Type 2 Diabetes

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  • The risk of CAD and stroke is increased two to four times in patients with diabetes. Cardiovascular disease is a major cause of morbidity and mortality in diabetes. Morbidity and mortality rates are two to four times higher than in age- and sex-matched groups in the population without diabetes. The eye and the kidney are common sites for microvascular complications of diabetes. Diabetic retinopathy is the leading cause of adult blindness in North America. Cataracts and glaucoma are also significantly more frequent in patients with diabetes, especially those over age 65. Diabetes is the leading cause of end-stage renal failure. Foot problems, a frequent consequence of neuropathy and peripheral vascular disease, constitute a major complication. Diabetes is the leading cause of non-traumatic lower-extremity amputations in North America.
  • OASIS study: total mortality The OASIS study also supports the concept of diabetes as a CHD risk equivalent. This study is more generalizable than the Finnish East-West study since it was based in 6 different countries and has a larger population. Reference: Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102:1014-1019.
  • The Canadian Lipid Working Group developed target levels for LDL, TC/HDL ratio and triglycerides, as listed in the chart. Diabetes itself is a potent risk factor for CAD in both men and women over age 30.
  • Natural History of Type 2 Diabetes Natural History of Type 2 Diabetes Prior to type 2 diabetes insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to an increases in circulating insulin. So as insulin resistance increases, so does the production of insulin needed to keep blood sugars normal. As time progresses, the insulin resistance reach a peak and stabilize while the insulin producing cells begin to wear out. We call it pooped out pancreas. First, Impaired Glucose Tolerance (IGT): This is the point that the Beta cell begins to fail and blood sugars begin to elevate, especially after a large CHO load.. Type 2 Diabetes: Following the onset of Beta-cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time.  
  • Type 2 Diabetes

    1. 1. Diabetes mellitus & Cardiovascular Disease Cardiology Grand Rounds May 11, 2004 Dr. William Harper Assistant Professor of Medicine, McMaster University. Endocrinologist, Hamilton General Hospital www.drharper.ca
    2. 2. DM & Cardiovascular Disease <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    3. 3. Diabetes: Complications Macrovascular Microvascular Stroke Heart disease and hypertension 2-4 X increased risk Foot problems Diabetic eye disease (retinopathy and cataracts) Renal disease Peripheral Neuropathy Peripheral vascular disease Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29. Complications Erectile Dysfunction
    4. 4. Fatal and Non-Fatal Myocardial Infarction 14% decrease per 1% decrement in HbA1c p<0.0001 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
    5. 5. Disease Burden of Diabetes Mellitus <ul><li>Leading cause of blindness (12.5% of cases) </li></ul><ul><li>Leading cause of ESRD (42% of cases) </li></ul><ul><li>50% of all non-traumatic amputations </li></ul><ul><li>2.5x increase risk of stroke </li></ul><ul><li>2-4x increase in cardiovascular mortality </li></ul><ul><li>DM responsible for 25% of cardiac surgeries </li></ul><ul><li>Mortality in DM: 70% due to Cardiovascular disease </li></ul>
    6. 6. How is CAD Different in Diabetes ? <ul><li>> CAD extent </li></ul><ul><ul><ul><li>Multi-vessel disease </li></ul></ul></ul><ul><ul><ul><li>Distal disease – more difficult to revascularize </li></ul></ul></ul><ul><li>Silent ischemia/MI </li></ul><ul><li>Younger </li></ul><ul><li>Women </li></ul><ul><li>Worse outcomes despite revascularization </li></ul><ul><ul><ul><li>Increased re-stenosis after PCI even with stents </li></ul></ul></ul><ul><ul><ul><li>ACB: worse periop & long-term outcomes </li></ul></ul></ul>
    7. 7. Haffner et al, NEJM, 339(4):229-34, 1998.
    8. 8. Was Haffner right? <ul><li>Conclusions based on no difference found between 2 groups: </li></ul><ul><ul><ul><li>No DM, prior MI N= 69 </li></ul></ul></ul><ul><ul><ul><li>DM, no prior MI N = 890 </li></ul></ul></ul><ul><li>Underpowered! </li></ul>
    9. 9. Evans et al. <ul><li>BMJ 324: 939-942 </li></ul><ul><li>April 2002 </li></ul><ul><li>Cross-sectional study </li></ul><ul><ul><ul><li>DM 1155 patients </li></ul></ul></ul><ul><ul><ul><li>MI 1347 patients </li></ul></ul></ul><ul><li>Cohort study </li></ul><ul><ul><ul><li>DM 3477 patients </li></ul></ul></ul><ul><ul><ul><li>MI 7414 patients </li></ul></ul></ul>
    10. 10. OASIS Study: Total Mortality Event Rate Months 6 9 15 3 18 21 12 RR=2.88 (2.37–3.49) Malmberg K et al. Circulation 2000;102:1014-1019. ©2000 Lippincott Williams & Wilkins. 24 RR=1.99 (1.52–2.60) RR=1.71 (1.44–2.04) RR=1.00 Diabetes/CVD (n = 1148) No Diabetes/CVD (n = 3503) Diabetes/No CVD (n = 569) No Diabetes/No CVD (n = 2796)
    11. 11. Canadian Lipid Working Group: Target Levels in Diabetes = established CVD <ul><li>Canadian recommendations place patients with diabetes in “very high” risk group for CAD (1999): </li></ul><ul><li> LDL TC/HDL ratio TG </li></ul><ul><li>< 2.5 mmol/L < 4 < 2.0 mmol/L </li></ul>
    12. 12. Heart Protection Study & DM <ul><li>n = 20,530 (3982 with Diabetes Mellitus) </li></ul><ul><li>hi-risk patients </li></ul><ul><ul><ul><li>age 40-80, prior CAD or PVD, DM, HTN (males age > 65) </li></ul></ul></ul><ul><ul><ul><li>Non-fasting TC > 3.5 mM </li></ul></ul></ul><ul><li>5.5 year RCT: Simvastatin 40 mg od vs placebo </li></ul><ul><ul><ul><li>Mortality ARR 1.8% (NNT 56) </li></ul></ul></ul><ul><ul><ul><li>Vascular Event ARR 5.4% (NNT 19) </li></ul></ul></ul><ul><ul><ul><ul><li>Coronary event, Stroke, Revascularisation </li></ul></ul></ul></ul><ul><li>Benefit obtained even in low cholesterol patients: </li></ul><ul><ul><ul><li>LDL baseline 2.5 mM  1.7 mM with Rx </li></ul></ul></ul><ul><ul><ul><li>Prior LDL targets for hi-risk patients too high? </li></ul></ul></ul><ul><ul><ul><ul><li>Canadian Lipid Work Group 2.5 mM </li></ul></ul></ul></ul><ul><ul><ul><ul><li>NCEP 2.6 mM </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CARE 3.2 mM </li></ul></ul></ul></ul>
    13. 13. T2DM & Atherosclerosis <ul><li>How much risk !?! </li></ul>
    14. 14. T2DM & Atherosclerosis <ul><li>How much risk !?! </li></ul><ul><li>Epidemiological data: 2-4x increased </li></ul>
    15. 15. T2DM & Atherosclerosis <ul><li>How much ABSOLUTE risk !?! </li></ul><ul><li>It depends on the particular patient! </li></ul><ul><li>i.e. the patient in the study or the patient in your office! </li></ul>
    16. 16. T2DM & Atherosclerosis <ul><li>UKPDS </li></ul><ul><ul><ul><li>Cntrl group event rates </li></ul></ul></ul><ul><ul><ul><li>MI 1.74% per year </li></ul></ul></ul><ul><ul><ul><li>Fatal MI 0.8% per year </li></ul></ul></ul><ul><ul><ul><li>CVA 0.5% per year </li></ul></ul></ul><ul><ul><ul><li>Amputation for PVD 0.16% per year </li></ul></ul></ul><ul><li>HOPE (> 55 y.o., DM + 1 CV risk factor) </li></ul><ul><ul><ul><li>MI, CVA, or death from CVD </li></ul></ul></ul><ul><ul><ul><li>Cntrl group event rate (i.e. no ramipril): 4% per year </li></ul></ul></ul>
    17. 17. T2DM & Atherosclerosis <ul><li>What about the patient in your office? </li></ul><ul><li>UKPDS Risk Engine </li></ul><ul><li>Download at www.dtu.ox.uk </li></ul><ul><li>Weigh the cardiovascular risk with the cost and side effects of preventative medications </li></ul>
    18. 18. DM & Cardiovascular Disease <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    19. 19. Glycemic Control & atherosclerosis <ul><li>UKPDS 33, Lancet 352:837-53, 1998. </li></ul><ul><li>RCT of a policy of intensive BS control </li></ul><ul><ul><ul><li>FPG < 6 mM v.s. FPG < 15 mM </li></ul></ul></ul><ul><ul><ul><li>Achieved a number of ways: </li></ul></ul></ul><ul><ul><ul><ul><li>Sulfonylurea (chlorpropamide or glibenclamide/glyburide) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Metformin (overweight subgroup, add-on) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Insulin (bedtime basal +/- basal/bolus regimens) </li></ul></ul></ul></ul>
    20. 20. <ul><li>UKPDS 33: Main study </li></ul><ul><li>Any DM related end point: 12% RRR </li></ul><ul><li>Microvascular complications: 25% RRR </li></ul><ul><ul><ul><li>Reduced eye disease: retinal laser Sx (19%), cataract Sx (24%), DM retinopathy (21%) </li></ul></ul></ul><ul><ul><ul><li>33% RRR microalbuminuria, 74% RRR in doubling of creatinine </li></ul></ul></ul><ul><li>MI: 16% RRR (P = 0.052 NS) </li></ul><ul><li>No mortality benefit </li></ul>Glycemic Control & atherosclerosis
    21. 21. <ul><li>UKPDS 34: overweight metformin substudy </li></ul><ul><li>Unlike sulfonylurea & insulin: no weight gain </li></ul><ul><li>Any DM related end point: 32% RRR </li></ul><ul><li>DM related death: 42% RRR </li></ul><ul><li>All cause mortality: 36% RRR </li></ul><ul><li>MI: 39% RRR </li></ul><ul><li>Metformin + SU: increased mortality? </li></ul>Glycemic Control & atherosclerosis
    22. 22. T2DM & Macrovascular disease <ul><li>Why no clear benefit in UKPDS to glycemic cntrl? </li></ul><ul><li>Low CV risk patients: </li></ul><ul><ul><ul><li>UKPDS cntrl death rate: 1.2 % per year </li></ul></ul></ul><ul><ul><ul><li>HOPE cntrl death rate: per year 2.5% per year </li></ul></ul></ul><ul><li>Unable to maintain glycemic cntrl due to limited interventions: </li></ul><ul><ul><ul><li>Available: glyburide, chlorpropamide, metformin, regular insulin </li></ul></ul></ul><ul><ul><ul><li>No newer sulfonylureas: glimepiride (Amaryl), gliclazide (diamicron) </li></ul></ul></ul><ul><ul><ul><li>No meglitinides: repaglinide (Gluconorm), nateglinide (Starlix) </li></ul></ul></ul><ul><ul><ul><li>No TZD’s: rosiglitazone (Avandia), pioglitazone (Actos) </li></ul></ul></ul><ul><ul><ul><li>No insulin analogues: (Humalog, Novorapid, Lantus) </li></ul></ul></ul>
    23. 23. DCCT, NEJM 329:977-86, 1993. UKPDS 33, Lancet 352:837-53, 1998.
    24. 24. Natural History of Type 2 Diabetes Normal Impaired glucose tolerance Type 2 diabetes Time Insulin resistance Insulin production Glucose level  -cell dysfunction
    25. 25. ACS: Glycemic Control <ul><li>2/3 of ACS patients may have dysglycemia: </li></ul><ul><ul><ul><li>1/3 overt DM (FBS > 7.0 mM, 2hPG > 11.1 mM) </li></ul></ul></ul><ul><ul><ul><li>1/3 IGT (2hPG > 7.8 mM) </li></ul></ul></ul><ul><ul><ul><li>At time of discharge & 3 months later </li></ul></ul></ul><ul><li>Higher BS predicts worse outcomes: </li></ul><ul><ul><ul><li>Increased mortality </li></ul></ul></ul><ul><ul><ul><li>Increased CHF, cardiogenic shock (non-DM) </li></ul></ul></ul><ul><li>Stress hyperglycemia? </li></ul><ul><li>Epiphenomenon? </li></ul>
    26. 26. <ul><li>DIGAMI </li></ul><ul><ul><ul><li>620 patients AMI, prior dx DM or BS > 11 mM </li></ul></ul></ul><ul><ul><ul><li>IV insulin gtt started @ 5 U/h </li></ul></ul></ul><ul><ul><ul><li>Titrated to keep BS 7-10.9 mM </li></ul></ul></ul><ul><ul><ul><li>Insulin IV > 24h  MDI > 3 months </li></ul></ul></ul><ul><ul><ul><li>No in-hospital mortality benefit. </li></ul></ul></ul><ul><ul><ul><li>Rx Increased hospitalization by 1.8d </li></ul></ul></ul><ul><ul><ul><li>0.5% reduction HbA1c @ 3 months </li></ul></ul></ul><ul><ul><ul><li>@ 1 year % on Insulin: 72% Rx Group 49% Cntrl Group </li></ul></ul></ul><ul><ul><ul><li>1 year mort: ARR 7 % (26 - 19 %), NNT 14 </li></ul></ul></ul><ul><ul><ul><li>3.4 y mort: ARR 11% (44 – 33 %), NNT 9 </li></ul></ul></ul>ACS: Glycemic Control
    27. 27. ACS: DIGAMI <ul><li>Small study (N=620), single centre </li></ul><ul><li>Primary outcome negative </li></ul><ul><li>What part of intervention beneficial? </li></ul><ul><ul><ul><li>Few days of IV insulin? </li></ul></ul></ul><ul><ul><ul><li>3 months of SC insulin M.D.I. ? </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Benefit only seen at 1 year </li></ul></ul></ul></ul></ul><ul><li>DIGAMI 2… </li></ul>
    28. 28. Multifactorial DM Rx: STENO-2 <ul><li>Jan 2003, NEJM 348:383-93 </li></ul><ul><li>RCT mimicking real life clinic </li></ul><ul><li>160 T2DM patients with microalbuminuria </li></ul><ul><li>Randomized: </li></ul><ul><ul><ul><li>Conventional Rx as per National Guidelines </li></ul></ul></ul><ul><ul><ul><li>versus </li></ul></ul></ul><ul><ul><ul><li>Intensive Rx </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Behaviour modification </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pharmacotherapy: targeting BS, BP, Lipids, proteinuria, ASA (initially 2  prevention only, 1  prevention after 1999) </li></ul></ul></ul></ul></ul>
    29. 29. Multifactorial DM Rx: STENO-2
    30. 30. Multifactorial DM Rx: STENO-2
    31. 31. UKPDS 33, Lancet 352:837-53, 1998. STENO-2, NEJM, 348:383-93, 2003. DCCT, NEJM 329:977-86, 1993.
    32. 32. Multifactorial DM Rx: STENO-2
    33. 34. Insulin Glargine (Lantus) <ul><li>Substitution of glycine and arginine residues gives name “glargine” </li></ul><ul><li>2 arginine residues make glargine more soluble in acidic pH of injection medium but less soluble in physilogic pH of subQ tissues </li></ul><ul><li>Once injected, glargine precipitates leading to slower absorption </li></ul><ul><li>Glycine substitution prevents degradation in subQ tissues </li></ul>
    34. 35. Insulin Glargine (Lantus) Little to no peak effect  Less hypoglycemia
    35. 36. DM & Cardiovascular Disease <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    36. 37. Sites of Action of Currently Available Therapeutic Options GLUCOSE ABSORPTION GLUCOSE PRODUCTION Metformin Thiazolidinediones MUSCLE PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin PANCREAS INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide ADIPOSE TISSUE LIVER Alpha-glucosidase inhibitors INTESTINE
    37. 38. Gliclazide 2+ + 0  0  + Glimepiride 2+ + 0  0  + Repaglinide 1+ + 0 0 0 0 + Nateglinide 1+ ? 0 0 0 0 + Metformin 0 0 0 2+ + 0 - Acarbose 0 0 0 3+ 0   Rosiglitazone 0 + + 0 0  * + Pioglitazone 0 + + 0 0  * + Hypoglycemia Wt. Gain Edema GI Lactic Liver Use in effects Acidosis Toxicity Renal Failure Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933 * Liver enzyme monitoring recommended in product monographs Glyburide 4+ + 0  0  -
    38. 39. TZD adverse effects <ul><li>Edema </li></ul><ul><ul><ul><li>4-5% of patients get mild-moderate edema </li></ul></ul></ul><ul><ul><ul><li>15% if TZD used in combo with insulin </li></ul></ul></ul><ul><li>Mild anemia (dilutional) </li></ul><ul><li>Weight gain </li></ul><ul><ul><ul><li>Increase in subcutaneous not visceral fat </li></ul></ul></ul><ul><li>Myalgia (pioglitazone only) </li></ul><ul><ul><ul><li>Myalgia 5.4% pioglitaz. versus 2.7% placebo </li></ul></ul></ul><ul><ul><ul><li>Few patients with unexplained CK > 10x ULN </li></ul></ul></ul><ul><li>Contraindicated in class II, III and IV CHF </li></ul><ul><li>Contraindicated if ALT > 2.5x ULN or active liver disease </li></ul>
    39. 40. No $90/mos Start 80 mg bid Max 160 mg bid Diamicron Gliclazide Exp Sect 8 $ 60/mos $ 120/mos Start 4 mg od Max 4 mg bid Avandia Rosiglitazone Exp Sect 8 $92/mos Start 15-30 mg od Max 45 mg od Actos Pioglitazone Yes $14/mos Start 500 mg od-bid Max 1000 mg bid Glucophage Metformin No $45/mos Start 60-120 mg tid Max 180 mg tid Starlix Nateglinide Exp Sect 8 $45/mos Start 0.5 mg tid-qid Max 4 mg qid Gluconorm Repaglinide No $30-40/mos Start 1-2 mg od Max 8 mg od Amaryl Glimepiride Exp Sect 8 $30/mos Start 30 mg od Max 120 mg od Diamicron MR Gliclazide MR Yes $14/mos Start 1.25-5 mg od Spit dose bid > 10mg/d Max 10 mg bid Diabeta Glyburide ODB Cost Dose Trade Drug
    40. 42. Targeting Insulin Resistance? <ul><li>Does targeting insulin resistance > insulin secretion reduce CV risk? </li></ul>
    41. 43. Metabolic Syndrome: Clinical Diagnosis <ul><li>Presence of any 3 of the following: </li></ul><ul><li>Abdominal obesity (M > 102 cm, F > 88 cm) </li></ul><ul><li>TG > 1.7 mM </li></ul><ul><li>Low HDL (M < 1.0 mM, F < 1.3 mM) </li></ul><ul><li>BP > 130/85 </li></ul><ul><li>FPG > 6.1 mM </li></ul>
    42. 45. TZDs: effect on Metabolic Syndrome <ul><li>Reduce insulin resistance/blood sugar </li></ul><ul><li>Mild decrease in diastolic BP (2-4 mmHg) </li></ul><ul><li>Decrease PAI-1 (reduces procoagulant state) </li></ul><ul><li>Lipids: </li></ul><ul><ul><li>↓ TG ↑HDL (pioglitazone > rosiglitazone?) </li></ul></ul><ul><ul><li>↓ LDL (pioglitazone) </li></ul></ul><ul><ul><li>↑ LDL (rosiglitazone) </li></ul></ul><ul><ul><ul><li>No change in ApoB so ↑ due to larger less atherogenic particle size </li></ul></ul></ul><ul><li>Decrease in carotid artery intimal-media thickness (IMT) </li></ul>
    43. 46. Effect of Pioglitazone on Carotid Arterial Wall Thickness Intimal-medial thickness (mm) * † * p<0.005 † p<0.001 vs baseline Koshiyama H et al. JCEM 2001;86:3452-6
    44. 47. Targeting Insulin Resistance? <ul><li>Does targeting insulin resistance > insulin secretion reduce CV risk? </li></ul><ul><li>We don’t know yet! </li></ul><ul><li>BARI-2D: </li></ul><ul><ul><ul><li>CV outomes </li></ul></ul></ul><ul><ul><ul><li>Insulin sparing regimen (avandia, metformin) </li></ul></ul></ul><ul><ul><ul><li>versus </li></ul></ul></ul><ul><ul><ul><li>Insulin providing regimen (sulfonylurea, insulin) </li></ul></ul></ul><ul><li>PPAR, RECORD, PROACTIVE </li></ul><ul><ul><ul><li>TZD’s, CV outcomes </li></ul></ul></ul>
    45. 48. Targeting insulin Secretion ? <ul><li>Improve glycemic control in hi-risk patients to reduce CV risk </li></ul><ul><li>Using novel agents to get there! </li></ul><ul><li>ACCORD – glycemic cntrl arm HbA1c < 6 % </li></ul><ul><ul><ul><li>glimepiride, insulin glargine, (and metformin, rosiglitazone) </li></ul></ul></ul><ul><li>NAVIGATOR – nateglinide </li></ul><ul><li>ORIGIN, STREAM – insulin glargine </li></ul><ul><li>DIGAMI II - insulin </li></ul>
    46. 49. DM & Cardiovascular Disease Bottom Line… <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    47. 50. DM & Cardiovascular Disease Bottom Line… <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><ul><ul><li>DM increased risk (< than established CAD?) </li></ul></ul></ul><ul><ul><ul><li>Risk extends into BS levels below diagnostic threshold for DM </li></ul></ul></ul><ul><ul><ul><li>ACS: higher BS  worse prognosis </li></ul></ul></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    48. 51. DM & Cardiovascular Disease Bottom Line… <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><ul><ul><li>Glycemic cntrl alone may reduce CVD (UKPDS, DIGAMI) </li></ul></ul></ul><ul><ul><ul><li>Glycemic cntrl combined with other risk factor modification reduces CVD (STENO-2) </li></ul></ul></ul><ul><li>Glycemic control & CVD: best practice </li></ul>
    49. 52. DM & Cardiovascular Disease Bottom Line… <ul><li>Understanding cardiovascular risk in patients with diabetes </li></ul><ul><li>Glycemic control & CVD: evidence </li></ul><ul><li>Glycemic control & CVD: best practice </li></ul><ul><ul><ul><li>Patients with CVD: Glycemic target? </li></ul></ul></ul>
    50. 53. Patients with CVD: glycemic target <ul><li>Prevent microvascular complications (HbA1c < 7.0%) </li></ul><ul><li>Prevent macrovascular complications? </li></ul><ul><ul><ul><li>CDA 2003 Guidelines: HbA1c < 6.0% (if can be safely done) </li></ul></ul></ul><ul><ul><ul><li>No definitive evidence yet </li></ul></ul></ul><ul><li>Choice of DM therapy? </li></ul><ul><ul><ul><li>Sensitizers > Secretagogues/Insulin </li></ul></ul></ul><ul><ul><ul><li>No definitive evidence yet </li></ul></ul></ul><ul><ul><ul><li>No hypoglycemia with sensitizers alone, metformin weight-sparing </li></ul></ul></ul><ul><li>ACS? </li></ul><ul><ul><ul><li>CDA 2003 Guidelines: DIGAMI protocol </li></ul></ul></ul><ul><ul><ul><li>No definitive evidence yet </li></ul></ul></ul>
    51. 54. END
    52. 56. Insulin IV gtt <ul><li>CPG q1h x 2, then q2h: </li></ul><ul><li>Adjust Insulin IV infusion rate as per scale below: </li></ul><ul><li>< 4.0 Call MD </li></ul><ul><li>4.1-6.0 0.5 U/h (5cc/h) </li></ul><ul><li>6.1-8.0 1.0 U/h (10cc/h) </li></ul><ul><li>8.1-10.0 1.5 U/h (15cc/h) </li></ul><ul><li>10.1-12.0 2.0 U/h (20cc/h) </li></ul><ul><li>12.1-15.0 2.5 U/h (25cc/h) </li></ul><ul><li>15.1-18.1 3.0 U/h (30cc/h) </li></ul><ul><li>18.1-22.0 3.5 U/h (35cc/h) </li></ul><ul><li>> 22.1 Call MD </li></ul>
    53. 58. TZD Safety: Hepatotoxicity 2 liver dysfn 2 liver dysfn (1 case likely shock liver) 45 liver failure 28 death 15 liver Tx Post-marketing 0.26% pioglitaz. 0.25% placebo 0.17% rosiglitaz. 0.18% placebo 1.9% troglitaz. 0.6% placebo ALT > 3x ULN 1526 4500 2510 # of patients pre-marketing No No Yes Toxic to hepatocytes in vitro ? Pioglitazone Rosiglitazone Troglitazone

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