India has a large pool of diabetic patients ICMR-INDIAB study – extrapolated estimations suggest 62.4 million people with diabetes and 77.2 million are prediabetic Estimates show ~ 85.5% men and 97.8% women who are diabetic in India have concomitant dyslipidemia

2. Lipoprotein Metabolism
Introduction to Diabetic dyslipidemia
Extent of Diabetic dyslipidemia in India
Lipid metabolism in Diabetes Mellitus
Guidelines
Treatment
Recent advances in the management
2

3.  Lipoproteins – macromolecules that transport hydrophobic lipids
(triglycerides, cholesterol & fat-soluble vitamins) through body
fluids (plasma, interstitial fluid, and lymph) to and from tissues.
 Lipoproteins contain a core of hydrophobic lipids (triglycerides and
cholesteryl esters) surrounded by hydrophilic lipids (phospholipids,
unesterified cholesterol) and proteins that interact with body fluids.
3

4. Lipoprotein Metabolism 4
• 5 classes of lipoproteins classified based on the density
• Most plasma triglyceride is transported in chylomicrons or VLDLs
• Most plasma cholesterol is carried as cholesteryl esters in LDLs and HDLs.

5.  Proteins associated with lipoproteins – apolipoproteins
 Assembly, structure, and function of lipoproteins
 Activate enzymes of lipoprotein metabolism & are ligands for cell-
surface receptors
 ApoA-I - found on virtually all HDL particles
 ApoA-II - second most abundant HDL apolipoprotein found on about
2/3rd of all HDL particles
 ApoB - major structural protein of chylomicrons, VLDLs, IDLs, and
LDLs (apoB48 and apoB100)
 ApoE is present on chylomicrons, VLDLs, and IDLs & Three
apolipoproteins of the C series - metabolism and clearance of
triglyceride-rich particles
Lipoprotein Metabolism 5

6. Lipoprotein Metabolism 6

7. Lipoprotein Metabolism
7

8.  Cardiovascular disease - more common in diabetic patients than in
the general population
 Dyslipidemia – common in patients with both types of diabetes.
 Hyperglycemia –microvascular complications
Dyslipidemia –macrovascular complications
 Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk
factor for CVD
 Aggressive lipid treatment goals have been recommended for
patients with type 2 diabetes
8

9. Introduction 9
↔ LDL-C
↑sd-LDL-C
↓HDL-C
↑TG
The Triad of
Diabetic
Dyslipidemia

10.  Insulin resistance contributes to this characteristic dyslipidemia
 Propensity to develop atherosclerotic disease - much higher in these
patients – also called Atherosclerotic Diabetic Dyslipidemia (ADD)
 Disturbance of lipid metabolism – early event, potentially preceding
the disease by several years.
 Monitoring of the conventional (LDL-C) may be misleading in
diabetic patients– requires specific monitoring
Introduction 10

11. Introduction 11
9 Modifiable factors account for 90% of first-MI risk worldwide

12.  India has a large pool of diabetic patients
 ICMR-INDIAB study – extrapolated estimations suggest 62.4 million
people with diabetes and 77.2 million are prediabetic
 Estimates show ~ 85.5% men and 97.8% women who are diabetic
in India have concomitant dyslipidemia
Extent of DD in India 12

13. 13
Research in 2004 forecast that the Indian
diabetic population would reach ~80 million
by 2030
Extent of DD in India

14. Extent of DD in India 14
Worldwide

15. Extent of DD in India 15
85.5%
97.8 %85.5 %
Prevalence of Dyslipidemia (%) in
Male T2 DM
Prevalence of Dyslipidemia (%)
in Female T2DM
In India
• Nearly 90% Indian diabetics compared to 72% worldwide
• >55 millions patients of diabetic dyslipidemia in India

16. Factors affecting higher prevalence in indians
1. Diet
• Dyslipidemic profile - seen in vegetarians
• Indian diets rich in carbohydrate and low in Omega-3 PUFA-
exacerbates hypertriglyceridemia
2. Physical Activity
• Asian Indians-more physically inactive
3. Genetic Factors
• Abnormal variants of ApoC 3 and ApoE 3 genes common in India
• The "Starvation Gene Theory"
4. Body composition
• Excess body fat in relation to body mass index
• High waist-to-hip ratio
• High intra-abdominal fat
Extent of DD in India
16

17. Extent of DD in India
17
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)
Comparison of Indian vs. Western Dyslipidemia

18. Lipid metabolism in Diabetes 18

19. Lipid metabolism in Diabetes 19

20. Lipid metabolism in Diabetes 20

21. Lipid metabolism in Diabetes 21

22. Triglycerides and VLDL
 Hypertriglyceridemia – secondary to increase in VLDL
 Triglycerides increase by 50 – 100% above baseline only
 If TG >400 mg/dl – likely genetic defect in lipoprotein metabolism
 High VLDL and TG - due to increased substrate* flow into liver
 VLDL does not get cleared easily
 VLDL – apoB is over produced, but triglycerides increase more than
apoB – Thus VLDL is richer in TG (increased ratio of triglyceride to
apoB )
Lipid metabolism in Diabetes 22

23. Triglycerides and VLDL
 Increased VLDL α Insulin resisitance
a) Glucose and Fatty acid levels - Increased substrate into the liver for
VLDL synthesis
b) Triglycerides in the liver inhibit apoB degradation – Increased
secretion of VLDL
c) Lipoprotein lipase levels reduced in insulin resistance – reduced VLDL
clearance
 Altered VLDL composition - contributes to the atherosclerotic
propensity
Lipid metabolism in Diabetes 23

24. Lipid metabolism in Diabetes 24
Lipoprotein Alterations
VLDL ↑ • Increased production of triglyceride and apoB
• Decreased clearance of triglyceride and apoB
• Abnormal composition
LDL ↑ • Increased production of LDL apoB
• Triglyceride enrichment
• Decreased receptor mediated clearance
• Smaller (more dense) particle distribution
• Glycation
• Oxidation
HDL ↓ • Increased clearance of apoA
• Decreased proportion of large HDL
• Triglyceride enrichment
• Glycation
• Diminished reverse cholesterol transport

25. LIPOPROTEINS IN TYPE 1 DIABETES
 Triglyceride-rich lipoproteins - increased hypertriglyceridemia
 Severe insulin deficiency in DKA – Poor lipoprotein lipase activity –
poor clearance of TG rich cholesterol molecules
 As TG rich molecules are not catabolized, LDL particles remain same or
low
 HDL decreases in a mechanism similar to Type 2 Diabetes (High VLDL
– High rate of TG transfer to HDL – faster clearance)
Lipid metabolism in Diabetes 25

26.  Widespread agreement that LDL cholesterol should be less than
130 mg/dL in almost all persons with diabetes
 American Diabetes Association recommends an LDL-cholesterol
goal of less than 100 mg/dL in diabetic persons.
 Most persons with diabetes will require an LDL-lowering drug to
reach the LDL goal of <100 mg/dL.
26

27. Using Non-HDL-C as a marker for Diabetic Dyslipidemia
 Presently Non-HDL cholesterol – 2nd therapeutic target (according
to the ATP III & AACE 2012) in individuals with triglyceride levels >
200 mg/dl
 Non-HDL-C (Total cholesterol – HDL) – ApoB containing cholesterol
 Need not be a fasting sample
 LDL-C unreliable as a predictor of CV events when on lipid lowering
agents, while Non-HDL-C continue to be a good predictor even on
therapy*
 Non-HDL-C recommended normal levels are 30 mg/dl higher than
LDL-C thresholds
 Very simple to calculate (unlike apoB)
Guidelines 27

28. • 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 is a better indicator of residual risk than
LDL-C
Guidelines 28

29. Global Guidelines (Goal for TG)
ESC
< 150 mg/dl
AHA
ACC
ADA
Guidelines 29
TG Designate
1984 NIH
Consensus
Panel
1993 NCEP
Guidelines
2001 NCEP
Guidelines
2011 AHA
Statement
<100
(optimal)Desirable <250 <200 <150
Triglyceride Goals over time

30. 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.
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
Guidelines 30

31. Guidelines 31
NCEP – ATP III Guidelines
Other targets
• Total Cholesterol < 200 mg/dl
• HDL-C > 40 mg/dl

32. American Heart Association guidelines 2013
The expert panel identified 4 groups that would benefit from
statin therapy:
1) Individuals with clinical ASCVD
2) Individuals with LDL >190 mg/dl
3) Individuals with Diabetes mellitus, 40-75 yrs with LDL 70-189
mg/dl and without clinical ASCVD
4) Individuals without clinical ASCVD or Diabetes mellitus with
LDL 70-189 mg/dl and estimated 10-year ASCVD risk >7.5%
Guidelines 32

33. American Diabetes Association guidelines
1. LDL Cholesterol: Less than 100 mg/dl
2. HDL Cholesterol: Higher than 40 mg/dl for men and 50 mg/dl for
women
3. Triglycerides: Less than 150 mg/dl
Guidelines
33

34. 1. Lifestyle changes (TLC)
2. Pharmacologic therapy
i. Lipid management
ii. Anti-diabetic therapy
3. Combination therapy
4. New agents
34

35. 1. Therapeutic lifestyle changes (TLC) includes the following:
Treatment of diabetic dyslipidemia 35
LDL reduction
8-10%
3-5%
6-15%
3-5%
20-30%
Cumulatively

36. Examples of Moderate Physical Activity in Healthy Adults*
 Brisk walking (4-7 kmph) for 30–40 minutes
 Swimming—laps for 20 minutes
 Bicycling for pleasure or transportation, 8 km in 30 minutes
 Volleyball (noncompetitive) for 45 minutes
 Home care—heavy cleaning
 Basketball for 15–20 minutes
 Social dancing for 30 minutes
Treatment of diabetic dyslipidemia 36

37. Macronutrient Recommendations for the TLC Diet
Treatment of diabetic dyslipidemia 37

38. 2. Pharmacological therapy
A. Lipid lowering therapy
 Statins (HMG Co-A reductase inhibitors) -initial
pharmacological treatment for lowering LDL-C in
diabetics
 Effects on HDL-C and other lipoproteins may also play a
role
 Decrease in CHD and total mortality, myocardial
infarctions, revascularization procedures, stroke and
peripheral vascular disease
Treatment of diabetic dyslipidemia 38

39. HMG Co-A reductase inhibitors
 Pleotropic effects* (anti-inflammatory & NO mediated
vasodilation)
 Reductions in triglycerides  7-30%
 If TG <150 mg/dl – reduction is inconsistent, but if
>200 mg/dl, the drop is significant
 Statins reduce the concentration of all LDL particles,
(including the small LDL particles) as well as IDL and
VLDL remnants.
 Generally given at night but Atorvastatin - very long
half-life  morning administration equally effective
Treatment of diabetic dyslipidemia 39

40. HMG Co-A reductase inhibitors
Treatment of diabetic dyslipidemia 40

41. HMG Co-A reductase inhibitors
Treatment of diabetic dyslipidemia 41

42. Fibric acid derivatives (fibrates)
 The fibrates are primarily used for
lowering triglycerides (~50%)
 Agonists for the nuclear transcription
factor peroxisome proliferator-
activated receptor-alpha (PPAR-
alpha).
 Beneficial effect on cardiovascular
outcomes - not been observed in all
large fibrate trials*
 There is concern about an increase in
the non cardiac mortality in patients
on long term fibrates
Treatment of diabetic dyslipidemia 42

43. Fibric acid derivatives (fibrates)
Treatment of diabetic dyslipidemia 43

44. Omega–3 fatty acids
Treatment of diabetic dyslipidemia 44
PATIENT POPULATION RECOMMENDATION
No documented history of CHD Eat a variety of fish (preferably oily)
at least twice per week. Include oils
and foods rich in alphalinolenic acid
(flaxseeds and walnuts).
Documented history of CHD Consume approximately 1 g of EPA
plus DHA daily, preferably from oily
fish. EPA plus DHA capsule
supplements may be used in
consultation with a physician.
Needs to lower triglyceride level Consume 2 to 4 g of EPA plus DHA
daily in capsules in consultation with
a physician.

45. Nicotinic acid
 Niacin - most effective agent for raising HDL-C levels, high doses can
worsen hyperglycemia
 LDL cholesterol - ↓ 5–25%
 HDL cholesterol - ↑ 15–35%
 Triglycerides - ↓ 20–50%
 Flushing, itching, nausea, gastrointestinal upset, hypotension, and
tachycardia – common
 Combination lipid-lowering therapy (statin with a fibrate or niacin)
 The risk of myopathy –greater in niacin + statin
 Niacin plus laropiprant - a prostaglandin D2 receptor antagonist
reduces flushing
Treatment of diabetic dyslipidemia 45

46. Bile acid sequestrants
 Sequestrants add to the LDL-lowering effects of other drugs, notably
statins
 Bind bile acids in the intestine through anion exchange; reducing
enterohepatic recirculation of bile acids
 10 g/day cholestyramine or 10–20 g/day colestipol reduce LDL by
10–20 %
 Colesevelam – much more potent (12-18%)
 Combining with statins – LDL reduction upto 44% reported
 Other drugs should be taken an hour before or 4 hours after
administration of the sequestrant (absorption)*
Treatment of diabetic dyslipidemia 46

47. Treatment of diabetic dyslipidemia 47
Bile acid sequestrants

48. Others
 Ezetimibe, a selective cholesterol absorption inhibitor in the
intestine - an effective lipid-lowering agent
 Can also be used in combination with statin therapy
 Ezetimibe plus atorvastatin, for example, can provide LDL-C
lowering equivalent to that achieved with high-dose atorvastatin
 Adjunctive therapy in patients with type 2 diabetes who
inadequately respond to statins
Treatment of diabetic dyslipidemia 48

49. Insulin sensitizers
 Drugs that improve insulin resistance may have effects on lipid
levels, especially TG levels
 Alter the ratio of lipoproteins in HDL towards more anti-
atherogenic HDL particles
 Metformin has been shown to reduce LDL-C, TC, and TG levels
and increase HDL-C
 The other class of insulin sensitizers – PPARγ agonists
(Thiazolidenediones) are very effective in improving the lipid
profile
Treatment of diabetic dyslipidemia 49

50. Insulin sensitizers
 Pioglitazone has been shown to
reduce TG levels and increase
HDL-C* when used as an add-on
therapy in patients with type 2
diabetes who are already
receiving metformin or
sulfonylurea therapy
 Pioglitazone increases LDL
particle size and decreases LDL
oxidation
 Adv effects - Peripheral edema,
CHF, weight gain, fractures,
macular edema.
Treatment of diabetic dyslipidemia 50

51. 51

52.  Saroglitazar – world’s first drug targeting diabetic dyslipidemia
 Discovered in 2001 – approved 2013
 Dual action – PPARα and PPARγ agonist
 Completely different in structure compared to Thiazolidinediones
 TZD ring – known to cause edema and weight gain in PPARγ
agonists – absent in Saroglitazar
 Also binds to PPARα stronger than Fenofibrate
Recent advances 52

53.  PPARα > PPARγ
 Conclusions of preclinical trials
 Safe, well tolerated
 No hepatotoxic, nephrotoxic, cardiotoxic or myotoxic effects
 Not teratogenic
 Usual dose 0.5 – 4 mg /day
Recent advances 53

54. Conclusions of Clinical trials
 Reduced Triglycerides by ~45%
 Reduced LDL by ~5%
 Reduced VLDL by ~ 45%
 Reduced ApoB by ~11%
 Reduced FBS and HbA1c levels
 2.5 times more patients met all 3 criteria of NCP-ATP III in
Saroglitazar + Atorvastatin group vs. Atorvastatin only
 Adverse effects – Gastritis, pyrexia (mild)
Recent advances 54

55. 1. Diabetic Dyslipidemia is highly prevalent in the Indian diabetic
population
2. Dyslipidemia in diabetes differs significantly with
hypertriglyceridemia and small dense LDL-C
3. Non-HDL-C is a better indicator of CV risk than LDL-C in diabetic
patients
4. Most diabetic patients do not achieve optimum lipid targets
despite present treatment options
5. Saroglitazar – novel drug approved for the metabolic changes in
Diabetic dyslipidemia
55

56.  Joslin’s Diabetes Mellitus – 14th Ed
 Harrison's Principles of Internal Medicine, 18th Ed
 Goodman & Gilman’s - The Pharmacological Basis of Therapeutics -
12th Ed
 Mechanisms in Medicine – Animated Video Library
 NCEP ATP III Guidelines booklet
 Treatment of Diabetic Dyslipidemia - Vijayaraghavan Lipids in
Health and Disease 2010, 9:144
 Aggressive Approach to Diabetic dyslipidemia J Am Osteopath Assoc.
2009;109(suppl 1):S2-S7
 Association of Physicians of India – Medicine Update Vol 24.2 | 2014
56