Type 2. Diabetes. What do you think of when told: Redefining the Treatment Algorithm for Type 2 Diabetes /22/2009

Transcription

1 Redefining the Treatment Algorithm for Type 2 Diabetes 29 Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco What do you think of when told: fold increased risk of CHF 2-3 fold increase in risk for initial MI Type 2 3 fold increase in risk for pancreatitis Decreased leukocyte function Risk for lactic acidosis Diabetes Increased risk for renal failure, retinopathy, neuropathy 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 Decrease mortality or kill people Fundamental Questions Is there anything wrong with the older 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 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 Recommendation of the International Expert Committee for the Diagnosis of Diabetes Diabetes should be diagnosed when the A1c is 6.5%. Diagnosis should be confirmed with a repeat A1c test. Confirmation is not required in symptomatic subjects with plasma glucose levels > 2 mg/dl (>11.1 mmol/l). If A1c testing is not possible, previously recommended diagnostic methods (eg, fasting plasma glucose or 2-hour OGTT plasma glucose), with confirmation, are acceptable. A1c testing is indicated in children in whom diabetes is suspected, but the classic symptoms and a casual plasma glucose >2 mg/dl (>11.1 mmol/l) are not found. Diabetes Care 31: , 28 The relationship between baseline A1C group and observed reduction from baseline in A1C and in FPG Baseline A1C (%) n enrolled in clinical trials Change in A1C (%) Change in FPG (mmol/l) , , , Overview on self-monitoring of blood glucose Martina Montagnana, Marco Caputo, Davide Giavarina, Giuseppe Lippi Clin Chim Acta 29 42:7-13. Diabetes Care 29: , 26 4

5 Overview on self-monitoring of blood glucose The SMBG is recommended in patients on insulin therapy. For type 1 diabetes, SMBG should be performed at least 3 times daily. SMBG is also recommended in patients treated with oral hypoglycemic agents and in all the patients not fulfilling the optimal therapeutic target. Overview on self-monitoring of blood glucose The SMBG is recommended in patients on insulin therapy. For type 1 diabetes, SMBG should be performed at least 3 times daily. SMBG is also recommended in patients treated with oral hypoglycemic agents and in all the patients not fulfilling the optimal therapeutic target. 2 Glucose Checks per day 4 Time 1 Time 2 high HgA 1c low Overview on self-monitoring of blood glucose In patients with type 2 diabetes, SMBG can help to achieve a better glycemic control, especially at the beginning of therapy or following adjustments, although there are not sufficient lines of evidence to attest that strict monitoring in these patients is associated with an improved outcome on the long term. The role of SMBG in patients with type 2 diabetes managed by diet control alone is still unknown. ADVANCE: Action in Diabetes and Vascular Disease 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 11,14 Enrollees 6% male 4% female Mean age 66 5% macrovascular dx 1% microvascular Baseline HgA1c: 7.51% standard : 7.3% Intensive: 6.53% 5

6 ADVANCE: Relative Effects of Glucose-Control Strategy on All Prespecified Primary and Secondary Outcomes ACCORD: Action to Control Cardiovascular Risk in Diabetes 1,251 Enrollees 6% male 4% female Mean age 62.2 Baseline HgA1c 8.1% BMI % macrovascular dx Duration DM: 1 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group The ADVANCE Collaborative Group. N Engl J Med 28;358: Primary and Secondary Outcomes ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 28;358: The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 28;358:

7 VADT - Veterans Administration Diabetes Trial VADT - Veterans Administration Diabetes Trial 1742 Enrollees 97% male Mean age 6.4 BMI 31.3 Majority had multiple CV risk factors 72% HTN 4% macrovascular dx 62% retinopathy 43% neuropathy Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES Standard: 29.3% (predicted 4%) 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 VADT - Veterans Administration Diabetes Trial When duration of DM factored in: Intensive glycemic control showed benefit Benefit declines until about years of disease 7

8 Trends In Control of Cardiovascular Disease and Diabetes Blood Pressure Control Trends In Control of Cardiovascular Disease and Diabetes Glycemic Control Ann Intern Med. 29;15: Ann Intern Med. 29;15: Trends In Control of Cardiovascular Disease and Diabetes Total Cholesterol Control Explaining Decline in Early Mortality with Type 2 DM Trends in Drug Utilization All cause 2 year mortality: 48/1 person-years (1996) to 25/1 p-y (26) 16 43% 43 14% 5 71% 21 55% Ann Intern Med. 29;15: X(1996) y(26)% (use in 1 st year) Diabetes Care. 28; 31:

9 UKPDS: 1 year follow-up Glucose Control Between-group differences in HgA1c gone after 1 year In the sulfonylurea insulin group, relative reductions in risk persisted at 1 years for: any diabetes-related end point (9%, P=.4) microvascular disease (24%, P=.1) risk reductions for myocardial infarction (15%, P=.1) death from any cause (13%, P=.7) In the metformin group: any diabetes-related end point (21%, P=.1) myocardial infarction (33%, P=.5) and death from any cause (27%, P=.2). Effect of Metformin-Containing Antidiabetic Regimens on All-cause Mortality in Veterans With Type 2 Diabetes Mellitus Decreased Hazard Ratio for all cause mortality for patients on metformin vs no metformin.77 (p<.1) Increased Hazard Ratio for all cause mortality for patients on insulin: 1.62 (p<.1) Decreased Hazard Ratio for all cause mortality for patients on metformin and insulin vs insulin.62 (p<.4) Published at September 1, 28 Am J Med Sci 28; 336: Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes ADA Targets for Glycemic Control Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group Biochemical Index Goal Preprandial plasma glucose 8 13 mg/dl (5-7.2 mmol/l) Peak postprandial plasma glucose <18 mg/dl (<1 mmol/l) Hemoglobin A 1c <7 (%) Gaede P et al. N Engl J Med 28;358:

10 ADA Targets for Glycemic Control Key concepts in setting glycemic goals: A1C is the primary target for glycemic control. Goals should be individualized based on: duration of diabetes age/life expectancy comorbid conditions known CVD or advanced microvascular complications hypoglycemia unawareness individual patient considerations Goals for Type 2 Diabetes For Decreasing Cardiovascular Disease: Focus on blood pressure Lipids anti-platelet therapy Smoking cessation. Early aggressive glucose control More or less stringent glycemic goals may be appropriate for individual patients. Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals. Goals for Type 2 Diabetes Class Generic Name (Brand Name) Sulfonylureas Mechanism of Action Dosage Relative Effective -ness 1 Major Side Effects / Interactions / Uses Weight Cost Effects (average) 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. Glyburide (Micronase) Glipizide (Glucotrol) glimepiride (Amaryl) mg bid Stimulate insulin release from beta cells 5-2 mg bid of the pancreas.5-4 mg qd 1 1 Hypoglycemia Gain 2 lbs $ Avoid hypoglycemia. 1

11 Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Sulfonylureas Meglitinides repaglinide (Prandin) nateglinide (Starlix) Stimulate insulin release Stimulate insulin release from beta cells of the pancreas.5-2 mg tid (before meals) 6-36 mg tid (before meals) 1 Hypoglycemia Gain 2 lbs 1.8 Hypoglycemia Useful in pts on glucocorticoids and in pts with renal failure who Gain 1 lb $$$ often have good FBS and high BS over the course of the day Prandin is short-acting. Starlix is very short-acting $ Sulfonylureas Stimulate insulin release 1 Hypoglycemia Gain 2 lbs Meglitinides Stimulate insulin.8-1 Hypoglycemia short-acting Gain 1 lb $$$ Biguanide metformin (Glucophage) Primarily inhibits hepatic gluconeogen -esis. 5-2 mg daily with meals 1 Diarrhea, nausea, vomiting Increased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use $ 2-3 lbs $ 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. 26: Diabet Med 21; 18: Diabet Med 27; 24: Metformin and egfr 186 x (Creat / 88.4) x (Age) -.23 x (.742 if female) x (1.21 if black) Current Guidelines call for discontinuation of Metformin serum creatinine >15 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 11

12 Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Bile Acid Sequestrants Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin.8-1 Hypoglycemia short-acting Gain 1 lb $$$ Bile acid sequestrants lower LDL cholesterol Biguanide Alphaglucosidase Inhibitor acarbose (Precose) inhibits hepatic gluconeogenesis. Inhibits enzymes needed to break down complex CHO in the small intestine 5 mg with 1 st bite of each meal (start at 12.5 mg and titrate up over weeks) 1 Diarrhea lactic acidosis 2-3 lbs.7 Gas/ GI upset 1-2 lbs $ $$$ Colesevelam (Welchol) a bile acid sequestrant, lowers glucose levels and AIC levels in T2D patients Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Bromocriptine Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin 1 Hypoglycemia short-acting Gain 1 lb $$$ Biguanide Alpha-glucosidase Inhibitor Bile Acid Sequestrants Colesevelam (Welchol) inhibits hepatic gluconeogenesis. Decreased CHO absorption.7 unknown 3.75 g/d (3-625 mg tabs bid) 1 Diarrhea lactic acidosis.7 Gas/ GI upset esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation 2-3 lbs 1-2 lbs $ $$$ neutral $$$ Ergot derivative. Sympatholytic dopamine D2 receptor agonist, inhibits serotonin turnover in CNS. Improved glucose control associated with improved glucose tolerance (enhanced stimulated insulinmediated glucose disposal). Diabetes Care 2. 23:

13 Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin 1 Hypoglycemia short-acting Gain 1 lb $$$ Thiazolidenediones Biguanide Alpha-glucosidase Inhibitor Bile Acid Sequestrants inhibits hepatic gluconeogenesis. Bromocriptine improved glucose tolerance (enhanced stimulated insulinmediated glucose disposal). Decreased CHO absorption.7 1 Diarrhea lactic acidosis Gas/ GI upset unknown.7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation.25.5 mg/d.7 Nasal Stuffiness, Nausea, headache, constrictive pericarditis, neuroleptic malignant syndrome, hypotension 2-3 lbs 1-2 lbs $ $$$ -- $$$ ---- $$ 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: 4-3% Unresponsive to diuretics BUT: Increased Cardiac Index Increased Stroke volume Decreased systemic resistance Decreased Blood Pressure 13

14 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 3: , 27 The NEW ENGLAND JOUR NAL of MEDICINE ESTABLISHED IN 1812 JUNE 14, 27 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. Meta-analysis of MI and Death risk with rosiglitazone n = 15,56 on rosiglitazone; n = 12,283 on comparator drug or placebo Rosiglitazone group Control group Study No. of events/total no. (%) Myocardial infarction Small trials combined DREAM ADOPT Overall 44/1,28 (.43) 15/2635 (.57) 27/1456 (1.85) 86 22/615 (.36) 9/2634 (.34) 41/2895 (1.44) 72 Odds ratio (95% CI) P 1.45 ( ) 1.65 ( ) 1.33 ( ) 1.43 ( ) 86/14371 (.6%) 72/11634 (.62%) Relative Risk = 86/72 = 1.19 Absolute Risk = -.2% Nissen SE, Wolski K. N Engl J Med. 27;

15 Comparison of RSG to SU or MET MI/CV Death/Stroke Meta-analysis database (ICT), ADOPT and RECORD 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=2611) 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 3, 27 David Graham, MD MPH 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 3, 27 David Graham, MD MPH 15

16 PANIC RECORD: Kaplan-Meier Plots of time to the Primary Endpoint (Cardiovascular Death or Cardiovascular Hospitalization) Lancet. 29 Jun 5. [Epub ahead of print] BARI 2D: Enrollment and Randomization BARI 2D: Rates of Survival and Freedom from Major Cardiovascular Events The BARI 2D Study Group. N Engl J Med 29;36: The BARI 2D Study Group. N Engl J Med 29;36:

17 BARI 2D: Kaplan-Meier Estimates for Event Rates at 5 Years Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From ADOPT The BARI 2D Study Group. N Engl J Med 29;36: Diabetes Care Publish Ahead of Print, published online on February 5, 28 Changes in BMD during pioglitazone or placebo treatment in patients with PCOS J Clin Endocrinol Metab. 28 Feb 19 [Epub ahead of print] Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin 1 Hypoglycemia short-acting Gain 1 lb $$$ Biguanide inhibits hepatic gluconeogenesis. 1 Diarrhea lactic acidosis 2-3 lbs $ Alpha-glucosidase Inhibitor Bile Acid Sequestrants Bromocriptine Thiazolidine -diones rosiglitazone (Avandia) pioglitazone (Actos) Decreased CHO absorption.7 Gas/ GI upset unknown.7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation improved glucose tolerance (enhanced stimulated insulinmediated glucose disposal). Insulin sensitizers Activate receptor molecules inside cell nuclei to decrease insulin resistance.25.5 mg/d mg daily mg daily 1 1 Nasal Stuffiness, Nausea, headache, constrictive pericarditis, neuroleptic malignant syndrome, hypotension Weight gain, edema which is resistant to diuretic therapy, CHF. Associated with bone loss and fractures. 1-2 lbs $$$ -- $$$ ---- $$ Gain 12 lbs $$$ 17

18 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 1% Body mass index 25 Time course of reduction in glycated haemoglobin (HbA1c) in patients receiving pioglitazone (O), metformin ( ), or glimepiride ( ). Data are mean ±sd. *P <.5; **P <.1; ***P <.5 vs. baseline. Diabetes Medicine 25; 22: Diabetes Medicine 25; 22: Mean Change (mg/dl) Fasting Plasma glucose: Mean Change From Baseline Weeks Diabetes 452:146, 1993 Continued glyburide (n=29) Switched to metformin (n=21) Metformin + glyburide (n+213) 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 18

19 Weight Changes Associated with Anti- Hyperglycemic Therapies for Type 2 Diabetes Sulfonylurea Metformin Insulin TZD Postprandial Glucose Control Change in Weight ADA Scientific Meeting 25 ABS 13-or Serum Glucose Value (mg/ml) Postprandial Glucose Excursions in Subjects With or Without Diabetes Meal Event Time (hours) Shin J et al. Abstract 424-P. ADA; 24: New Orleans, La. Subjects Without diabetes Type 1 diabetes Type 2 diabetes Contribution, % Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles Postprandial glucose < >1.2 n=58 n=58 n=58 n=58 n=58 Monnier L et al. Diabetes Care. 23;26: A1C Fasting glucose 19

20 INCRETINS Gut factors that promote insulin secretion in response to nutrients Major incretins: GLP-1, CCK, GIP Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a Role for Incretins Plasma Insulin Responses to Oral and Intravenous Glucose Non-Diabetic Insulin (µu/ml) Oral Intravenous Insulin (µu/ml) Diabetic Oral Intravenous Minutes Minutes J Clin Invest 1967; 46: Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes Glucose Insulin Glucagon mmol/l pmol/l pmol/l * * * * * * * * * * * * * * * * * * * Infusion Minutes Adapted with permission from Nauck MA et al. Diabetologia. 1993;36: Copyright 1993 Springer-Verlag. mg/dl mu/l pmol/l Placebo GLP-1 *P <.5 Patients with type 2 diabetes (N=1) When glucose levels approach normal values, insulin levels decreases. When glucose levels approach normal values, glucagon levels rebound. 2

21 GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal Incretin Drugs Intestinal GIP and GLP-1 release GIP-(1 42) GLP-1(7 36) Intact GIP and GLP-1 Actions DPP-4 (Dipeptidyl Peptidase IV) Enzyme Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes GIP-(3 42) GLP-1(9 36) Metabolites GLP Agonists Exenatide Liraglutide CJC-1131 AVE-1 Albugon Glp-1-transferin Exenatide Lar DPP IV Inhibitors Vildagliptin Sitagliptin Saxagliptin PSN-931 Takeda-Syrrx Deacon CF et al. Diabetes. 1995;44: *Meier JJ et al. Diabetes. 24;53: Improvements in HbA 1C With Initial Coadministration of Sitagliptin and Metformin Mean Baseline HbA 1C = 8.8% N=191 Placebo -.5 Sita 1 mg QD HbA 1C (%)* Met 5 mg BID Met 1 mg BID Sita 5 mg BID + Met 5 mg BID Sita 5 mg BID + Met 1 mg BID * Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42 nd Annual Meeting; September 26; Copenhagen. 21

22 Proportion of Patients Achieving HbA 1C Goals DPP-4 Study Summary To Goal (%) HbA 1C <6.5% HbA 1C <7.% Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42 nd Annual Meeting; September 26; Copenhagen. Placebo Sita 1 mg QD Met 5 mg BID Met 1 mg BID Sita 5 mg BID + Met 5 mg BID Sita 5 mg BID + Met 1 mg BID Vildagliptin plus insulin Patients on >3 U/d, added 1 mg/d Baseline HgA1c 8.5 Drop in HgA1c.5% vildagliption,.2% placebo >65 y/o-- Drop in HgA1c.7% vildagliption,.% placebo Hypoglycemia: Placebo: 45patients; 185 events; 6 severe Vildagliptin: 33patients; 113 events; severe Sitagliptin vs glipizide added to metformin 52 weeks, 1 mg/d vs 2 mg/d Baseline HgA1c 7.5 Both.67% reduction in HgA1c Both about 6% reached HgA1c <7 Hypoglycemia glipizide: 32% sitagliptin: 4.9% Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin 1 Hypoglycemia short-acting Gain 1 lb $$$ Biguanide Alpha-glucosidase Inhibitor inhibits hepatic gluconeogenesis. Decreased CHO absorption.7 1 Diarrhea lactic acidosis Gas/ GI upset 2-3 lbs 1-2 lbs Thiazolidinediones Insulin 1 Weight gain, edema, fractures Gain 12 lbs Incretins exenatide (Byetta) sitagliptin (Januvia) Mimics GLP-1 (gut hormone which affects insulin, 5-1 mcg glucagon, gastric bid SQ emptying and satiety) DPP-4 inhibitor 1, 5, or (enzyme that 25 mg daily breaks down (dose by Cr GLP-1) Cl) Nausea, Vomiting, constipation, pancreatitis (?) Weight loss achieved through appetite suppression Side effects are rare. Occ GI side effects. 8 lbs Neutral $ $$$ $$$ $$$ $$$ DIGAMI2 (European Heart J. Prepublication Feb 25) Group 1 IV insulin then long term SQ insulin Group 2 IV insulin then standard treatment Group 3 Standard treatment Mortality 22

23 Effect of different updated glucose lowering treatments on mortality and morbidity Conventional Therapies Do Not Influence β-cell Failure: UKPDS Overweight Non-Overweight Overweight 1 Conventional Chlorpropamide Metformin Insulin Glibenclamide 1 1 HbA1c(%) cohort, median values ß cell function (%) ß cell function (%) Years from randomization Years from randomization Conventional Sulphonylurea Metformin Mellbin, L. G. et al. Eur Heart J 28 29: UKPDS 34. Lancet 1998; 352: UKPDS 16: Diabetes 1995; 44: Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effective -ness Major Side Effects / Interactions / Uses Weight Cost Effects (average) Sulfonylureas Stimulate insulin 1 Hypoglycemia Gain $ release 2 lbs Meglitinides Stimulate insulin.8-1 Hypoglycemia short-acting Gain 1 lb $$$ Biguanide Alpha-glucosidase Inhibitor inhibits hepatic gluconeogenesis. Decreased CHO absorption.7 1 Diarrhea lactic acidosis Gas/ GI upset 2-3 lbs 1-2 lbs $ $$$ Insulin Therapy in Type 2 Diabetes: What is the evidence Thiazolidinediones Insulin 1 Weight gain, edema, fractures Gain 12 lbs $$$ Incretins exenatide sitagliptin Increase insulin, decrease glucagon 1 1 Nausea Weight loss Side effects are rare. 8 lbs Neutral $$$ Mariëlle J. P van Avendonk and Guy E. H. M Rutten Insulin Titrated to need 1+ Hypoglycemia Gain 8 lbs $$ Diabetes, Obesity and Metabolism. 29. epub. 23

24 Insulin Therapy in Type 2 Diabetes: Bottom Line Basal Insulin Premixed Insulin Basal Bolus Drug Cost Comparison Drug and Dose Glucose Strips (2 per day) $6 Cost/month Sulfonylurea Generic $4-14 Brand $5 Rapaglinide 2 mg tid $175 Acarbose 1 mg tid $88 Metformin 1 bid Generic $ 4-32 Brand $132 Rosiglitazone 8 mg qd $223 Pioglitazone 45 mg/d $222 Sitagliptin $181 Exenatide 5mcg $23 1mcg $255 Colesevelam 375 mg/d $212 Bromocriptine 2.5-5mg $62-13 Glargine, 45 U/d $15 24 hour fitness center $44 YMCA $6 HgA1c 29 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm Drugs 3 Drugs Insulin added 8 1 Drug 7 No Meds An American Diabetes Association consensus statement represents the authors collective analysis, evaluation, and opinionat the time of publication and does not represent official associationopinion. Diabetes Care. Published online Oct 22, 28 24

25 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 27 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 1,11 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 < 11 mg/dl FPG indicated for insulin-using patients < 11 mg/dl Preprandial 4 Preferred first agent in most patients < 14 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 1 A recent report (NEJM; 6/14/7) 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. 27;13: Continuous Titration of Rx ( 2 Monitor - 3 months / ) 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 Monitor / adjust Rx to Intensify Lifestyle Modification maximal Intensify or combine Rx, effective dose including incretin mimetic with SU, TZD, and/or to meet ACE metformin Glycemic Goals 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 27 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without 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 OBESE Exenatide Goal Not Met 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) 25

26 26