Cardiovascular disease - more common in diabetic patients than in the general population
Dyslipidemia โ common in patients with both types of diabetes.
Aggressive lipid treatment goals have been recommended for patients with type 2 diabetes
Diabetic Dyslipidemia is highly prevalent in the Indian diabetic population
Dyslipidemia in diabetes differs significantly with hypertriglyceridemia and small dense LDL-C
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. ๏ง Lipoproteins โ macromolecules that transport hydrophobic
lipids (triglycerides, cholesterol & fat-soluble vitamins)
through body fluids (plasma, interstitial fluid, and lymph) to
and from tissues.
๏ง 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
โข 5 classes of lipoproteins classified based on the density
โข Most plasma triglyceride is transported in chylomicrons or VLDLs
โข Most plasma cholesterol is carried as cholesteryl esters in LDLs and
HDLs.
5. ๏ง Proteins associated with lipoproteins โ apolipoproteins
๏ง Assembly, structure, and function of lipoproteins
๏ง Activate enzymes of lipoprotein metabolism & are ligands for
cell-surface receptors
๏ง ApoA-I - found on virtually all HDL particles
๏ง ApoA-II - second most abundant HDL apolipoprotein found on
about 2/3rd of all HDL particles
๏ง ApoB - major structural protein of chylomicrons, VLDLs, IDLs,
and LDLs (apoB48 and apoB100)
๏ง ApoE is present on chylomicrons, VLDLs, and IDLs & Three
apolipoproteins of the C series - metabolism and clearance of
triglyceride-rich particles
Lipoprotein Metabolism 5
8. ๏ง Cardiovascular disease - more common in diabetic patients than
in the general population
๏ง Dyslipidemia โ common in patients with both types of diabetes.
๏ง Hyperglycemia โmicrovascular complications
Dyslipidemia โmacrovascular complications
๏ง Elevated low-density lipoprotein cholesterol (LDL-C) is a major
risk factor for CVD
๏ง Aggressive lipid treatment goals have been recommended for
patients with type 2 diabetes
8
10. ๏ง Insulin resistance contributes to this characteristic
dyslipidemia
๏ง Propensity to develop atherosclerotic disease - much higher in
these patients โ also called Atherosclerotic Diabetic
Dyslipidemia (ADD)
๏ง Disturbance of lipid metabolism โ early event, potentially
preceding the disease by several years.
๏ง Monitoring of the conventional (LDL-C) may be misleading in
diabetic patientsโ requires specific monitoring
Introduction 10
12. ๏ง India has a large pool of diabetic patients
๏ง ICMR-INDIAB study โ extrapolated estimations suggest 62.4
million people with diabetes and 77.2 million are prediabetic
๏ง 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
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
โข Nearly 90% Indian diabetics compared to 72% worldwide
โข >55 millions patients of diabetic dyslipidemia in India
16. Factors affecting higher prevalence in indians
1. Diet
โข Dyslipidemic profile - seen in vegetarians
โข Indian diets rich in carbohydrate and low in Omega-3 PUFA-
exacerbates hypertriglyceridemia
2. Physical Activity
โข Asian Indians-more physically inactive
3. Genetic Factors
โข Abnormal variants of ApoC 3 and ApoE 3 genes common in India
โข The "Starvation Gene Theory"
4. Body composition
โข Excess body fat in relation to body mass index
โข High waist-to-hip ratio
โข 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
22. Triglycerides and VLDL
๏ง Hypertriglyceridemia โ secondary to increase in VLDL
๏ง Triglycerides increase by 50 โ 100% above baseline only
๏ง If TG >400 mg/dl โ likely genetic defect in lipoprotein
metabolism
๏ง High VLDL and TG - due to increased substrate* flow into
liver
๏ง VLDL does not get cleared easily
๏ง VLDL โ apoB is over produced, but triglycerides increase more
than apoB โ Thus VLDL is richer in TG (increased ratio of
triglyceride to apoB )
Lipid metabolism in Diabetes 22
23. Triglycerides and VLDL
๏ง Increased VLDL ฮฑ Insulin resisitance
a) Glucose and Fatty acid levels - Increased substrate into the liver
for VLDL synthesis
b) Triglycerides in the liver inhibit apoB degradation โ Increased
secretion of VLDL
c) Lipoprotein lipase levels reduced in insulin resistance โ reduced
VLDL clearance
๏ง Altered VLDL composition - contributes to the atherosclerotic
propensity
Lipid metabolism in Diabetes 23
24. Lipid metabolism in Diabetes 24
Lipoprotein Alterations
VLDL โ โข Increased production of triglyceride and apoB
โข Decreased clearance of triglyceride and apoB
โข Abnormal composition
LDL โ โข Increased production of LDL apoB
โข Triglyceride enrichment
โข Decreased receptor mediated clearance
โข Smaller (more dense) particle distribution
โข Glycation
โข Oxidation
HDL โ โข Increased clearance of apoA
โข Decreased proportion of large HDL
โข Triglyceride enrichment
โข Glycation
โข Diminished reverse cholesterol transport
25. LIPOPROTEINS IN TYPE 1 DIABETES
๏ง Triglyceride-rich lipoproteins - increased ๏ hypertriglyceridemia
๏ง Severe insulin deficiency in DKA โ Poor lipoprotein lipase
activity โ poor clearance of TG rich cholesterol molecules
๏ง As TG rich molecules are not catabolized, LDL particles remain
same or low
๏ง HDL decreases in a mechanism similar to Type 2 Diabetes (High
VLDL โ High rate of TG transfer to HDL โ faster clearance)
Lipid metabolism in Diabetes 25
26. ๏ง Widespread agreement that LDL cholesterol should be less
than 130 mg/dL in almost all persons with diabetes
๏ง American Diabetes Association recommends an LDL-
cholesterol goal of less than 100 mg/dL in diabetic persons.
๏ง 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
๏ง Presently Non-HDL cholesterol โ 2nd therapeutic target
(according to the ATP III & AACE 2012) in individuals with
triglyceride levels > 200 mg/dl
๏ง Non-HDL-C (Total cholesterol โ HDL) โ ApoB containing
cholesterol
๏ง Need not be a fasting sample
๏ง 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*
๏ง Non-HDL-C recommended normal levels are 30 mg/dl higher
than LDL-C thresholds
๏ง Very simple to calculate (unlike apoB)
Guidelines 27
28. โข NonโHDL-C is as good as or better than LDL-C in the prediction
of future cardiovascular events
JAMA. 2005;294:326-333
โข When triglycerides are between 200- 500 mg/dl a nonโHDL-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)
โข 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: 1468โ1476
โข Among statin-treated patients, the strength of this association
with CVD is greater for nonโHDL-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 โ ATP III Guidelines
Other targets
โข Total Cholesterol < 200 mg/dl
โข 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*
๏ง Brisk walking (4-7 kmph) for 30โ40 minutes
๏ง Swimmingโlaps for 20 minutes
๏ง Bicycling for pleasure or transportation, 8 km in 30 minutes
๏ง Volleyball (noncompetitive) for 45 minutes
๏ง Home careโheavy cleaning
๏ง Basketball for 15โ20 minutes
๏ง Social dancing for 30 minutes
Treatment of diabetic dyslipidemia 36
38. 2. Pharmacological therapy
A. Lipid lowering therapy
๏ง Statins (HMG Co-A reductase inhibitors) -initial
pharmacological treatment for lowering LDL-C in
diabetics
๏ง Effects on HDL-C and other lipoproteins may also
play a role
๏ง 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
๏ง Pleotropic effects* (anti-inflammatory & NO
mediated vasodilation)
๏ง Reductions in triglycerides ๏ 7-30%
๏ง If TG <150 mg/dl โ reduction is inconsistent, but if
>200 mg/dl, the drop is significant
๏ง Statins reduce the concentration of all LDL
particles, (including the small LDL particles) as
well as IDL and VLDL remnants.
๏ง Generally given at night but Atorvastatin - very
long half-life ๏ morning administration equally
effective
Treatment of diabetic dyslipidemia 39
42. Fibric acid derivatives (fibrates)
๏ง The fibrates are primarily used for
lowering triglycerides (~50%)
๏ง Agonists for the nuclear
transcription factor peroxisome
proliferator- activated receptor-
alpha (PPAR-alpha).
๏ง Beneficial effect on cardiovascular
outcomes - not been observed in all
large fibrate trials*
๏ง There is concern about an increase
in the non cardiac mortality in
patients on long term fibrates
Treatment of diabetic dyslipidemia 42
44. Omegaโ3 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
๏ง Niacin - most effective agent for raising HDL-C levels, high
doses can worsen hyperglycemia
๏ง LDL cholesterol - โ 5โ25%
๏ง HDL cholesterol - โ 15โ35%
๏ง Triglycerides - โ 20โ50%
๏ง Flushing, itching, nausea, gastrointestinal upset, hypotension,
and tachycardia โ common
๏ง Combination lipid-lowering therapy (statin with a fibrate or
niacin)
๏ง The risk of myopathy โgreater in niacin + statin
๏ง Niacin plus laropiprant - a prostaglandin D2 receptor
antagonist reduces flushing
Treatment of diabetic dyslipidemia 45
46. Bile acid sequestrants
๏ง Sequestrants add to the LDL-lowering effects of other drugs,
notably statins
๏ง Bind bile acids in the intestine through anion exchange;
reducing enterohepatic recirculation of bile acids
๏ง 10 g/day cholestyramine or 10โ20 g/day colestipol reduce LDL
by 10โ20 %
๏ง Colesevelam โ much more potent (12-18%)
๏ง Combining with statins โ LDL reduction upto 44% reported
๏ง Other drugs should be taken an hour before or 4 hours after
administration of the sequestrant (absorption)*
Treatment of diabetic dyslipidemia 46
48. Others
๏ง Ezetimibe, a selective cholesterol absorption inhibitor in the
intestine - an effective lipid-lowering agent
๏ง Can also be used in combination with statin therapy
๏ง Ezetimibe plus atorvastatin, for example, can provide LDL-C
lowering equivalent to that achieved with high-dose
atorvastatin
๏ง Adjunctive therapy in patients with type 2 diabetes who
inadequately respond to statins
Treatment of diabetic dyslipidemia 48
49. Insulin sensitizers
๏ง Drugs that improve insulin resistance may have effects on
lipid levels, especially TG levels
๏ง Alter the ratio of lipoproteins in HDL towards more anti-
atherogenic HDL particles
๏ง Metformin has been shown to reduce LDL-C, TC, and TG
levels and increase HDL-C
๏ง The other class of insulin sensitizers โ PPARฮณ agonists
(Thiazolidenediones) are very effective in improving the
lipid profile
Treatment of diabetic dyslipidemia 49
50. Insulin sensitizers
๏ง 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
๏ง Pioglitazone increases LDL
particle size and decreases
LDL oxidation
๏ง Adv effects - Peripheral edema,
CHF, weight gain, fractures,
macular edema.
Treatment of diabetic dyslipidemia 50
52. ๏ง Saroglitazar โ worldโs first drug targeting diabetic
dyslipidemia
๏ง Discovered in 2001 โ approved 2013
๏ง Dual action โ PPARฮฑ and PPARฮณ agonist
๏ง Completely different in structure compared to
Thiazolidinediones
๏ง TZD ring โ known to cause edema and weight gain in PPARฮณ
agonists โ absent in Saroglitazar
๏ง Also binds to PPARฮฑ stronger than Fenofibrate
Recent advances 52
53. ๏ง PPARฮฑ > PPARฮณ
๏ง Conclusions of preclinical trials
๏ง Safe, well tolerated
๏ง No hepatotoxic, nephrotoxic, cardiotoxic or myotoxic effects
๏ง Not teratogenic
๏ง Usual dose 0.5 โ 4 mg /day
Recent advances 53
54. Conclusions of Clinical trials
๏ง Reduced Triglycerides by ~45%
๏ง Reduced LDL by ~5%
๏ง Reduced VLDL by ~ 45%
๏ง Reduced ApoB by ~11%
๏ง Reduced FBS and HbA1c levels
๏ง 2.5 times more patients met all 3 criteria of NCP-ATP III in
Saroglitazar + Atorvastatin group vs. Atorvastatin only
๏ง Adverse effects โ 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 โ novel drug approved for the metabolic
changes in Diabetic dyslipidemia
55
56. ๏ง Joslinโs Diabetes Mellitus โ 14th Ed
๏ง Harrison's Principles of Internal Medicine, 18th Ed
๏ง Goodman & Gilmanโs - The Pharmacological Basis of
Therapeutics - 12th Ed
๏ง Mechanisms in Medicine โ Animated Video Library
๏ง NCEP ATP III Guidelines booklet
๏ง Treatment of Diabetic Dyslipidemia - Vijayaraghavan Lipids in
Health and Disease 2010, 9:144
๏ง Aggressive Approach to Diabetic dyslipidemia J Am Osteopath
Assoc. 2009;109(suppl 1):S2-S7
๏ง Association of Physicians of India โ Medicine Update Vol 24.2
| 2014
56
Editor's Notes
Apo AI synthesized in the liver and intestine
The human liver synthesizes apoB100, and the intestine makes apoB48, (same gene involved )
INTERHEART Study 2004
Physical Activity:
Asian Indians are more physically inactive as compared to many other ethnic groups** May be due to fast economic development in recent years**
Genetic Factors:
variants of Apo C3(cause Lipo lipase inhibition) and ApoE3 (formation of VLDL) genes are common in India which can lead to more dyslipidemia^
Indians have excessive body fat and more abdominal adiposity which is harmful even if BMI is under control*
Indians more prone to Syndrome X - The "Starvation Gene Theory" India suffered droughts for hundreds of years. Fats and carbohydrates provide energy to the body. So our genes adapted to survive long periods of drought by consuming fats and carbohydrates slowly to make them last longer
Now our bodies get adequate supplies of food, but these genes are still in action as they take a long time to adapt, so our food continues to be metabolised slowly resulting in the dysfunctional biochemical profile that constitutes Syndrome X.
*Glucose and Free Fatty acid
Lipo lipase in adipose โ insulin increases activity โ resistance reduces activity
Opposite in muscle
Type 2 diabetics have an increased rate of HDL clearance โ Apo AI and AII are cleared faster
Neither Total Chol or HDL are affected by meals โ TG is and LDL is calculated = TC-HDL-TG/5
TNT (treating to new targets) & IDEAL (Incremental decrease in endpoints through aggressive lipid lowering)
28
Secondary causes of elevated triglycerides: diabetes mellitus, chronic renal failure, nephrotic syndrome, Cushingโs disease, lipodystrophy,
pregnancy, and various drugs (corticosteroids, beta-blockers, retinoids,
oral estrogens [not transcutaneous estrogen], tomoxifen, protease inhibitors for
AIDS).
ESC : European Society of Cardiology
AHA: American Heart Association
ACC: American College of Cardiology
ADA: American Diabetes Association
ย A following reference suggests that 85 % of total LDL will be Small Dense LDL(sdLDL). when TG is 250. so to reduce the sdLDL,TG should be reduced to 100 mg/dl (when sdLDL is just 15%). As sdLDL is known to be more atherogenic, keeping TG at 200-250 may not reduce atherosclerosis completely. and target of TG < 100 mg/dlย may be considered.
ALP โ Atherogenic Lipoprotein Phenotype
"A threshold appears to exist for a fasting TG concentration above which there will be a predominance of small, dense LDL particles(pattern B) and below which large, more buoyant particles will predominate (pattern A). The TG concentration that produces a shift from one subclass pattern to another varies with each patient. At a fasting TG concentration ,100 mg/dL, 85% of the population has pattern A, whereas at a fasting TG concentration .250 mg/dL, 85% will have pattern B ย
17. Thus, lowering the TG concentration from 600 mg/dL to 260 mg/dL is unlikely to change a patientโs LDL particle size because most patients have a threshold for shifting LDL subclass pattern within the range of 100 to 250 mg/dL"
DM โ CHD Equivalent
Risk Factors
Cigarette smoking
Hypertension (BPย 140/90 mmHg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dl)* - ย HDL cholesterolย 60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the total count
Family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years)
Age (menย 45 years; womenย 55 years)
Saturated - cream,ย cheese,ย butter,ย ghee
50-70% of maximum heart rate
Unsat โ avacados, nuts, meat, fish
mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules.
Elevated hepatic transaminases generally occur in <2% of cases and are dose-dependent, usually transient.
Progression to liver failure is exceedingly rare
Discontinued only if enzymes >3 ULN
Myopathy is common, however most cases are not related to statins.
Muscle aches, soreness, or weakness, and elevated creatine kinase levels โ significant myopathy
Elevated hepatic transaminases generally occur in <2% of cases and are dose-dependent, usually transient.
Progression to liver failure is exceedingly rare
Discontinued only if enzymes >3 ULN
Myopathy is common, however most cases are not related to statins.
Muscle aches, soreness, or weakness, and elevated creatine kinase levels โ significant myopathy
*FIELD (Fenofibrate Intervention and Event Lowering in Diabetes)
Concomitant therapy with statin and fibrate increases risk of muscle related Adverse events esp gemfibrozil
Colesevelam exception
Colesevelam exception
Rosiglitazone on the other hand increase LDL-C, TC, and HDL-C levels
Rosiglitazone on the other hand increase LDL-C, TC, and HDL-C levels
Rosiglitazone may increase risk of CV disease
Pioglitazone banned and revoked โ bladder cancer
Predominantly alpha activity with optimal gamma activity
Predominantly alpha activity with optimal gamma activity