1、Coronary artery disease, Hypertension and Lipids In Diabetes,Dr. SPURGEON Dept of EndocrinologyChristian Medical CollegeVellore,Case 1,58-year-old Mr.A presented to the emergency with worsening dyspnoea of 24 hr duration. Two days ago he was referred to an orthopedician by his family doctor when he
2、had presented with acute onset neck pain, shoulder pain and vague discomfort. He was on irregular drugs for diabetes for last 8 years. He had quit smoking 1 year ago subsequent to the development of right leg claudication.,On examination his BP was 100/60 mm Hg, had crepts over lung base and absent
3、right leg pulse. ECG showed fully evolved MI with Q-waves in the anterolateral leads. RBS was 326 mg/dl and urine ketone was trace positive.,Case 2,A 55 year old obese woman came to the OPD for check up.She had stopped her anti-diabetic medications for last 6 months.Her BP was 160/100, HbA1c 8.2 %,F
4、PG - 210,2hr PPBG- 300,TC- 256,LDL-151,TGL- 286 & HDL - 48mg/dl. What is the appropriate line of management?,The problem,CAD -the main cause of mortality in diabetes. Diabetes increasing in epidemic proportionsThe increasing life expectancy - so the numbers are expected to go upsignificantly.Dyslipi
5、demia and hypertension -the common co-morbid conditions in diabetes significantly affect the outcome.The crucial role of physician in screening and management is important.,What is different with diabetes ?,Coronary artery disease is 3-4 times more common. Sudden death is higher by 50% in males and
6、100% in females. Loss of premenopausal protection in females. Triple vessel disease, multiple lesions per patients and more distal involvement of coronary arteries. Atypical presentation delays diagnosis. LV dysfunction is more common.,the difference,Coexisting diabetic cardiomyopathy worsens the ou
7、tcome. Revascularization procedures have less favorable outcome. Restenosis is more common.Defective lipid metabolism in diabetes. Autonomic neuropathy in diabetes worsens the outcome.,Pathogenesis of accelerated atherosclerosis,Hyperglycemia Obesity Dyslipidemia of diabetes Hypertension Altered hem
8、orheology Oxidative stress Hyperinsulinemia selective MAPK pathway,Clinical Manifestations ,With the classical symptoms of stable angina, unstable angina or myocardial infarction. Silent or painless ischemic symptoms -dyspnoea, hypotension,sweating,syncope or asymptomatic. Complications like shock,
9、conduction disturbances, cardiac failure, re-infarction and ketoacidosis.Atypical symptoms - dyspepsia, arm pain, toothache, sudden falls, vomiting, and giddiness.,Evaluation,Resting ECG - has a low sensitivity A normal resting ECG does not rule out an acute coronary syndrome unless - a combination
10、of a) Clinical features, b) Serial cardiac enzyme and ECGs and c) Significant relief with treatment of non-cardiac illness,Further evaluation,Stress ECG - excludes triple vessel disease but not single or double vessel disease.Stress Echo - valuable, reliable and cost-effective but does not give info
11、rmation on the nature of the lesion.Angiography - describes the nature and site of the lesion but does not give 3D image and eccentric lesions are not visualized.Nuclear imaging -widespread availability is a problem. SPECT and PET assess viable myocardium.,Glycaemic control CAD,Role of optimal glyca
12、emic control in preventing or retarding complications of diabetes applies to cardiovascular diseases also. ACCORD/ADVANCE and VADT STENO-2 Metabolic memory/Legacy effect,Hypertension -the problem statement,Affects 2060% of patients with diabetes.Substantially increases the risk of both macro vascula
13、r and micro vascular complications. Increases mortality by 7 folds.In diabetic nephropathy increases mortality by 37 folds. 85% of nephropathy patients have hypertension.,How crucial is BP control ?,Each 10-mmHg decrease in mean Sbp = 12% reductions in risk for any complication =15% for deaths relat
14、ed to diabetes =11% for myocardial infarction=13% for micro vascular complications.,What is the target BP?,Blood pressures lower than 125/75 mmHg are recommended for people who have proteinuria higher than 1gm/day and renal insufficiency regardless of etiology.A target blood pressure goal of 130/80
15、mmHg is reasonable if it can be safely achieved.,Non-pharmacological management,Moderate sodium restriction Weight reduction Moderately intense physical activitySmoking cessation and moderation of alcohol intake,Pharmacotherapy of hypertension,ACE inhibitors and ARBs have a favorable effect on renal
16、 and cardiovascular systems. Diuretics are recommended when BP control is still uncontrolled. -blockers along with ACE inhibitors help in reducing myocardial infarction and heart failure. Non-DCCBs (i.e., Verapamil and Diltiazem) may reduce microalbuminuria. DCCBs (i.e.,Amlodipine) in combination wi
17、th ACE inhibitors, -blockers, and diuretics help in controlling blood pressure.,When to start therapy?,Bp should be measured at every visit both in thesitting and lying down positions.SBP 130, DBP 80 - needs repeated readings.SBP of 120139 mmHg or a DBP of 8089 mmHgrequires lifestyle/behavioral ther
18、apy for a maximum of3 months. SBP 140 mmHg or DBP 90 mmHg should receive drug therapy in addition.,Special situations,Ischemic Heart Disease Stable angina beta blockers or long acting CCBsUnstable angina/MI beta blockers +ACE InhibitorsPost MI CCFACE-Is + beta blockers + aldosterone antagonists Preg
19、nancy Alpha methyldopa, vasodilators and calcium channel blockers are safe,Cardio protective drugs,Anti-platelet drugs: Aspirin and Clopidogrel ACE inhibitors: reduce cardiac remodeling, infarct size, improve endothelial function and fibrinolysis. Beta-blockers: cardio-selective drugs reduce sympath
20、etic load on the heart and improve the outcome. As a primary prevention strategy aspirin is recommended in those with risk factors like hypertension, smoking and dyslipidemia.,Surgical intervention,PTCA (Percutaneous Transluminal Coronary Angioplasty) less effective due to extensive disease and re-s
21、tenosisCABG (Coronary bypass grafting) with internal mammary artery -is better than bypass grafting with the saphenous vein and more effective than PTCA.,Dyslipidemia in Diabetes,Kolovo GD. Postgrad Med J. 2005;81;358-366.,Mechanisms of Dyslipidemia in the Metabolic Syndrome,FFA: free fatty acids TG
22、: triglycerides LPL: lipoprotein lipase HDL: high density lipoprotein CETP: cholesterol ester transfer protein CE: cholesterol ester VLDL: very low density lipoprotein,Proteolysis of Apo B-100, Clearance LPL, APO CIII,VLDL,HDL,Hepatic lipase (removes PL&TG),(CETP),LDL,SD LDL, TG Apo B VLDL,Hepatic l
23、ipaseor lipoprotein lipase (remove PL&TG),TG,CE,Fat Cells,Liver,FFA,Kidney,Lipid-poor Apo A-1,IR,X,Insulin,(CETP),CE,TG,CETP=cholesterol ester transfer protein.,CE on TGRL,HDL,SD LDL,“Atherogenic Dyslipidemia” of DM-2,Ginsberg HN. J Clin Invest. 2000;106(4):453-457.,“Atherogenic Dyslipidemia” (=Dysl
24、ipidemia of Diabetes Mellitus/ Insulin Resistance),Hypertriglyceridemia (HTG) Low HDL-C Small, dense LDL (Increased VLDL-C) (NonHDL-C),NCEP Guidelines-TG and NonHDL-C as Important Parameters for Lipid Management,HDL-C = high-density lipoprotein cholesterol; LDL-C = low density lipoprotein cholestero
25、l; NCEP = National Cholesterol Education Program; TG = triglyceride; VLDL-C = very low-density lipoprotein cholesterol,Treatment Objectives for Elevated Triglycerides,Primary Objective: LDL-C goal Secondary Objective: non-HDL C reduction (VLDL-Ca and LDL-C),“Very High” TG 500,“High” TG 200-499,Prima
26、ry Objective: TG reduction Secondary Objective: LDL-C and non HDL reduction,aVLDL-C levels are influenced by triglyceride levelsPrescription Omega-3 is indicated for the reduction of very high triglycerides, in addition to diet, in adult patients with triglycerides 500 mg/dL,Third Report of the NCEP
27、 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421.,Non-HDL Includes All Atherogenic Lipoprotein Classes,Very low-density lipoprotein Made in the liver TG CE Carries lipids from the liver to peripheral tissues,HDL,LDL,
28、IDL,VLDL,Intermediate-density lipoprotein Formed from VLDL due to loss of TG Also known as a VLDL remnant,Low-density lipoprotein Formed from IDL due to loss of TG CETG,High-density lipoprotein Removes cholesterol from peripheral tissues,Lp(a),Lipoprotein (a) Formed from LDL w/ addition of apo (a)?
29、Very atherogenic,NonHDL-C = Total C HDL-C (all atherogenic lipids) NonHDL-C goal = LDL-C goal + 30:NonHDL-C is a stronger predictor of CHD risk than LDL-C,Management of dyslipidemia,In all patients with diabetes and IGT check lipid profile at diagnosis and during annual screening. R/o alcohol, estro
30、gen use, physical inactivity,renal impairment, hypothyroidism, steroids,diuretics and familial hyperlipidemia.,Drugs available:,Life style modification Glycaemic control Statins Fibrates Niacin Ezetimibe Bile acid resins,Dietary modification,Diet - reduces LDL cholesterol 1525 mg/dl.carbohydrate - 5
31、0 to 60% fat - 24 to 28% protein 10 to 15% Saturated fat 7% mufa and pufa 10% each of the total fat.The total cholesterol intake 200 mg / day.,Management of dyslipidemia,Physical activity: help in reducing TGL only a minimal effect on HDL levels.,Statin therapy,Lovastatin 2080 mg Pravastatin 2040 mg
32、 Fluvastatin 2080 mg Simvastatin 2080 mg Atorvastatin 1080 mg Rosuvastatin 520 mg Cerivastatin 0.40.8 mg,36,Time course of Statin effects,* Time course established,Days,Years,LDL-C lowered*,Inflammation reduced,Vulnerable plaques stabilized,Endothelial function restored,Ischemic episodes reduced,Car
33、diac events reduced*,Common side effects Headache, Myalgia, Fatigue, GI intol. Flu-like symptoms Increase in liver enzymes serious problems are very rare Occurs in 0.5 to 2.5% of cases in dose-dependent manner Myopathy occurs in 0.2 to 0.4% of patients Rare cases of Rhabdomyolysis We can reduce this
34、 risk by Cautiously using statins in impaired renal function Using the lowest effective dose Cautiously combining statins with fibrates Muscle toxicity requires the discontinuation of statin,Cholesterol Treatment Trialist Collaboration Findings,Prospective meta-analysis from 90,056 patients in 14 ra
35、ndomized trials of statins demonstrated: Decreasing LDL-C with a statin by 1 mmol/L in patients with and without established cardiovascular disease, decreased the following: All cause mortality 12% CHD 19% Major vascular event 21% Non-fatal MI 26% CHD death 19% Need for revascularization 24% Stroke
36、17%,Lancet 2005;366:1267-78,Fenofibrate,Enhances the activity of lipoprotein lipase Reduces hepatic fatty acid synthesis Inhibits HMG co-enzyme A reductase activity Reduces the CETP activity Increases the LCAT activity Increases the production of Apo AI and Apo A II,40,Fibric Acid Derivatives,Major
37、actions Lower TG 2050%,VLDL synthesis Raise HDL-C 1020% LDL (TG is N), LDL (TG is ) Increase the SDL particle size (less athero) Side effectsDyspepsia, gallstones, myopathy, Abn. LFT ContraindicationsSevere renal or hepatic / biliary disease,41,Fibric Acid Derivatives,Drug Dose Clofibrate 1000 mg BI
38、D Bezafibrate 200 mg BID Gemfibrozil 600 mg BID Fenofibrate 200 mg OD Fenofibrate micronized 160 mg OD,42,Effect of Niacin on Lipoproteins,Adapted from Knopp RH. N Engl J Med 1999;341:498-511,43,Nicotinic Acid,Products available Immediate-release, 24 g/d, Sustained Release 3 g /d Extended-release (N
39、iaspan) 12 g/d Best agent to raise HDL-C Reduces coronary events Adverse effects Flushing, itching, headache (immediate-release, Niaspan) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity Contraindications Active liver disease or unexplai
40、ned LFT elevations Peptic ulcer disease,44,Bile Acid Resins (BAR),Major actions Reduce LDLc by 1530% Raise HDLc by 35% May increase TG Side effects GI distress / constipation / nausea Decreased absorption of other drugs Contra indications Dysbetalipoproteinemia, Biliary Obstruction Raised TG (especi
41、ally 400 mg/dL),45,Bile Acid Resins,Drug Dose Range Cholestyramine 416 g Colestipol 520 g Colesevelam 2.63.8 g,46,How do we treat ?,Increased LDL Statins +/- EZ Increased TG Fibrates Decreased HDL Niacin Increased Lp(a) Niacin Increased LDL + TG Statin + Fibrate LDL + HDL Statin + Niacin TG + HDL Fi
42、brate + Niacin,Agents That Raise HDL-C,Agent HDL-C Primary Use Nicotinic acid 15-35% HDL Fibrates 5-20% TG Statins 5-15% LDL Rx omega-3a 5-10% TG Bile-acid resinsa 2-5% LDL Ezetimibea 1-3% LDL Pioglitazonea 5-20% Glucose Estrogensa 10-25% Hot flashes -blockersa 10-20% BPH Alcohol* 5-10% Social,After
43、 Belalcazar LM, et al. Prog Cardiovasc Dis. 1998;41:151-174.Insull W, et al. Mayo Clin Proc. 2001;76:971-982.McKenney JM, et al. Pharmacotherapy. 2007;27:715-728.,Monitoring,Targets (in mg/dl) HDL 40 (50 in women)TGL 150LDL 100Total cholesterol 180. Therapy is monitored with muscle enzymes and liver enzyme estimation.Discontinue if liver enzymes are increased by 10 times the basal values.Reduce dose of drugs and monitor renal functions while combining with fibrates.,
