD & ACCORD Trial 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

ACCORD Study

• 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

By lowering TG, PPAR α agonists can reduce the macro- & microvascular complications of T2DM

-20 -24 -28 -32 -36 -40 0 -4 -8 -12 -16 Major CV events -10 P=0.048

Coronary events -13 P<0.0001

Albuminuria -14 P=0.025

Revascularization Retinopathy -12 P=0.02

-37 P<0.0001

18 trials metaanalysis, > 45000 patients Jun M et al, Lancet 2010; 375: 1875 –84

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) TG > 204 mg/dl and HDL < 34 mg/dl TG < 204 mg/dl and HDL > 34 mg/dl

P<0.05

N Engl J Med. 2010:363(7):692-4 Diabetes Care 32:493 –498, 2009

N=4726

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)

Let’s look how good Glycemic Control helps…

Optimal glycemic control leads to ~24% risk reduction for microvascular diseases

(Microvascular diseases included are photocoagulation, vitreous hemorrhage, renal failure) UKPDS 80. NEJM 2008;359:1577-89

Let’s understand what the PROactive trial about the benefits of glycemic control and CV outcomes through PPAR γ therapy

Prospective, randomised, double-blind, placebo-controlled, study 5238 patients with type 2 diabetes (with macrovascular disease) Pioglitazone 15-45 mg (n=2605) Baseline Values: TG – 160 mg/dL Placebo (n=2633) End Point: Time to death, MI (except silent MI) and stroke Follow up: 34.5 months

PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) JA Dormandy et al,Lancet 2005; 366: 1279 –89

PPAR γ agonist reduced CV end points (Death, MI, stroke) significantly (by 16%) in DM patients with baseline TG 160 mg/dL 16% risk reduction

JA Dormandy et al, Lancet 2005; 366: 1279 –89

A meta analysis of 19 trials, 16,390 patients with T2DM suggested that PPAR γ agonist agent reduces CV events by 18% Composite Events (Death, Nonfatal MI, Stroke)

5.7% 4.4%

HR 0.82

95% CI 0.72-0.94

P=0.005

Control

Lincoff et al. JAMA 2007;298:1180-1188

Pioglitazone

We understood the importance of TG reduction and good Glycemic Control- now what next?

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.

Conclusion Non-HDL-C was a stronger indicator of CV risk than LDL-C

Paul Ridkar JAMA. 2005;294:326-333

Non-HDL-C is a better indicator of residual risk than LDL-C

AACE 2012 - Dyslipidemia Guidelines 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 established LDL-C risk levels

Jellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)

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) Conclusion Non-HDL-C decrease outperforms ApoB decrease for prediction of CHD and CVD risk.

Its decrease is a better predictor of CHD and CVD

Robinson J,,Am J Cardiol 2012;110: 1468 –1476

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.

Conclusion 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)

8 studies: 4S, LIPID , AFCAPS, WOSCOPS, CARDS, IDEAL, TNT, SPARCL JUPITER Boekholdt S, JAMA. 2012;307(12):1302-1309

To sum up - Non-HDL-C is a better indicator of residual risk than LDL-C

• 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

Non-HDL-C targets are related to LDL-C targets but differ by patient categories Patient Category

CHD + DM CHD/CHD risk equivalent No CHD, 2+ RF No CHD, <2 RF

LDL-C target (mg/dL)

<70 <100 <130 <160

Non-HDL-C target (mg/dL)

<100 <130 <160 <190

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Agenda

• 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?

Current Management of ADD

•

Lifestyle changes and Rx of secondary causes

•

Pharmacologic therapy

•

Anti-diabetic therapy

•

Lipid management

Statins Fibrate Niacin Omega-3 fatty acids •

Combination therapy

ADA/EASD guidelines for management of diabetes

Algorithm/treatment protocol

Diabetes Care 2012:35:1364-79

Limitations of current treatment of uncontrolled hyperglycemia after metformin therapy in T2DM

•

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

Current Management of ADD

•

Lifestyle changes and Rx of secondary causes

•

Pharmacologic therapy

•

Anti diabetic therapy

•

Lipid management

Statins Fibrate Niacin Omega-3 fatty acids •

Combination therapy

Managing Dyslipidemia in T2DM reduces CV events

CARDS: Atorvastatin Significantly Reduces Major CV Events in DM patients*

TG LDL HDL

Baseline

173 mg/dl 118.5 mg/dl 54 mg/dl

*Acute CHD event, coronary revascularization, stroke.

Colhoun HM et al. Lancet. 2004;364:685-696.

End of Study

143 mg/dl 82 mg/dl 49 mg/dl

Managing Dyslipidemia in T2DM reduces CV events

ASCOT-LLA: Total CV Events reduced by 23% with Atorvastatin in Patients With HT+DM

TG LDL HDL

Baseline

169 mg/dl 129 mg/dl 48 mg/dl

Server PS et al. Diabetes Care, 2005; 28:1151-1157

End of Study

128 mg/dl 83 mg/dl 48 mg/dl

Residual CHD risk in major statin trials

Residual CVD risk remains in patients with diabetes treated with statins

12 8 4 0 28 24 20 16 HPS 1 : n = 5963* 25,1 20,2 Placebo Simvastatin 22% Risk Reduction 78% Residual CVD Risk CARDS 2 : N = 2838 16 13,4 12 8 4 9,4 32% Risk Reduction 68% Residual CVD Risk 0 Placebo Atorvastatin

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.

Fibrates do not seem to be the optimal solution for managing residual risk either

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 have adverse effect on renal function in CKD patients

A meta analysis of 10 studies, 16,800 patients with CKD (eGFR < 60 ml/min) Fibrate therapy significantly reduces eGFR by 2.67 ml/min (p=0.01) in CKD patients

Jun M et al, (J Am Coll Cardlol 2012;60:2061-71)

In mixed dyslipidemia, Statin + Fibrate combination is not always safe

Statins combined with fibrate increases the incidence of statin induced myopathies, by 5.5-fold compared with statin use alone MH Davidson et al, Am J Cardiol 2007;99[suppl]:3C –18C

JAMA

2004;292:2585 –2590

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) 20 15

Risk ratio 0.96 (95% CI 0.90 – 1.03) Log rank P=0.29

15.0% 14.5%

10

Placebo ERN/LRPT

5 0 0 1 2

Years of follow-up

3

ERN/LRPT: Extended release niacin + Laropiprant 25673 CVD patients were randomized to ERN/LRPT or placebo (all on simvastatin)

European Heart Journal (2013) 34 , 1279 –1291

4

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.

Omega 3 Fatty acids have shown inconsistent effects on CV outcomes in different studies

J Am Coll Cardiol 2011;58:2047 –67

Agenda

• 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?

The importance of controlling both glucose and lipid levels in Diabetic dyslipidemia gave rise dual agonists

Diabetes. 2005 Aug;54(8):2460-70

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. Conclusion

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

Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate

R/F: Rosiglitazone/Fenofibrate R: Rosiglitazone Boden G, et al.

Diabetes 56:248–255,

2007

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

Thank You