UPDATE ON MANAGEMENT OF TYPE 2 DIABETES NEW AND OLD TREATMENT OPTIONS Mayer B. Davidson, MD Professor of Medicine Charles Drew University & David Geffen School of Medicine at UCLA CURRENT AMERICAN DIABETES ASSOCIATION GUIDELINES Frequency Goal 1. Hb A1c every 6 months if <7% goal attained; every 3 months if greater 2. LDL Cholesterol yearly or more often <100 mg/dl as necessary 3. Triglycerides yearly or more often <150mg/dl* as necessary *Once LDL cholesterol at goal, the NCEP suggests considering treatment for triglyceride concentrations >200 mg/dl if the non- HDL cholesterol is >130 mg/dl. 1
ELEVEN CLASSES OF DRUGS TO TREAT DIABETES Metformin Sulfonylureas Glinides α-glucosidase Inhibitors Thiazolidinediones Colesvelam (WelChol ) DPP-4 Inhibitors Incretin Agonists Pramlintide (Sodium-Glucose Transporter Inhibitor) Characteristics of Oral Antidiabetes No hypoglycemia No weight gain Favorable lipid effects Generic available Metformin (glucophage) Adverse GI effects Slow dose titration CI: renal/hepatic dysfxn alcoholism, CHF, >80yo Potential for lactic acidosis? BID/TID dosing Characteristics of Oral Antidiabetes Sulfonylureas Rapid onset of action Few adverse effects Dosing often qd Generic formulations avail Hypoglycemia Weight gain IDENTIFICATION OF TYPE 2 DIABETES All three components must be present: Minority status Obesity At least one first degree relative, i.e., parent, sibling or child, must have type 2 diabetes* *Very important criterion 2
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Characteristics of Oral Antidiabetes Glinides (repaglinide, nateglinide) Rapid onset of action Short time to peak Short half life Enhances insulin response to meals?hypoglycemia?weight gain Freq admin Characteristics of Oral Antidiabetes α-glucosidase Inhibitors (acarbose, miglitol) Characteristics of Oral Antidiabetes Thiazolidinediones (TZD s) (Glitazones) (Rosiglitazone, Pioglitazone) No hypoglycemia* No weight gain Flatulence common Very slow dose titration Dosing three times a day Contraindications (creatinine >2 mg/dl; intestinal disorders) *If hypoglycemia occurs due to SU s, glinides or insulin, it must be treated with glucose tablets or milk (drugs do not block enzyme that breaks down lactose to glucose) No hypoglycemia Dosing once daily Renal insufficiency not a contra-indication Slow onset of action Weight gain (increased fat) Edema (fluid retention) Heart failure Decreased bone mineral density Increased fractures Expensive Effect of Glitazones as Triple Oral Therapy Characteristics of Oral Antidiabetes Colesvelam (WelChol )* Lowers LDL cholesterol Less GI side effects than other bile acid resins Raises triglycerides Some GI side effects *Other bile acid resins do not claim to lower glycemia 4
THE INCRETIN AXIS (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) 120 60 0 140 120 100 360 300 240 110 80 Deficient : Hypersecreted Glucagon TYPE 2 DIABETES Without Diabetes (n=14) Type 2 Diabetes (n=12) Meal -60 0 60 120 180 240 Time (min) Defects in diabetes: Deficient insulin release Glucagon not suppressed (postprandially) Hyperglycemia Data from Muller WA, et al. N Engl J Med 1970; 283:109-115 Postprandial Glucagon is Excessive and Not Corrected by Exogenous IMBALANCED GLUCOSE APPEARANCE AND DISAPPEARANCE Values After Infusion Values Before Infusion One wonders if the development of a pharmacological means of suppressing glucagon to appropriate levels would not increase the effectiveness of available insulin, markedly reduce insulin requirements, and perhaps improve control of the diabetic state. R.H. Unger 300 μu/ml 100 60 ng/ml 20 120 100 80 CHO Meal Glucagon * * * * Incretin Effect * * * 60 Subjects with diabetes Data from Unger RH, et al. N Engl J Med 1971; 285:443-449 -60 0 60 120 180 240 Time (min) GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal Intestinal GIP and GLP-1 release GIP-(1 42) GLP-1(7 36) Intact GIP and GLP-1 Actions DPP-4 Enzyme Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes GIP-(3 42) GLP-1(9 36) Metabolites DIPEPTIDYL PEPTIDASE (DPP)-4 INHIBITORS Deacon CF et al. Diabetes. 1995;44:1126 1131. *Meier JJ et al. Diabetes. 2004;53:654 662. 5
Characteristics of Oral Antidiabetes DPP-4 Inhibitors (Sitagliptin) No hypoglycemia Oral administration* Weight neutral* Expensive *Compared to injectable GLP-1 agonist EXENATIDE Characteristics of Injectable Antidiabetes Drugs Glucagon-Like Peptide (GLP) 1 Agonists Exenatide (Byetta) THE FIRST INCRETIN AGONIST Weight loss No hypoglycemia Initial nausea common Expensive LIRAGLUTIDE LEAD 6: Change in A1C at 26 Weeks THE SECOND INCRETIN AGONIST 6
EXENATIDE ONCE WEEKLY EXENATIDE ONCE WEEKLY Lancet 372:1240, 2008 Lancet 372:1240, 2008 EXENATIDE ONCE WEEKLY SYMLIN (PRAMLINTIDE) Lancet 372:1240, 2008 Healthy male adults (n = 6) Amylin Is Co-Secreted With Plasma Amylin (pm) 30 25 20 15 10 Meal Meal Meal 5 7 am 12 noon 5 pm Midnight Time (24 h) Amylin 600 400 200 0 Plasma (pm) Plasma Glucagon (pg/ml) 60 50 40 30 Pramlintide Reduces Postprandial Glucagon Type 2 Diabetes, Late Stage Sustacal Placebo or 100 µg/h pramlintide infusion 0 1 2 3 4 5 Time (h) Type 2 diabetes: AUC 1-4 h : P = 0.005 (n = 12) Type 1 diabetes: AUC 1-5 h : P <0.001 (n = 9) Plasma Glucagon (pg/ml) 30 20 10 0-10 Type 1 Diabetes Sustacal Placebo Pramlintide Placebo or 25 µg/h pramlintide infusion -20 0 1 2 3 4 5 Time (h) Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398 Data from Fineman M, et al. Metabolism 2002; 51:636-641 Data from Fineman M, et al. Horm Metab Res 2002; 34:504-508 7
Pramlintide Improves Postprandial Glucose TYPE 1 DIABETES PRAMLINITIDE ADDED TO BASAL INSULIN OAD S Mean (SE) Plasma Glucose (mg/dl) Mean (SE) Plasma Glucose (mg/dl) Lispro 300 Pramlintide 60 μg Lispro 250 200 150 100 0 60 120 180 240 300 250 200 150 Regular Pramlintide 60 μg Regular 100 0 60 120 180 240 Time Relative to Meal and Pramlintide (min) Evaluable population; Mean (SE) Pramlintide Lispro insulin (n = 20) Pramlintide Regular insulin (n = 18) Diabetes Care 32:1656, 2009 Pramlintide Acetate Prescribing Information, 2005 Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079 PRAMLINITIDE ADDED TO BASAL INSULIN OAD S PRAMLINTIDE VS. PRE-PRANDIAL INSULIN IN PATIENTS ON BASAL INUSLIN OAD S Diabetes Care 32:1656, 2009 Diabetes Care 32:1577, 2009 PRAMLINTIDE VS. PRE-PRANDIAL INSULIN IN PATIENTS ON BASAL INSULIN OAD S PRAMLINTIDE VS. PRE-PRANDIAL INSULIN Diabetes Care 32:1577, 2009 Diabetes Care 32:1577, 2009 8
Characteristics of Another Injectable Antidiabetes Drug Most effective drug SMBG required Hypoglycemia Weight gain Consistency of life style required American Diabetes Association s Recommended Treatment Tier 1: Well validated core therapies At diagnosis: Lifestyle Metformin Basal insulin Lifestyle Lifestyle Metformin Metformin Sulfonylurea a STEP 1 STEP 2 STEP Tier 2: Less well validated therapies 3 Lifestyle Metformin Pioglitazone No hypoglycaemia,oedema/chf, bone loss Lifestyle Metformin GLP-1 agonist b No hypoglycaemia, weight loss, nausea/vomiting Lifestyle Metformin Pioglitazone Sulfonylurea a Lifestyle Metformin Basal insulin Lifestyle Metformin Intensive insulin Rx of Type 2 Diabetes CRITERIA FOR SELECTING A CLASS OF DRUGS OR ONE DRUG WITHIN A CLASS OF DRUGS (IN DECREASING ORDER OF IMPORTANCE) 1. Effectiveness 2. Adverse effects 3. Ease of adherence 4. Cost Davidson MB: Diabetes Care 32:370, 2009 9
Short Term Goal TREATMENT ALGORITHM () Add Bedtime NPH* Long Term Goal FPG 70-130 mg/dl at least 50% of time Fail A1C < 7.5% 3 months later* Split/Mixed Regimen (Basal/Bolus Regimen) D/C SU (and metformin if lean) Preprandial PG 70-130 mg/dl at least 50% of time A1C < 7.0% Ongoing * After achieving short term goal If occurs, reduce dose of SU Hb A1c Outcomes of Nurse Following Treatment Algorithms for One Year in a Minority Population (~75% Latinos, 25% African-Americans) Kaiser Protocols Study #1 (N = 367 randomized patients) Hb A1c levels fell from 8.8% to 7.0% Study #2 (N = 178 referred patients) Hb A1c levels fell from 11.1% to 7.2% 10
Kaiser Protocols Kaiser Protocols Kaiser Protocols Kaiser Protocols Kaiser Protocols Kaiser Protocols 11
AN INCONVENIENT TRUTH Treatment of diabetes is straight forward. Treating the diabetic patient is challenging. THANK YOU 12