Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options.

Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options

• 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

*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…

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

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

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

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

• 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

*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

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

↔ 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

• How big is the challenge of Diabetic dyslipidemia (DD) in INDIA?


• Why management of Dyslipidemia and Diabetes becomes important?


• What is the current management approach in DD?


• 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

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.



↑HSL

• How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD) in

INDIA?


• Why management of Diabetes and Dyslipidemia becomes important?





• How LipaglynTM is different?



Agenda

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*

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

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

*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

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

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.

*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

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

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

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

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

Lets look how TG reduction benefits in outcome…

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

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

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

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)

• 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

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

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)

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

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

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)

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…

(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

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%

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.

Paul Ridkar JAMA. 2005;294:326-333

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

Conclusion

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

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

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

•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

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











Agenda

•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

Algorithm/treatment protocol

Diabetes Care 2012:35:1364-79

ADA/EASD guidelines for management of diabetes

•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

•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

*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*

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

Residual CHD risk in major statin trials

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

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

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)

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

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)

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

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

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

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

Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate

R/F: Rosiglitazone/FenofibrateR: 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

Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options.

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Transcript of Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options.