Type 2 Diabetes Mellitus 2011

Transcription

1 2011 Michael T. McDermott MD Director, Endocrinology and Diabetes Practice University of Colorado Hospital Diabetes Mellitus Diagnosis 2011 Diabetes Mellitus Fasting Glucose > 125 mg/dl 2 Hour PP Glucose > 200 mg/dl A1C > 6.5% Pre-Diabetes Fasting Glucose: mg/dl 2 Hour PP Glucose: mg/dl A1C: % (underestimates DM)* *Consider OGTT Consensus Recommendation: ADA, EASD, IDF: ADA 2009 Diabetes Mellitus: US Statistics US Population in 2010: 308,745,538 US People with Diabetes: 25.8 Million (8.3%) US People with Pre-Diabetes: 79 Million (26%) Leading Cause Blindness Renal Failure Amputations Myocardial Infarctions High Blood Glucose Above 100 mg/dl High Blood Pressure Above 130/85 Metabolic Syndrome Diagnosis: Any 3 Abdominal Obesity Waist: 35 inches or more (women) Waist: 40 inches or more (men) High Triglycerides Above 150 mg/dl Low HDL Cholesterol Below 40 mg/dl Metabolic Syndrome in the USA Overall Prevalence 24% Diabetes Mellitus in the US Projection Population Size through % 33% 22% Prevalence (%) 14% 6% Over 59 Age Categories NHANES III data Huang ES, Diabetes Care 2009; 32:

2 Pathophysiology Diabetes Prevention Program Cumulative Incidence of DM Nondiabetic Subjects with IFG +/or IGT Mean age: 51 yr Mean BMI: 34 kg/m2 (68% W, 34% M) RCT: Lifestyle Modification vs Metformin vs Control h Glucose CNS Role Hyperglycemia i h Glucagon i Incretin i 31% i 58% DPP Research Group, N Engl J Med 2002; 346: Finnish DPS 522 IGT Individual BMI > 25 DPP 2161 IGT BMI > 24 FPG > Individual Da Quing 259 IGT 45 6 Group Toranomon 458 IGT BMI = 24 Men Diabetes Prevention Trials Lifestyle Modification Study Study N Subjects Age (Yrs) Intervention (Daily Dose) 55 4 Individual Indian DPP 269 IGT Individual Conversion In Controls Relative (%/yr) Risk ( ) ( ) ( ) ( ) ( ) Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet 322 Obese Subjects (BMI 31) [14% W, 86% M; age 52] Low Carbohydrate, Unrestricted Calorie Diet vs Low Carbohydrate, Low Calorie Mediterranean Diet vs Low Fat, Low Calorie Diet Duration: 2 years 36 (11%) Diabetic Subjects Diabetics LC Diet LCM Diet LF Diet P-value FBG h 1.2 mg/dl i 32.8 mg/dl h 12.1 mg/dl <.001 A1C i 0.9% i 0.5% i 0.4% <.05 i 2.2 mu i 4.0 mu i 1.5 mu NS Tuomilehto J, N Engl J Med 2001; 344: Knowler WC, N Engl J Med 2002; 346: Pan XR, Diabetes Care 1997; 20: Kosaka K, Diab Res Clin Pract 2005; 67: Ramachandran A, Diabetologia 2006; 49: Shai I, N Engl J Med 2008; 359: Mediterranean Diet Meta-Analysis of s on Metabolic Syndrome Component Metabolic Syndrome i 31% incidence Waist Circumference i 0.42 cm Glucose i 3.89 mg/dl Triglycerides i 6.14 mg/dl HDL Cholesterol Systolic Blood Pressure h 1.17 mg/dl i 2.35 mm Hg Diastolic Blood Pressure i 1.58 mm HG Kastorini CM, J Am Coll Cardiol 2011; 57: DPP 2155 IGT BMI > Metformin 1700 mg FPG > 95 Indian DPP 269 IGT Metformin 500 mg Stop NIDDM 1419 Diabetes Prevention Trials Medications Study Study N Subjects Age (Yrs) IGT FPG > Acarbose 300 mg XENDOS 3277 BMI > Orlistat 360 mg DREAM 5269 IGT or 55 3 Rosiglitazone 8 mg IFG Knowler WC, N Engl J Med 2002; 346: Ramachandran A, Diabetologia 2006; 49: Chiasson JL, Lancet 2002; 359: Conversion Intervention In Controls Relative (Daily Dose) (%/yr) Risk ( ) ( ) ( ) ( ) ( ) Torgerson JS, Diabetes Care 2004; 27: Gerstein HC, Lancet 2006; 368:

3 Pioglitazone In Pre-Diabetes: Act Now 602 Subjects with Pre-Diabetes (IGT +/- IFG): RCT: Pioglitazone vs Placebo x 4 Years Kaplan Meier Plot of Hazard Ratios for Time to Development of Diabetes. DeFronzo RA, N Engl J Med 2011;364: Treatment Lifestyle Modification Diet No consensus regarding ideal diet for DM; Mediterranean Diet may be best. Main Goal: Calorie Restriction 1 lb = 3500 kcal 500 kcal/d deficit = 1 lb/week = 52 lb/year Exercise Walk 30 min/day ~ 130 kcal 130 kcal/d deficit = 1 lb/27 days = 14 lb/yr Weight Loss Metformin i Glucose i Pathophysiology Based Therapy Bromocriptine CNS Euglycemia i Meglitinide h i Glucagon h Incretin i Glucose Incretin Physiology h i Glucagon i Gastric Emptying L-Cells h Satiety i Appetite Glucose Dependent T1/2 = 2 min = Glucagon Like Peptide-1 Incretin Based Therapy (7-36) T ½ : 1-2 min Dipeptidyl Peptidase 4 [DPP4] (9-36) Inactive / Agonist Resistant to DPP4 Action Prolonged Duration of Action Prevents Native Breakdown Prolongs Duration of Action of Native Incretin Based Therapy / Agonist Exenatide (Byetta) Liraglutide (Victoza) Exenatide QW (Bydurion) Sitagliptin (Januvia) Saxagliptin (Onglyza) 3

4 Metformin i Glucose i Pathophysiology Based Therapy CNS Euglycemia i Meglitinide h i Glucagon h Incretin Type 2 Diabetes Medications Personalized Medication Choice BG Target Other Key Features Fasting BG Metformin Weight Neutral, Inexpensive Hypoglycemia Rare Basal Most ive Postprandial BG Weight Loss, Hypoglycemia Rare Weight Neutral, Hypoglycemia Rare Rapid Acting, Inexpensive Meglitinide Rapid Acting Pramlintide Weight Loss, Hypoglycemia Rare A1C < 7% A1C 7-9% Lifestyle Intervention Metformin (egfr > 60 ml/min) 3 Months: A1C Still > 7%, Add: : Personalized Management DPP4 Inhibitor 3 Months: A1C Still > 7%, Add: DPP4 Inhibitor DPP4 Inhibitor TZD +/- Metformin SU Basal or Intensive MTM Recommendation 2011 Basal Basal or Intensive A1C 9-11% Metformin PLUS DPP4 TZD SU Inhibitor OR 3 Months: A1C Still > 7%, Add: Amylin Amylin Amylin Basal A1C > 11% Basal O R Intensive OR 2 Oral Agents: Met + SU Preparations Onset Peak Duration Lispro 5-15 min 1-2 hr 3-5 hr Aspart min 1-3 hr 3-5 hr Glulisine 5-20 min 1-3 hr 3-5 hr Glargine 1-4 hr none hr Detemir 1-4 hr none hr Regular min 2-4 hr 6-8 hr NPH 1-4 hr 8-12 hr hr Injection Pharmacokinetics 1-2 hr 2-4 hr 8-12 hr Lispro / Aspart / Glulisine Glargine / Detemir Regular NPH +/- 24 hr +/- Peakless 4-5 hr 6-8 hr hr 24 hr Basal Therapy Indications A1C > 11% FBG > 250 mg/dl Random BG > 300 mg/dl Ketonuria / Ketonemia Weight Loss, Polydipsia, Polyuria A1C > 7% on 1-3 Oral Agents 4

5 Injection Basal Therapy Glargine / Detemir +/- Oral Agents +/- 24 hr Basal Therapy Initiate and Titrate Agents: Glargine / Detemir Start: U Daily (0.25 U/kg if Severe h BG) Titrate: FBG x 3 Days Calculate Mean FBG Protocol: Mean FBG Dose > 130 h 3 U No D < 80 i 3 U Summary: h by 3 U every 3 days until FBG < 130 mg/dl Mealtime Bolus Therapy Indications FBG at Goal - but A1C > 7% FBG at Goal - but PPBG > 180 mg/dl Mealtime Therapy Initiate and Titrate Agents: Lispro / Aspart / Glulisine Start: 4-5 U at Largest Meal or Each Meal Titrate: Check Pre-Meal BG and HS BG Daily h 2-3 U Every 2-3 days Until: Next Pre-Meal BG < 130 mg/dl or 2 Hour PPBG < 180 mg/dl Progress: Learn Carbohydrate Counting Establish a C:I Ratio and Correction Factor (CF) Basal Bolus Long Acting and Short Acting s Detemir / Glargine / Pump Aspart / Glulisine / Lispro Microvascular Complications Glucose Control Study A1C % Retinopathy Nephropathy Neuropathy DCCT 9 v 7 i 76% i 54% i 60% UKPDS 7.9 v 7 i 17-21% i 24-33% Kumamoto 9 v 7 i 69% i 70% i (ss) ADVANCE 7.3 v 6.5 i 21% B L D Basal ~ 50% Bolus ~ 50% Good Glucose Control (A1C < 7%) in Recent Onset and Long Standing DM i the Risk of Microvascular Complications. Total Daily Dose (DM2): U/kg or 0.4 U/lb 5

6 Macrovascular Complications Glucose Control DM A1C Macrovascular Study (yr) Goal A1C Events Mortality DCCT/EDIC 1-15 < 7 9 v 7 i 42%, p=.016 i 67%, p=ns UKPDS-10 New < v 7 i 15-33%, p<.01 i 13-27%, p<.01 ACCORD 10 < v 6.4 i 10%, p=ns h 22%, p=.04 ADVANCE 8 < v 6.5 i 6%, p=ns i 7%, p=ns VADT 11.5 < v 6.9 i 13% p=ns h 26%, p=ns Good Glucose Control (A1C < 7%) in Recent Onset DM i the Risk of Macrovascular Complications. Tight Glucose Control (A1C < 6-6.5%) in Chronic DM Has Not Been Shown to i Macrovascular Risk in Patients and may h Mortality. Glycemic Goals in Adults ADA Clinical Practice Recommendations 2011 A1C < 7% reasonable goal for non-pregnant adults (B) More stringent A1C goals suggested for selected individuals if this can be achieved without significant hypoglycemia or other adverse effects (B). Less stringent A1C goals suggested for patients with a history of severe hypoglycemia, limited life expectancy, advanced vascular complications or co-morbid conditions and those with long standing diabetes in whom control is difficult to attain. (C). Diabetes Care 2011; 34 (Suppl 1):S1-S98 (S4-5) Individualizing Glycemic Targets in DM2 Appendix 2011 by American College of Physicians Ismail-Beigi F, Ann Intern Med 2011;154:554-9 Treatment Lifestyle Modification Diet No consensus regarding ideal diet for DM; Mediterranean Diet may be best. Main Goal: Calorie Restriction 1 lb = 3500 kcal 500 kcal/d deficit = 1 lb/week = 52 lb/year Exercise Walk 30 min/day ~ 130 kcal 130 kcal/d deficit = 1 lb/27 days = 14 lb/yr Weight Loss Metformin Mechanism: Reduce insulin resistance (liver > muscle) Reduce hepatic glucose production Metformin Glucophage XR Glumetza Start: 500 mg qd short acting preparation; h weekly to mg qd (BID dosing) Start: 1000 mg qd long acting preparation; h to 2000 mg qd in 1-2 weeks (QD dosing) Avoid: Creat > 1.4 F, > 1.5 M, egfr < 60 ml/min; Severe liver disease 6

7 s Mechanism: Reduce insulin resistance (fat, muscle, liver) Pioglitazone (Actos) Rosiglitazone (Avandia) Start: low or middle dose; h every 4-6 weeks, as needed, to highest dose Avoid: Class 2-4 CHF; significant edema; Liver disease (except NASH) Caution: Chronic renal failure (edema) s Mechanism: stimulate insulin secretion Glyburide Glipizide, Glipizide XL/ER Glimepiride (Amaryl) Start: low, h to maximum dose, as needed Avoid: Chronic renal failure (Glipizide OK) Meglitinides Mechanism: stimulate insulin secretion Repaglinide (Prandin) Nateglinide (Starlix) Start: lowest dose before each meal; h to highest dose TID, as needed Avoid: Chronic renal failure (Repaglinide OK) Incretin Based Therapy Mechanism: Glucose-dependent Stimulation Glucose-dependent Glucagon Suppression Products Available / Agonist Exenatide (Byetta): Start 5 mcg BID; h to 10 mcg BID in 1 month Liraglutide (Victoza): Start 0.6 mg QD, h to 1.2 mg QD in 2 wks, h to 1.8 mg QD in 2 wks Sitagliptin (Januvia): 100 mg QD ( i dose in renal failure) Saxagliptin (Onglyza): 2.5 or 5 mg QD ( i dose in renal failure) Amylin Based Therapy Mechanism: Glucagon Suppression Postprandial Glucose Reduction Pramlintide (Symlin) Type 1 DM: Start 15 ug TID. h q 3 days to 30 ug TID, to 45 ug TID, and to 60 ug TID. Type 2 DM: Start 60 ug TID. h in 3-7 days to 120 ug TID. Flexible Mealtime Bolus Bolus Components C:I Ratio: Gm of Carb covered by 1U CF: BG i expected from 1U Add to bolus if pre-meal BG high Starting Calculations C:I = 500/TDD CF = 1650/TDD Dose Adjustment Goal PPBG < 180 mg/dl or PPBG mg/dl above pre-meal BG 7