Atherosclerosis Diabetes correlation

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

2. • 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

3. *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…

4. 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
…however, it has breached 60 Mn in 2011
itself

5. 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

6. 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
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

7. 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

8. • 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

9. *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

10. 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

11. ↔ LDL-C (>100) &
↑sd-LDL-C
↓HDL-C
<40 for Males
<50 for Females
↑TG>150
The Triad of
ADD
Sarma ,IHJ, 2000, 52: 173-177
Sarma, Am J Med, 1998, vol 105(1A), 48S-56S
ADD affects TG, LDL-C and HDL-C

12. • 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

13. 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.

14. 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

15. 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.

16. 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

17. • 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

18. 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
Whitehall
Study
Mortality
rate
(deaths
per
1,000
patient-years)
Paris Prospective
Study
Helsinki
Policemen Study
N = 10087 N= 6908 N= 657
Mortality rate is doubled in individuals
with diabetes*

19. 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

20. 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

21. *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

22. 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

23. 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.

24. *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
1
Increased Risk

25. The Emerging Risk Factors Collaboration
JAMA. 2009 November 11; 302(18): 1993–2000
N=302,430
Hazard Ratio for CHD is directly related to
TG concentration

26. 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

27. • 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

28. 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

29. TG Designate
1984 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/dl
AHA
ACC
ADA
Circulation. published online April 18, 2011
With the realization of importance of TG, the
suggested target for TG has kept coming down

30. Lets look how TG reduction benefits
in outcome…

32. 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

33. 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
Placebo
N=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

34. 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
5.2%
5.9%
0%
2%
4%
6%
Fenofibrate Placebo
N= 9795
PPAR-α agonist showed no clear benefit in
primary endpoints

35. 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%
%
patients
developing
events
↓27%
0
2
4
6
8
10
12
14
16
18
20
TG>204 mg/dl
Fenofibrate Placebo
N=2517
0
2
4
6
8
10
12
14
16
18
20
TG>204 mg/dl + Low HDL
Fenofibrate Placebo
%
patients
developing
events
P=0.005 N=2014
PPAR-α agonists reduce CV events in T2DM
patients with high TG and low HDL (ADD)

36. • 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

37. 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
%
patients
developing
primary
end
Point
2.2
2.4
0
0.5
1
1.5
2
2.5
3
Fenofibrate
Placebo
However, ACCORD results did not show any
significant CV benefits in overall population

38. 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
%
patients
developing
events
0
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)

39. 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

40. 18 trials metaanalysis, > 45000 patients
Jun M et al, Lancet 2010; 375: 1875–84
-10
-13 -14
-12
-37
-40
-36
-32
-28
-24
-20
-16
-12
-8
-4
0
P=0.048
P<0.0001
P=0.025
P=0.02
P<0.0001
Change
in
relative
Risk
(%)
Major CV events Coronary events Albuminuria Revascularization Retinopathy
By lowering TG, PPAR-α agonists can reduce the
macro- & microvascular complications of T2DM

41. N Engl J Med. 2010:363(7):692-4
Diabetes 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)

42. 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)

43. Let’s look how good Glycemic
Control helps…

44. (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

45. 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

46. 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

47. HR 0.82
95% CI 0.72-0.94
P=0.005
Lincoff et al. JAMA 2007;298:1180-1188
Composite Events (Death, Nonfatal MI, Stroke)
Patients
%
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%

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

49. 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

50. 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 established LDL-C risk levels
Jellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)
AACE 2012 - Dyslipidemia Guidelines

51. 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

52. 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

53. • 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

54. 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

55. • 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

56. •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

57. Algorithm/treatment protocol
Diabetes Care 2012:35:1364-79
ADA/EASD guidelines for management of
diabetes

58. • 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

59. •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

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

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

62. Residual CHD risk in major statin trials

63. 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 = 2838
HPS1: n = 5963*
22% Risk
Reduction 32% Risk
Reduction
Major
Vascular
Event
Rate
(%)
78%
Residual
CVD Risk
68% Residual
CVD Risk
Acute
CVD
Event
Rate
(%)
13.4
9.4
0
4
8
12
16
Placebo Atorvastatin
25.1
20.2
0
4
8
12
16
20
24
28
Placebo Simvastatin
Residual CVD risk remains in patients with
diabetes treated with statins

64. 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

65. 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)

66. JAMA 2004;292:2585–2590
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
In mixed dyslipidemia, Statin + Fibrate
combination is not always safe

67. 0 1 2 3 4
Years of follow-up
0
5
10
15
20
Patients
suffering
events
(%)
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)

68. 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.

69. Omega 3 Fatty acids have shown inconsistent
effects on CV outcomes in different studies
J Am Coll Cardiol 2011;58:2047–67

70. • 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

71. Diabetes. 2005 Aug;54(8):2460-70
The importance of controlling both glucose and lipid
levels in Diabetic dyslipidemia gave rise dual agonists

72. 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

73. Change in body water with Rosiglitazone Vs
Rosiglitazone + Fenofibrate
R/F: Rosiglitazone/Fenofibrate
R: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007

74. 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

75. Thank You