Redefining the Treatment Algorithm for Type 2 Diabetes Redefining the Treatment Algorithm for Type 2 Diabetes 2008 The June Addition 6/16/2008

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1 Redefining the Treatment Algorithm for Type 2 Diabetes 2008 Robert J. Rushakoff, MD Clinical Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Redefining the Treatment Algorithm for Type 2 Diabetes 2008 The June Addition Robert J. Rushakoff, MD Clinical Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Insulin secretion β β α Postprandial glucagon secretion Hyperglycemia Hyperglycemia hepatic glucose output Glucose uptake glucose utilization 1

2 Incretins β α β α Hyperglycemia Hyperglycemia FFA Lipotoxicity β α Hyperglycemia Altered glucose reabsorption β α Hyperglycemia Altered Hypothalamic Appetite Control 2

3 Ominous Octet β α Hyperglycemia Fundamental Questions Just because a drug may work at one or more of the sites of defect in Type 2 DM - what about: Efficacy Side effects Actually improve outcomes or make them worse Improve mortality or kill people Fundamental Questions Is there anything wrong with the current group of medications? Do the newer medications fix what is wrong with the older medications? Does it really matter what medication is used first, second, third? Does it really matter what medication is used? Today Assessing Goals What are the goals? What differentiates the medications? Does it really matter what medication is used? Put it all together ADA way, AACE way and of course, MY WAY 3

4 Relationship Between Plasma Glucose and HgA 1c ADA Targets for Glycemic Control Biochemical Index Goal Preprandial plasma glucose mg/dl (5-7.2 mmol/l) Peak postprandial plasma glucose <180 mg/dl (<10 mmol/l) Hemoglobin A 1c <7 (%) Diabetes Care 2002;25: ADVANCE: Action in Diabetes and Vascular Disease Characteristics of Participants at Baseline and at the End of the Follow-up Period Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM 11,140 Enrollees 60% male 40% female Mean age 66 50% macrovascular dx 10% microvascular The ADVANCE Collaborative Group. N Engl J Med 2008;358:

5 Relative Effects of Glucose-Control Strategy on All Prespecified Primary and Secondary Outcomes ACCORD: Three Medical Strategy Questions Glycemia: Intensive control (HbA1c<6.0% - reached 6.4) vs Standard control (HbA1c 7.0%-7.9% - reached 7.5) BP: Intensive control (SBP <120 mmhg) vs Standard control (SBP <140 mmhg) Lipids: Fibrates to increase HDL-C and lower TG + statins to lower LDL-C vs Statins to lower LDL-C alone The ADVANCE Collaborative Group. N Engl J Med 2008;358: ACCORD: Action to Control Cardiovascular Risk in Diabetes Primary and Secondary Outcomes 10,251 Enrollees 60% male 40% female Mean age 62.2 Baseline HgA1c 8.1% BMI % macrovascular dx Duration DM: 10 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

6 Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups VADT - Veterans Administration Diabetes Trial 1742 Enrollees 97% male Mean age 60.4 BMI 31.3 Majority had multiple CV risk factors 72% HTN 40% macrovascular dx 62% retinopathy 43% neuropathy The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: VADT - Veterans Administration Diabetes Trial Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES Standard: 29.3% (predicted 40%) Intensive: 27.4% (predicted 31.6%) VADT - Veterans Administration Diabetes Trial Baseline Predictor of CVD: Age and prior CVD event On-trial hypoglycemia low glucose and altered consciousness in the three months prior to an event was predictive of CVD outcome 6

7 VADT - Veterans Administration Diabetes Trial When duration of DM factored in: Intensive glycemic control showed benefit Benefit declines until about years of disease Goals for Type 2 Diabetes For Decreasing Cardiovascular Disease: Focus on blood pressure Lipids anti-platelet therapy Smoking cessation. Goals for Type 2 Diabetes For overall glucose control, an individualized approach is required, particularly for those patients with advanced disease. Lowering glucose is important, but primarily to prevent microvascular complications (renal, retinal, neuropathy). Goals for Type 2 Diabetes If glucose control reduces CVD risk, it does so modestly and primarily in those with early diabetes without advanced macrovascular disease. In these individuals, reduce the HbA1c to <7%. Further reductions may have long-term benefits, but the magnitude is unclear. 7

8 Goals for Type 2 Diabetes Be cautious in your glucose lowering strategies in older, high-risk patients with long standing diabetes. Maintaining HbA1c close to 7% (but not necessarily <7%) may be the optimal target for these individuals. Avoid hypoglycemia. Sulfonylureas Drug Usual Daily Dose Doses First Generation Acetohexamide mg 1-2 Dymelor Chlorpropamide mg 1 Diabinase Tolazamide mg 1-3 Tolinase Tolbutamide mg 1-3 Orinase Second Generation Glimepiride 2-4 mg 1 Amaryl Glipizide mg 1-2 Glucotrol Glucotrol XL 5-10 mg 1 Glyburide 5-20 mg 1-2 DiaBeta, Micronase Micronized 3-12 mg 1-2 Glynase Metformin and Lactic Acidosis Metformin may provoke lactic Acidosis which is most likely to occur in patients with renal impairment. It should not be used with even mild renal impairment 1 Metformin probably not as unsafe as previously thought. 25% users have relative contraindication 2 Patient s with lactic acidosis usually have acute renal failure 3 1. Joint Formulary Committee British National Formulary. 2006: Diabet Med 2001; 18: Diabet Med 2007; 24: Metformin and egfr Creatinine mg/dl x 88.4 µmol/l Current Guidelines call for discontinuation of Metformin serum creatinine >150 umol/l (1.7 mg/dl). Estimated GFR (egfr) being introduced as possible better measure of renal function than serum creatinine alone egfr of 36 ml/min per 1.73m 2 would be somewhat neutral to current use 8

9 Thiazolidenediones The bad The good The very ugly TZDs and Liver Disease From troglitazone contraindicated in patients with liver disease Diabetes patients frequently have fatty liver (NASH---Non- Alcoholic Steatorrhoeic Hepatosis) with elevated LFT TZDs decrease liver fat and improve NASH TZDs may be best treatment for NASH and preventing cirrhosis Rushakoff RJ: Normalization of abnormal liver function tests in Type 2 diabetic patients after administration of Troglitazone. Diabetes 48 supplement 1999 Current TZD Side Effects Weight Gain: 5-12 lbs in 1 year Blunted with metformin Worse with insulin Edema: 4-30% Unresponsive to diuretics BUT: Increased Cardiac Index Increased Stroke volume Decreased systemic resistance Decreased Blood Pressure Prevention of Type 2 Diabetes With Troglitazone in the Diabetes Prevention Program Diabetes 54: ,

10 Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention Positive Side to TZDs Reduction in glucose Reduces BP Reduces albuminuria Reduces CRP Possible DM prevention Reduces NASH Reduces LFT Reduces IMT Reduces stent failure Reduces death after CHF Increases adiponectin Increases HDL Diabetes Care 30: , 2007 The NEW ENGLAND JO URNAL of MEDICINE ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes CONCLUSIONS Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death that had borderline significance. Limitations to Analysis No access to actual data. No time to event calculation No confirmation of events No combined analysis (some may have had multiple events) 42 studies 11 peer reviewed 26 never published Small number of events Trials of short duration Trials not designed to capture or adjudicate events, thus events not endpoints, just investigator reports Many studies only zero or 1 report Hypothesis generating, not testing 10

11 Meta-analysis of MI and Death risk with rosiglitazone n = 15,560 on rosiglitazone; n = 12,283 on comparator drug or placebo Comparison of RSG to SU or MET MI/CV Death/Stroke Meta-analysis database (ICT), ADOPT and RECORD Rosiglitazone group Control group Study No. of events/total no. (%) Odds ratio (95% CI) P Myocardial infarction Small trials combined 44/10,280 (0.43) 22/6105 (0.36) 1.45 ( ) 0.15 DREAM 15/2635 (0.57) 9/2634 (0.34) 1.65 ( ) 0.22 ADOPT 27/1456 (1.85) 41/2895 (1.44) 1.33 ( ) 0.27 Overall ( ) /14371 (.60%) 72/11634 (0.62%) Relative Risk = 86/72 = 1.19 Absolute Risk = -.02% Nissen SE, Wolski K. N Engl J Med. 2007;356. Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Myocardial Infarction Uncorrected (Peto) Corrected (MH/CC) Small trials combined (N=16391) DREAM (N=5269) 1.45 ( ) 1.16 ( ) ADOPT (N=4351) Overall pooled data (N=26011) 1.43 ( ) 1.28 ( ) Odds ratio Odds ratio Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 David Graham, MD MPH 11

12 PANIC Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 David Graham, MD MPH Unadjusted and adjusted odds ratios (95% CIs) for all-cause mortality Sulfonylurea monotherapy Metformin monotherapy Metformin plus sulfonylurea TZD alone or in combination with other oral agents Number of deaths (%) Unadjusted odds ratio (95% CI) Adjusted odds ratio (95% CI) * 1,005 (5.3) (2.7) 0.51 ( ) 0.87 ( ) 468 (3.4) 0.63 ( ) 0.92 ( ) 48 (7.1) 1.37 ( ) 1.04 ( ) No drugs 132 (4.1) 0.78 ( ) 0.90 ( ) Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From ADOPT * Adjusted for propensity score plus age, diabetes duration, A1C, creatinine, diabetes-related physician visits, and utilization of lipid-lowering and hypertension medications. Diabetes Care 30: , 2007 Diabetes Care Publish Ahead of Print, published online on February 5,

13 Changes in BMD during pioglitazone or placebo treatment in patients with PCOS Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes 114 drug naïve patients Initial HgA1c Duration DM about 3 years Initial Hga1c 10% Body mass index 25 J Clin Endocrinol Metab Feb 19 [Epub ahead of print] Diabetes Medicine 2005; 22: Time course of reduction in glycated haemoglobin (HbA1c) in patients receiving pioglitazone (O), metformin ( ), or glimepiride ( ). Data are mean ±sd. *P < 0.05; **P < 0.01; ***P < vs. baseline. Diabetes Medicine 2005; 22: Mean Change (mg/dl) Fasting Plasma glucose: Mean Change From Baseline Weeks Diabetes 452:146, 1993 Continued glyburide (n=209) Switched to metformin (n=210) Metformin + glyburide (n+213) 13

14 Generic Oral Hypoglycemic Slide Change from Drug A to B, C, or D Add Drug A to B, or B to A HgA 1c Add Drug C Add Drug D Time Weight Changes Associated with Anti- Hyperglycemic Therapies for Type 2 Diabetes Change in Weight Sulfonylurea Metformin Insulin TZD ADA Scientific Meeting 2005 ABS 13-or Postprandial Glucose Excursions in Subjects With or Without Diabetes 350 Subjects Postprandial Glucose Control Serum Glucose Value (mg/ml) Meal Event Without diabetes Type 1 diabetes Type 2 diabetes Time (hours) Shin J et al. Abstract 424-P. ADA; 2004: New Orleans, La. 14

15 Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles 100 Postprandial glucose Fasting glucose INCRETINS Contribution, % Gut factors that promote insulin secretion in response to nutrients Major incretins: GLP-1, CCK, GIP 0 < >10.2 n=58 n=58 n=58 n=58 n=58 Monnier L et al. Diabetes Care. 2003;26: A1C Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a Role for Incretins Incretin Drugs GLP Agonists Exenatide Liraglutide CJC-1131 AVE-0010 Albugon Glp-1-transferin Exenatide Lar DPP IV Inhibitors Vildagliptin Sitagliptin Saxagliptin PSN-931 Takeda-Syrrx 15

16 BYETTA Continued to Reduce Weight at 2.5 Years Open-label Extension BYETTA 10 mcg BID (n = 241) Weight (lbs) ± 0.8 lbs Time (wk) 2.5-y completers; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc. See accompanying Prescribing Information and safety information included in this presentation DPP-4 Study Summary HgA1c Vildagliptin plus insulin Patients on >30 U/d, added 100 mg/d Baseline HgA1c 8.5 Drop in HgA1c 0.5% vildagliption, 0.2% placebo 10 3 Drugs Insulin added >65 y/o-- Drop in HgA1c 0.7% vildagliption, 0.0% placebo Hypoglycemia: Placebo: 45patients; 185 events; 6 severe Vildagliptin: 33patients; 113 events; 0 severe Sitagliptin vs glipizide added to metformin Drug 2 Drugs 52 weeks, 100 mg/d vs 20 mg/d Baseline HgA1c No Meds Both 0.67% reduction in HgA1c Both about 60% reached HgA1c <7 Hypoglycemia glipizide: 32% sitagliptin: 4.9% 16

17 Drug Cost Comparison Drug and Dose Cost/month Sulfonylurea Generic $4-14 Brand $50 Rapaglinide 2 mg tid $135 Acarbose 100 mg tid $88 Metformin 1000 bid Generic $ 4-32 Brand $132 Rosiglitazone 8 mg qd $214 Pioglitazone 45 mg/d $190 Sitagliptin $171 Exenatide 5mcg $213 10mcg $230 Welchol 3750 mg/d $196 Glargine, 45 U/d $145 DIGAMI2 (European Heart J. Prepublication Feb 2005) Group 1 IV insulin then long term SQ insulin Group 2 IV insulin then standard treatment Group 3 Standard treatment Mortality 24 hour fitness center $44 YMCA $60 Effect of different updated glucose lowering treatments on mortality and morbidity 2008 ADA Type 2 Diabetes Treatment Algorithm Mellbin, L. G. et al. Eur Heart J : Diabetes Care 31: ,

18 Road Maps to Achieve Glycemic Control In Type 2 Diabetes Mellitus ACE/AACE Diabetes Road Map Task Force Chairpersons Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Task Force Members Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Initial A1C% Lifestyle Modification Lifestyle Modification Achieve ACE Glycemic Goals ( FPG, PPG, and A1C ) Intervention Assess FPG and PPG Target: PPG and FPG Initial Therapy Preferred: Metformin 4 TZD 10,11 AGI DPP-4 Inhibitor Combine Therapies 6,7 Metformin Glinides AGI TZD SU DPP-4 Inhibitor Alternatives Glinides SU (low dose) Prandial insulin 5,8 Alternatives Prandial insulin 5,8 Premixed insulin preparations 8 Basal insulin analog 9 * Available as exenatide ACE Glycemic Goals 1 Indicated for patients not at goal despite SU and/or 6.5% A1C metformin or TZD therapy; incretin mimetic is not < 110 mg/dl FPG indicated for insulin-using patients < 110 mg/dl Preprandial 4 Preferred first agent in most patients < 140 mg/dl 2-hr PPG 5 Rapid-acting insulin analog (available as lispro, aspart and glulisine), inhaled insulin, or regular insulin 6 Appropriate for most patients 7 2 or more agents may be required 8 Analog preparations preferred 9 Available as glargine and detemir 10 A recent report (NEJM; 6/14/07) suggests a possible link of rosiglitazone to cardiovascular events that requires further evaluation. 11 Cannot be used in NYHA CHF Class 3 or 4 Access Roadmap at: Endocr Pract. 2007;13: Continuous Titration Monitor of Rx / ( 2-3 months ) adjust Rx to maximal effective dose to meet ACE Glycemic Goals Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals If 6.5% A1C Goal Not Achieved Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic *1 If 6.5% A1C Goal Not Achieved Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form w ithout the express permission of AACE. NO Start Metformin Referral for: Diet HGM Sick Day Rules Exercise (+/- EST) Foot Care TYPE 2 DIABETES SYMPTOMATIC And very high YES Continue Current Treatment Goal Met NO Add Medication YES Start on sulfonylurea or insulin Referral for: Diet HGM Exercise Foot Care Consider transition to metformin Exenatide Goal Not Met OBESE Add Sulfonylurea (consider TZD) TYPE 2 DIABETES Metformin THIN Sulfonylurea Sitagliptin (consider TZD) Goal Not Met Goal Not Met Start insulin use pens Add levemir, glargine or PM NPH (isolated fasting hyperglycemia or insurance)? of which existing meds to continue, generally all Change to bid premixed insulin? of which existing meds to continue, generally just metformin Change to basal and with premeal insulin? of which existing meds to continue, generally just metformin Thin or no injection Sitagliptin Goal Not Met Add Sulfonylurea (consider TZD) 18

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