T2DM Treatment

Views:
 
Category: Education
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

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

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 Diabetes: Complications Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29. Complications Erectile Dysfunction

Disease Burden of Diabetes Mellitus:

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

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

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

Evans et al.:

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

How is CAD Different in Diabetics ?:

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

T2DM: “Rx to Targets”:

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

What are the targets?:

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 ?

Canadian Lipid Working Group: Target Levels in Diabetes:

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 LDL 1 Fibrates are useful for raising HDL, lowering TG 1,2 Some OHA may improve lipids, but are not indicated for lipid management 3 may need to use combo or Niacin cautiously

Heart Protection Study & DM:

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

Heart Protection Study:

Heart Protection Study

Lipids & DM:

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

Lipids & DM:

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…

What are the targets?:

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 ?

DM: BP cntrl:

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

Renin-Angiotensin-Aldosterone Axis:

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

BP Trials in DM patients (some):

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

BP Trials in DM patients:

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

BP Trials in DM patients:

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

Effect of ACE Inhibition in Diabetes HOPE Study:

Effect of ACE Inhibition in Diabetes HOPE 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 HOPE investigators. Lancet 2000;355:253-259. Complications DM > 55 yo & 1 additional CV risk factor (HTN, microalbuminuria, current smoker, TC > 5.2 mM, HDL < 0.9 mM)

DM Nephropathy:

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

DM Nephropathy & BP:

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

DM Nephropathy & BP:

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

ACE-I & ARB Combination?:

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

CALM Study:

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

BP Cntrl in DM: CHEP guidelines:

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 Initial therapy 2 nd line therapy DM with nephropathy ACE-I or ARB Addition of 1 or more of thiazide, -blocker, CCB, or an ACE-I/ARB combo DM without nephropathy ACE-I, ARB, or thiazide Combo of 1 st line drugs or addition of -blocker and/or CCB

What are the targets?:

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 ?

Glycemic Control:

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)

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 Glycemic Control & Complications

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% Glycemic Control & Metformin

T2DM & Macrovascular disease:

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)

Natural History of Type 2 Diabetes:

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

Slide 34:

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

Traditional Therapies Do Not Influence b-Cell Failure :

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

Thiazolidinedione β-cell preservation: Animal studies:

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

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 Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5. Sites of Action of Currently Available Therapeutic Options

Slide 38:

Drug Trade Dose Cost ODB Glyburide Diabeta Start 1.25-5 mg od Spit dose bid > 10mg/d Max 10 mg bid $14/mos Yes Gliclazide Diamicron Start 80 mg bid Max 160 mg bid $90/mos No Gliclazide MR Diamicron MR Start 30 mg od Max 120 mg od $30/mos Exp Sect 8 Glimepiride Amaryl Start 1-2 mg od Max 8 mg od $30/mos No Repaglinide Gluconorm Start 0.5 mg tid-qid Max 4 mg qid $45/mos Exp Sect 8 Nateglinide Starlix Start 60-120 mg tid Max 180 mg tid $45/mos No Metformin Glucophage Start 500 mg od-bid Max 1000 mg bid $14/mos Yes Pioglitazone Actos Start 15-30 mg od Max 45 mg od $92/mos Exp Sect 8 Rosiglitazone Avandia Start 4 mg od Max 4 mg bid $ 60/mos $ 120/mos Exp Sect 8

Slide 39:

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  -

TZD adverse effects:

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

Metabolic Syndrome: Clinical Diagnosis:

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

TZDs: effect on Metabolic Syndrome:

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)

Targeting Insulin Resistance?:

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

Targeting insulin Secretion?:

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

Insulin:

Insulin Type Starts Peaks Duration Humalog NovoRapid 5-10 min 0.5-1hrs 3.5 hrs Regular 30 min 2-4 hrs 6-8 hrs NPH Lente 1-2 hrs 6-10 hrs 16-24 hrs Ultralente 4-6 hrs 8-24 hrs 24-36 hrs Glargine 1.5h None Up to 24 hrs

Insulin Glargine (Lantus):

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

Insulin Glargine (Lantus):

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

Insulin Glargine (Lantus):

Insulin Glargine (Lantus)

BIDS Therapy:

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

Putting it all together:

Putting it all together Any evidence that a multifactorial approach (targeting glycemic cntrl, BP, lipids, proteinuria, etc.) works?

Multifactorial DM Rx: STENO-2:

Multifactorial DM Rx: STENO-2 Jan 2003, NEJM 348:383-93 RCT mimicking real life clinic 160 T2DM patients with microalbuminuria Randomized: Conventional Rx as per National Guidelines versus Intensive Rx Behaviour modification Pharmacotherapy: targeting BS, BP, Lipids, proteinuria, ASA (initially 2  prevention only, 1 prevention after 1999)

Multifactorial DM Rx: STENO-2:

Multifactorial DM Rx: STENO-2

Multifactorial DM Rx: STENO-2:

Multifactorial DM Rx: STENO-2

Slide 55:

UKPDS 33, Lancet 352:837-53, 1998. STENO-2, NEJM, 348:383-93, 2003. DCCT, NEJM 329:977-86, 1993.

Multifactorial DM Rx: STENO-2:

Multifactorial DM Rx: STENO-2

Bottom Line: T2DM Surveillance:

Bottom Line: T2DM Surveillance HbA1c, BP: q3mos UMALB/Creat ratio: q6mos - q1y Dilated eye exam q1-2y Feet exam at least q1y Cardiac GxT: as indicated (symptoms, prior to new exercise regime)

Bottom Line: T2DM Intervention:

Bottom Line: T2DM Intervention BP cntrl: Target: < 130/80 (< 120/75 if proteinuria > 1g/d) 1 st Line: HOPE criteria met: ACE-I, ARB if ACE-I intolerant No HOPE criteria : ARB 2 nd Line: Thiazide 3 rd Line: -blocker or DHP-CCB (Norvasc, Plendil) Combine ACE-I + ARB ? (watch K + !) CHF (as per CHARM or Val-HeFT) Overt nephropathy + HOPE criteria met Angiotensin II blockade: Altace even if normal BP if HOPE criteria met > 55 y & 1 CV risk factor: HTN, microalbuminuria, current smoker, TC > 5.2 mM, HDL < 0.9 mM

Bottom Line: T2DM Intervention:

Bottom Line: T2DM Intervention Proteinuria BP < 120/75, HbA1c < 7.0 % No HOPE: ARB HOPE Criteria met, microalbuminuria: ACE-I HOPE Criteria met, macroalbuminuria: ACE-I + ARB (watch K + !) Lipids age > 40 or vascular disease, regardless of lipid profile Zocor 40 mg/d  target LDL 2.5 mM Still hi TG, low HDL: consider gemfibrozil or niacin TG > 6.0-11.0 mM: risk of pancreatitis ECASA 81 mg/d, Smoking cessation 2 prevention CAD: -blocker, ACE-I

CDA Guidelines 2003 www.diabetes.ca/cpg2003:

CDA Guidelines 2003 www.diabetes.ca/cpg2003 HbA1c FBS Preprandial 2h Postprandial Target < 7.0 % 4-7 mM 5-10 mM Normal Range * < 6.0 % 4-6 mM 5-8 mM * “Lowering Glycemic levels towards the normal range should be considered for patients in whom it can be achieved safely.” * Awaiting results of ACCORD

Slide 62:

Clinical assessment and initiation of nutrition and physical activity Mild to moderate hyperglycemia (A1C < 9.0%) Overweight (BMI 25 kg/m 2 ) Non-overweight (BMI 25 kg/m 2 ) Biguanide alone or in combination with 1 of: insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor 1 or 2 † antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor Marked hyperglycemia (A1C 9.0%) 2 antihyperglycemic agents from different classes † biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor Basal and/or preprandial insulin Add an oral antihyperglycemic agent from a different class of insulin* Intensify insulin regimen or add biguanide insulin secretagogue** insulin sensitizer* alpha-glucosidase inhibitor If not at target If not at target If not at target If not at target L I F E S T Y L E Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months

Bottom Line: T2DM Intervention:

Bottom Line: T2DM Intervention Glycemic control: HbA1c < 7.0 % 1 st line: insulin sensitizer (no hypoglycemia) Metformin (UKPDS sub-study, weight-sparing, $) Thiazolidinedione (potential pleiotrophic benefits) Metformin + Thiazolidinedione also possible 2 nd line: insulin secretagogue elderly,  CrCl ? Amaryl, Diamicron, Gluconorm, Starlix > Glyburide 3 rd line: insulin (analogues > regular) Lantus : lower FBS, less nocturnal hypo Humalog, Novorapid : lower postprandial BS, less hypo

The End:

The End

authorStream Live Help