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Type 2 Diabetes Mellitus Treating to Target

Type 2 Diabetes Mellitus Treating to Target. January 22, 2004. Dr. William Harper Endocrinology & Metabolism Assisstant Professor of Medicine McMaster University www.drharper.ca. Complications. Diabetes: Complications. Macrovascular. Microvascular. Diabetic eye disease

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Type 2 Diabetes Mellitus Treating to Target

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  1. Type 2 Diabetes MellitusTreating to Target January 22, 2004. Dr. William Harper Endocrinology & Metabolism Assisstant Professor of Medicine McMaster University www.drharper.ca

  2. Complications Diabetes: Complications Macrovascular Microvascular Diabetic eye disease (retinopathy and cataracts) Stroke Heart disease and hypertension 2-4 X increased risk Renal disease Peripheral vascular disease Erectile Dysfunction Peripheral Neuropathy Foot problems Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

  3. Disease Burden of Diabetes Mellitus • Leading cause of blindness (12.5% of cases) • Leading cause of ESRD (42% of cases) • 50% of all non-traumatic amputations • 2.5x increase risk of stroke • 2-4x increase in cardiovascular mortality • DM responsible for 25% of cardiac surgeries • Mortality in DM: 70% due to Cardiovascular disease

  4. Haffner et al, NEJM, 339(4):229-34, 1998.

  5. Evans et al. • BMJ 324: 939-942 • April 2002 • Cross-sectional study • DM 1155 patients • MI 1347 patients • Cohort study • DM 3477 patients • MI 7414 patients

  6. How is CAD Different in Diabetics ? • > CAD extent • Multi-vessel disease • Distal disease – more difficult to revascularize • Silent ischemia/MI • Younger • Women • Worse outcomes despite revascularization • Increased re-stenosis after PCI even with stents • ACB: worse periop & long-term outcomes

  7. T2DM: “Rx to Targets” What are the targets?

  8. What are the targets? • Cardiovascular risk factor modification • ASA, Smoking Cessation • Lipids • Blood Pressure • Proteinuria/DM nephropathy • Angiotensin II attenuation benefits independent of BP • Glycemic control • Microvascular benefit • Macrovascular benefit ? • Target insulin resistance > insulin deficiency ?

  9. Canadian Lipid Working Group:Target Levels in Diabetes • Canadian recommendations place patients with diabetes in “very high” risk group for CAD LDL TC/HDL ratio TG < 2.5 mmol/L < 4 < 2.0 mmol/L Statins effective in lowering LDL1 • Fibrates are useful for raising HDL, lowering TG1,2 • Some OHA may improve lipids, but are not indicated for lipid management3 • may need to use combo or Niacin cautiously

  10. Heart Protection Study & DM • n = 20,530 (3982 with Diabetes Mellitus) • hi-risk patients • age 40-80, prior CAD or PVD, DM, HTN (males age > 65) • Non-fasting TC > 3.5 mM • 5.5 year RCT: Simvastatin 40 mg od vs placebo • Mortality ARR 1.8% (NNT 56) • Vascular Event ARR 5.4% (NNT 19) • Coronary event, Stroke, Revascularisation • Benefit obtained even in low cholesterol patients: • LDL baseline 2.5 mM  1.7 mM with Rx • Prior LDL targets for hi-risk patients too high? • Canadian Lipid Work Group 2.5 mM • NCEP 2.6 mM • CARE 3.2 mM

  11. Heart Protection Study

  12. Lipids & DM • What about HDL & TG? • Fibrates > Statins at  HDL and  TG • VA-HIT, a “low HDL Study” • 2531 patients (620 DM), hi-risk with prior CAD • HDL < 1.0 mM, TG < 3.4 mM, LDL < 3.6 mM • RCT Gemfibrozil 600 mg po bid • Coronary death or MI ARR 4.4% (NNT 23) • LDL 2.3-3.6 mM at baseline • Not on a statin despite LDL > 2.5 mM

  13. Lipids & DM • In DM patients where LDL is already adequately controlled by a statin, will the addition of a fibrate provide further benefit? • ACCORD: • 10,000 patients with ½ Lipid control arm • RCT: simvastatin + fenofibrate v.s. placebo • Results…

  14. What are the targets? • Cardiovascular risk factor modification • ASA, Smoking Cessation • Lipids • Blood Pressure • Proteinuria/DM nephropathy • Angiotensin II attenuation benefits independent of BP • Glycemic control • Microvascular benefit • Macrovascular benefit ? • Target insulin resistance > insulin deficiency ?

  15. DM: BP cntrl • Difficult to consider BP cntrl in DM without also taking into account: • Proteinuria/DM nephropathy • Cardiovascular benefit of reducing angiotensin II action independent of BP

  16. Renin-Angiotensin-Aldosterone Axis Cough Rash Bradykinin - ACE-I ACE-I (ex. Ramipril/Altace) ACE Angiotensin I Angiotensin II ARB (ex. Losartan/Cozaar) Aldosterone + Renin Na retention K+ & H+ loss Angiotensinogen (Renin substrate)

  17. BP Trials in DM patients (some) • UKPDS • HOT • ALLHAT • LIFE • HOPE

  18. BP Trials in DM patients • UKPDS • atenolol = captopril at reducing outomes (UKPDS 39) • Benefit to reducing SBP < 120 (UKPDS 36, post-hoc subgroup analysis) • Currently SBP target < 120 being assessed in BP arm of the ACCORD Study

  19. BP Trials in DM patients • UKPDS: atenolol = captopril in  events • HOT: felodipine,  CV events with DBP < 80 • ALLHAT • Chlorthalidone > lisinopril or amlodipine (less CHF) • Chlorthalidone  BS/diagnosis of DM • LIFE (DM substudy) • 1195 patients with DM/HTN/LVH • Losartan > atenolol in  CV death/MI/CVA despite equivalent BP lowering effects • HOPE: not a BP trial per se

  20. Complications Effect of ACE Inhibitionin DiabetesHOPE Study Relative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes 22% Myocardial infarction p = 0.01 33% Stroke p = 0.0074 37% Cardiovascular death p = 0.0001 24% Overt nephropathy p = 0.027 17% Revascularization p = 0.031 20% Heart failure p = 0.019 DM > 55 yo & 1 additional CV risk factor (HTN, microalbuminuria, current smoker, TC > 5.2 mM, HDL < 0.9 mM) HOPE investigators. Lancet 2000;355:253-259.

  21. DM Nephropathy Microalbuminuria: 30-300 mg/d (20-200 ug/min) Macroalbuminuria: > 300 mg/d (> 200 ug/min)

  22. DM Nephropathy & BP • T1DM: • ACE-I  albumin excretion and progression to overt nephropathy (macroalbuminuria) in patients with microalbuminuria even if BP is normal • ACE-I  progression to ESRD or death in patients with overt nephropathy and serum creat > 132 uM

  23. DM Nephropathy & BP • T2DM: • ACE-I & ARB  progression of micro to macro albuminuria • In contrast to T1DM, no demonstrated benefit of ACE-I over other anti-HTN (ex. UKPDS 39 captopril vs atenolol) in preventing ESRD in patients with overt nephropathy • ARBs have been shown to be renal protective in T2DM with overt nephropathy: • IDNT: irbesartan (Avapro)  ESRD/death/creat 2x • RENAAL: losartan (Cozaar)  creat 2x and ESRD • Note: in both IDNT and RENAAL all ACE-I were stopped during the study

  24. ACE-I & ARB Combination? • STENO-2: part of a multifactorial approach (only 28% patients) • CHF Studies: • CHARM: candesartan (Atacand)  mortality, CHF admits, and onset of DM • Val-HeFT: valsartan (Diovan)  CHF admits • CALM Study: • Mogensen et.al. BMJ 2000;321:1440-1444 • T2DM, HTN, microalbuminuria • candesartan & lisinopril (Zestril, Prinivil) • 12 wk study • outcomes: BP, proteinuria

  25. CALM Study • Combo Rx with candesartan & lisinopril reduced BP • Lisinopril reduced proteinuria • Candesartan reduction of proteinuria was NS either alone or in combination with lisinopril

  26. BP Cntrl in DM: CHEP guidelines • Canadian Hypertension Education Program • BP target: • < 130/80 (SBP 120? (ACCORD) / HOT target DBP 80) • < 125/75 Proteinuria > 1 gm/d

  27. What are the targets? • Cardiovascular risk factor modification • ASA, Smoking Cessation • Lipids • Blood Pressure • Proteinuria/DM nephropathy • Angiotensin II attenuation benefits independent of BP • Glycemic control • Microvascular benefit • Macrovascular benefit ? • Target insulin resistance > insulin deficiency ?

  28. Glycemic Control • UKPDS 33, Lancet 352:837-53, 1998. • RCT of a policy of intensive BS control • FPG < 6 mM v.s. FPG < 15 mM • Achieved a number of ways: • Sulfonylurea (chlorpropamide or glibenclamide/glyburide) • Metformin (overweight subgroup, add-on) • Insulin (bedtime basal +/- basal/bolus regimens)

  29. Glycemic Control & Complications • UKPDS 33: Main study • Any DM related end point: 12% RRR • Microvascular complications: 25% RRR • Reduced eye disease: retinal laser Sx (19%), cataract Sx (24%), DM retinopathy (21%) • 33% RRR microalbuminuria, 74% RRR in doubling of creatinine • MI: 16% RRR (P = 0.052 NS) • No mortality benefit

  30. Glycemic Control & Metformin • UKPDS 34: overweight metformin substudy • Unlike sulfonylurea & insulin: no weight gain • Any DM related end point: 32% RRR • DM related death: 42% RRR • All cause mortality: 36% RRR • MI: 39% RRR • Metformin + SU: increased mortality? • DM related 96%, All-cause 60%

  31. T2DM & Macrovascular disease • Why no clear benefit in UKPDS to glycemic cntrl? • Low CV risk patients: • UKPDS cntrl death rate: 1.2 % per year • HOPE cntrl death rate: per year 2.5% per year • Unable to maintain glycemic cntrl due to limited interventions: • Available: glyburide, chlorpropamide, metformin, regular insulin • No newer sulfonylureas: glimepiride (Amaryl), gliclazide (diamicron) • No meglitinides: repaglinide (Gluconorm), nateglinide (Starlix) • No TZD’s: rosiglitazone (Avandia), pioglitazone (Actos) • No insulin analogues: (Humalog, Novorapid, Lantus)

  32. Natural History of Type 2 Diabetes Henry. Am J Med 1998;105(1A):20S-6S.

  33. UKPDS 33, Lancet 352:837-53, 1998. DCCT, NEJM 329:977-86, 1993.

  34. Conventional Chlorpropamide Metformin 10 Insulin Glibenclamide 100 Non obese Obese 100 9 80 80 60 60 8 ß cell function (%) ß cell function (%) 40 40 7 20 20 6 0 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 -1 0 2 4 6 8 10 Years from randomisation Years from randomisation Conventional Sulphonylurea Metformin Traditional Therapies Do Not Influence b-Cell Failure Non-Overweight Overweight overweight cohort, median values patients HbA1c (%) UKPDS 34. Lancet 1998; 352: 854-865 UKPDS 16: Diabetes 1995; 44: 1249-1258

  35. Thiazolidinedione β-cell preservation: Animal studies 12 weeks 16 weeks Control Zucker Rats ROSIG Zucker Rats

  36. Sites of Action of Currently Available Therapeutic Options MUSCLE ADIPOSE TISSUE LIVER PANCREAS GLUCOSE PRODUCTION Metformin Thiazolidinediones PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide INTESTINE GLUCOSE ABSORPTION Alpha-glucosidase inhibitors Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.

  37. Hypoglycemia Wt. Gain Edema GI Lactic Liver Use in effects Acidosis Toxicity Renal Failure Glyburide 4+ + 0  0  - 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 * + * Liver enzyme monitoring recommended in product monographs Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933

  38. TZD adverse effects • Edema • 4-5% of patients get mild-moderate edema • 15% if TZD used in combo with insulin • Mild anemia (dilutional) • Weight gain • Increase in subcutaneous not visceral fat • Myalgia (pioglitazone only) • Myalgia 5.4% pioglitaz. versus 2.7% placebo • Few patients with unexplained CK > 10x ULN • Contraindicated in class II, III and IV CHF • Contraindicated if ALT > 2.5x ULN or active liver disease

  39. Metabolic Syndrome: Clinical Diagnosis Presence of any 3 of the following: • Abdominal obesity (M > 102 cm, F > 88 cm) • TG > 1.7 mM • Low HDL (M < 1.0 mM, F < 1.3 mM) • BP > 130/85 • FPG > 6.1 mM

  40. TZDs: effect on Metabolic Syndrome • Reduce insulin resistance/blood sugar • Mild decrease in diastolic BP (2-4 mmHg) • Decrease PAI-1 (reduces procoagulant state) • Lipids: • ↓TG ↑HDL (pioglitazone > rosiglitazone?) • ↓LDL (pioglitazone) • ↑LDL (rosiglitazone) • No change in ApoB so ↑ due to larger less atherogenic particle size • Decrease in carotid artery intimal-media thickness (IMT)

  41. Targeting Insulin Resistance? • Does targeting insulin resistance > insulin secretion reduce CV risk? • We don’t know yet! • BARI-2D: • CV outomes • Insulin sparing regimen (avandia, metformin) versus Insulin providing regimen (sulfonylurea, insulin) • PPAR, RECORD, PROACTIVE • TZD’s, CV outcomes

  42. Targeting insulin Secretion? • Improve glycemic control in hi-risk patients to reduce CV risk • Using novel agents to get there! • ACCORD – glycemic cntrl arm HbA1c < 6 % • glimepiride, insulin glargine, (and rosiglitazone) • NAVIGATOR – nateglinide • DIGAMI II - insulin • ORIGIN, STREAM – insulin glargine

  43. Insulin

  44. Insulin Glargine (Lantus) • Substitution of glycine and arginine residues gives name “glargine” • 2 arginine residues make glargine more soluble in acidic pH of injection medium but less soluble in physilogic pH of subQ tissues • Once injected, glargine precipitates leading to slower absorption • Glycine substitution prevents degradation in subQ tissues

  45. Insulin Glargine (Lantus) Little to no peak effect  Less hypoglycemia

  46. Insulin Glargine (Lantus)

  47. BIDS Therapy • T2DM: “Introduction to insulin” • Keep on OHAs • Start 0.2 U/kg SC qhs NPH or Lantus • Increase by 2-4 U q4d until FBS 4-7

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