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Diabetic dyslipidemia

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India has a large pool of diabetic patients …

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

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  • 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 – insulin increases activity – resistance reduces activity
    Opposite in muscle
  • Type 2 diabetics have an increased rate of HDL clearance – Apo AI and AII are cleared faster
  • Neither Total Chol or HDL are affected by meals – 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, Cushing’s 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
  •   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/dl  may be considered.

    ALP – 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  

    17. Thus, lowering the TG concentration from 600 mg/dL to 260 mg/dL is unlikely to change a patient’s LDL particle size because most patients have a threshold for shifting LDL subclass pattern within the range of 100 to 250 mg/dL"
  • DM – CHD Equivalent

    Risk Factors
    Cigarette smoking
    Hypertension (BP 140/90 mmHg or on antihypertensive medication)
    Low HDL cholesterol (<40 mg/dl)* -  HDL cholesterol 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 (men 45 years; women 55 years)
  • Saturated - cream, cheese, butter, ghee
  • 50-70% of maximum heart rate
  • Unsat – 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 – 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 – 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 – bladder cancer
  • Predominantly alpha activity with optimal gamma activity
  • Predominantly alpha activity with optimal gamma activity
  • Transcript

    • 1. 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
    • 2.  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
    • 3. 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.
    • 4.  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
    • 5. Lipoprotein Metabolism 6
    • 6. Lipoprotein Metabolism 7
    • 7.  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
    • 8. Introduction 9 ↔ LDL-C ↑sd-LDL-C ↓HDL-C ↑TG The Triad of Diabetic Dyslipidemia
    • 9.  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
    • 10. Introduction 11 9 Modifiable factors account for 90% of first-MI risk worldwide
    • 11.  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
    • 12. 13 Research in 2004 forecast that the Indian diabetic population would reach ~80 million by 2030 Extent of DD in India
    • 13. Extent of DD in India 14 Worldwide
    • 14. 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
    • 15. 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
    • 16. 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
    • 17. Lipid metabolism in Diabetes 18
    • 18. Lipid metabolism in Diabetes 19
    • 19. Lipid metabolism in Diabetes 20
    • 20. Lipid metabolism in Diabetes 21
    • 21. 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
    • 22. 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
    • 23. 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
    • 24. 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
    • 25.  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
    • 26. 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
    • 27. • 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
    • 28. 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
    • 29. 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
    • 30. Guidelines 31 NCEP – ATP III Guidelines Other targets • Total Cholesterol < 200 mg/dl • HDL-C > 40 mg/dl
    • 31. 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
    • 32. 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
    • 33. 1. Lifestyle changes (TLC) 2. Pharmacologic therapy i. Lipid management ii. Anti-diabetic therapy 3. Combination therapy 4. New agents 34
    • 34. 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
    • 35. 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
    • 36. Macronutrient Recommendations for the TLC Diet Treatment of diabetic dyslipidemia 37
    • 37. 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
    • 38. 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
    • 39. HMG Co-A reductase inhibitors Treatment of diabetic dyslipidemia 40
    • 40. HMG Co-A reductase inhibitors Treatment of diabetic dyslipidemia 41
    • 41. 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
    • 42. Fibric acid derivatives (fibrates) Treatment of diabetic dyslipidemia 43
    • 43. 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.
    • 44. 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
    • 45. 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
    • 46. Treatment of diabetic dyslipidemia 47 Bile acid sequestrants
    • 47. 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
    • 48. 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
    • 49. 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
    • 50. 51
    • 51.  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
    • 52.  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
    • 53. 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
    • 54. 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
    • 55.  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